This document summarizes a study that analyzed Duffy blood group genotypes in Plasmodium vivax malaria patients and blood donors in four areas of the Brazilian Amazon region. The study found:
1) A high frequency of the FYA/FYB genotype in both patients and donors, followed by FYB/FYB.
2) Some Duffy genotypes showed significant differences in frequency between patients and donors.
3) Individuals with the FYA/FYB genotype may have higher susceptibility to malaria, while the presence of the FYB-33 allele could provide resistance.
This document analyzes the frequency of two polymorphisms (C282Y and H63D) in the HFE gene in malaria patients and blood donors from four states in the Brazilian Amazon region. The study found:
1) No individuals were homozygous for the C282Y polymorphism, and only 5 heterozygous individuals were detected, all from Pará State.
2) The most common genotype for the H63D polymorphism was heterozygous in both patient groups.
3) Allele frequencies for the H63D polymorphism were higher than for the C282Y polymorphism, consistent with other studies on Brazilian populations.
This study evaluated the frequency of asymptomatic Plasmodium carriers (APCs) among blood donors in four blood banks in the Brazilian Amazon region. Blood samples from 400 donors who passed screening were tested using PCR to detect Plasmodium DNA. The positivity rate varied from 1-3% between blood banks, with an overall rate of 2.3%. All positive samples contained mixed infections of P. vivax and P. falciparum. While screening methods used by the blood banks did not detect the infections, PCR revealed its superiority for detecting low levels of parasites. The results emphasize the need to improve screening for APCs in blood banks in malaria endemic areas to control transfusion-transmitted malaria.
We present evidence of Plasmodium vivax infection in two homozygous FY*B-33 (Duffy-negative) individuals from the Brazilian Amazon region. Molecular analysis confirmed P. vivax infection through detection of P. vivax small subunit rRNA and circumsporozoite protein genes. One individual had a mixed infection of VK210 and P. vivax-like genotypes, while the other was infected with VK210. Both individuals also had antibodies to the P. vivax merozoite surface protein 1. This provides rare evidence that P. vivax may be capable of invading Duffy-negative red blood cells in some regions, though additional studies are needed to better understand this finding.
Associations of MHC Ancestral Haplotypes with Resistance/Susceptibility to AI...Dr. Juan Rodriguez-Tafur
This document analyzes the association between MHC ancestral haplotypes and rates of progression to AIDS. It finds that the 8.1 and 44.2 ancestral haplotypes are associated with rapid progression to AIDS, while the 35.2 and 57.1 haplotypes are associated with slow progression. Analysis of recombinant fragments of these haplotypes identifies MHC regions within the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression, and within the 44.1 and 57.1 haplotypes associated with slow progression. Previous studies identified single HLA alleles associated with progression; this study confirms the direct role of HLA-B35 in rapid progression through haplotype analysis.
1. A study analyzed genetic and immune response differences between P. vivax circumsporozoite (CS) genotypes VK210 and P. vivax-like.
2. Phylogenetic analysis of 18S rRNA and CytB genes found high similarity between the genotypes, with zero nucleotide diversity, placing them in the same clade.
3. Individuals infected with P. vivax-like had a lower antibody response against CS repetitive region peptides than those with VK210, suggesting variation is limited to the CS repetitive region.
1) Field isolates of Plasmodium falciparum from Colombia and Peru were found to invade red blood cells through an atypical pathway that was resistant to all enzyme treatments, unlike what is typically seen.
2) The invasion pathways and ligand polymorphisms differed between Colombian, Peruvian, and Brazilian isolates, with Peruvian isolates showing a combination of Colombian and Brazilian characteristics.
3) The atypical resistant pathway was associated with specific variants of PfRh2a, PfRh5 and EBA-181, which may be major players in this pathway based on expression levels.
This study evaluated four recombinant proteins representing the 19 kDa C-terminal region of the Plasmodium vivax merozoite surface protein-1 (MSP119) for detecting P. vivax antibodies in human serum samples. The sensitivity of an ELISA using the recombinant proteins to detect antibodies in 200 samples from individuals with P. vivax infection ranged from 90-93.5%. Specificity using control samples without P. vivax exposure was 98.3-100%. The study demonstrates the potential of an ELISA using recombinant MSP119 proteins for serological detection of P. vivax infection.
This document analyzes the frequency of two polymorphisms (C282Y and H63D) in the HFE gene in malaria patients and blood donors from four states in the Brazilian Amazon region. The study found:
1) No individuals were homozygous for the C282Y polymorphism, and only 5 heterozygous individuals were detected, all from Pará State.
2) The most common genotype for the H63D polymorphism was heterozygous in both patient groups.
3) Allele frequencies for the H63D polymorphism were higher than for the C282Y polymorphism, consistent with other studies on Brazilian populations.
This study evaluated the frequency of asymptomatic Plasmodium carriers (APCs) among blood donors in four blood banks in the Brazilian Amazon region. Blood samples from 400 donors who passed screening were tested using PCR to detect Plasmodium DNA. The positivity rate varied from 1-3% between blood banks, with an overall rate of 2.3%. All positive samples contained mixed infections of P. vivax and P. falciparum. While screening methods used by the blood banks did not detect the infections, PCR revealed its superiority for detecting low levels of parasites. The results emphasize the need to improve screening for APCs in blood banks in malaria endemic areas to control transfusion-transmitted malaria.
We present evidence of Plasmodium vivax infection in two homozygous FY*B-33 (Duffy-negative) individuals from the Brazilian Amazon region. Molecular analysis confirmed P. vivax infection through detection of P. vivax small subunit rRNA and circumsporozoite protein genes. One individual had a mixed infection of VK210 and P. vivax-like genotypes, while the other was infected with VK210. Both individuals also had antibodies to the P. vivax merozoite surface protein 1. This provides rare evidence that P. vivax may be capable of invading Duffy-negative red blood cells in some regions, though additional studies are needed to better understand this finding.
Associations of MHC Ancestral Haplotypes with Resistance/Susceptibility to AI...Dr. Juan Rodriguez-Tafur
This document analyzes the association between MHC ancestral haplotypes and rates of progression to AIDS. It finds that the 8.1 and 44.2 ancestral haplotypes are associated with rapid progression to AIDS, while the 35.2 and 57.1 haplotypes are associated with slow progression. Analysis of recombinant fragments of these haplotypes identifies MHC regions within the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression, and within the 44.1 and 57.1 haplotypes associated with slow progression. Previous studies identified single HLA alleles associated with progression; this study confirms the direct role of HLA-B35 in rapid progression through haplotype analysis.
1. A study analyzed genetic and immune response differences between P. vivax circumsporozoite (CS) genotypes VK210 and P. vivax-like.
2. Phylogenetic analysis of 18S rRNA and CytB genes found high similarity between the genotypes, with zero nucleotide diversity, placing them in the same clade.
3. Individuals infected with P. vivax-like had a lower antibody response against CS repetitive region peptides than those with VK210, suggesting variation is limited to the CS repetitive region.
1) Field isolates of Plasmodium falciparum from Colombia and Peru were found to invade red blood cells through an atypical pathway that was resistant to all enzyme treatments, unlike what is typically seen.
2) The invasion pathways and ligand polymorphisms differed between Colombian, Peruvian, and Brazilian isolates, with Peruvian isolates showing a combination of Colombian and Brazilian characteristics.
3) The atypical resistant pathway was associated with specific variants of PfRh2a, PfRh5 and EBA-181, which may be major players in this pathway based on expression levels.
This study evaluated four recombinant proteins representing the 19 kDa C-terminal region of the Plasmodium vivax merozoite surface protein-1 (MSP119) for detecting P. vivax antibodies in human serum samples. The sensitivity of an ELISA using the recombinant proteins to detect antibodies in 200 samples from individuals with P. vivax infection ranged from 90-93.5%. Specificity using control samples without P. vivax exposure was 98.3-100%. The study demonstrates the potential of an ELISA using recombinant MSP119 proteins for serological detection of P. vivax infection.
1) The study analyzed HIV-1 sequences from 37 patients with high numbers (34 or more) of degenerate base codes in their protease/reverse transcriptase sequences, which can indicate either extensive viral evolution or dual infection. 2) Phylogenetic analysis of envelope and gag sequences from these patients found that 16 (43%) had dual HIV-1 infections, representing 1% of all sequences analyzed. 3) Patients with the highest numbers of degenerate base codes were more likely to have dual infections with different HIV-1 subtypes. The study demonstrates that routine HIV genotyping can help detect undiagnosed dual infections.
This study identified a novel single base deletion mutation in the BBS9 gene in a consanguineous Pakistani family with Bardet-Biedl syndrome (BBS). Whole genome SNP analysis identified a homozygous region linked to BBS on chromosome 7, within which Sanger sequencing revealed a c.299delC mutation in BBS9. This frameshift mutation is predicted to result in a truncated BBS9 protein lacking the C-terminal domain. BBS9 encodes a component of the BBSome protein complex involved in ciliogenesis. The mutation found in this family expands knowledge of the genetic causes of BBS and the mutational spectrum of BBS9.
Ong et al_The M694V mutation in Armenian-Americans_a 10-year retrospective st...Frank Ong, MD, CPI
This study retrospectively analyzed MEFV gene mutation testing results from 476 patients seen at UCLA between 2002-2012 to correlate genotypes with clinical phenotypes in different populations. They found:
1. The M694V mutation was significantly associated with Armenian ethnicity, seen in 35.3% of Armenian patients as a homozygous mutation and 77.3% of Armenian compound heterozygotes, compared to only 2.9% and 47.1% in non-Armenians respectively.
2. Armenian patients had a significant trend of increasing genetic contribution of the M694V mutation, while non-Armenians showed a decreasing trend.
3. The M694V mutation was also more prevalent in single mutation Armenian patients
1) The study found that the Plasmodium yoelii malaria parasite preferentially infects young red blood cells (RBCs) that express high levels of CD47.
2) Mice lacking CD47 (CD47-/- mice) were highly resistant to P. yoelii infection and developed a 9.3-fold lower peak parasitemia compared to wild-type mice.
3) Macrophages from CD47-/- mice were more effective at phagocytizing parasitized RBCs during acute infection, when parasitemia was rapidly rising, suggesting CD47 helps the parasite evade immune clearance.
Plasma levels of circulating nucleic acids (CNAs) were significantly higher in patients with Plasmodium vivax malaria compared to healthy donors. CNAs levels strongly correlated with clinical markers of malaria morbidity, including fever and thrombocytopenia. Higher CNAs levels were also associated with a more severe clinical presentation based on a scoring system. These findings suggest that CNAs have potential as sensitive biomarkers for assessing severity of P. vivax malaria infections.
This document summarizes a study that evaluated the Exome Aggregation Consortium (ExAC) database as a control cohort for classifying genetic variants. The researchers analyzed variants from 19 genes related to dominant and recessive disorders. They found:
1) The carrier frequencies and ethnic distributions of pathogenic variants in ExAC were generally consistent with published estimates, indicating ExAC is not overrepresented for pathogenic variants.
2) Only 3 of 871 pathogenic variants exceeded the estimated maximal pathogenic allele frequency for each gene.
3) Variants with frequencies above estimated thresholds were often reclassified as benign or uncertain significance.
A Retrospective Analysis of Exome Sequencing Cases Using the GenePool™ Genomi...Antoaneta Vladimirova
- GenePool, a cloud-based genomics software platform, was used to retrospectively analyze exome sequencing data from over two dozen probands and their families to help diagnose various medical conditions.
- For each proband, GenePool identified one or more likely causative gene variants that matched the family's inheritance pattern and the proband's clinical presentation.
- GenePool's integrated analysis workflows and ability to combine genomic and clinical data helped efficiently analyze each family and prioritize candidate variants and genes.
- This study demonstrates GenePool's utility as a tool for precision diagnosis and its high level of concordance with the Clinic for Special Children's own analysis results.
Karyotypic complexity and multiclonality: Two cytogenetic parameters to be co...Georgia Bardi
Karyotypic complexity and multiclonality (either cytogenetically unrelated clones or cytogenetically related clones) represent two parameters of prognostic significance in management of patients with Myelodysplastic syndromes.
Presented by Georgia Bardi, PhD at MDS workshop in Perugia 2008. Cytogenetic data produced by Eugenia Gourgouveli and Despina Iakovaki.
Whole-exome sequencing of three affected family members identified a frameshift mutation in LAMB3 as the cause of dominant hypoplastic amelogenesis imperfecta in the family. The mutation was a single base pair insertion that caused a premature stop codon and co-segregated with the disease phenotype in the family. This is the first report of dominant AI caused by a heterozygous LAMB3 mutation, as LAMB3 mutations typically cause the skin blistering disorder junctional epidermolysis bullosa in a recessive manner. Identification of the pathogenic variant was achieved without prior linkage analysis through filtering of variants shared between the affected individuals sequenced.
This study evaluated the use of targeted next-generation sequencing (NGS) for preimplantation genetic diagnosis (PGD) of single-gene disorders. The study compared NGS results from embryo biopsies to results from two established PGD methods. NGS provided 100% consistency with the established methods in diagnosing point mutations and small insertions/deletions in six couples at risk of transmitting single-gene disorders. Additionally, NGS allowed for parallel single-gene disorder screening and comprehensive chromosome screening from the same biopsy sample. The study demonstrates NGS can provide accurate and consistent PGD results and could serve as a model for further development of this emerging technology in PGD.
Ebola Associated Genes in the Human Genome Implications for Novel TargetsMedCrave
Ramaswamy Narayanan, Ph.D., professor in the Charles E. Schmidt College of Science at Florida Atlantic University, is working to blend the power of computers with biology to use the human genome to remove much of the guesswork involved in discovering cures for diseases.
Lombardi et al: XMRV/CFS Inflammatory Signaturedegarden
This document summarizes a study that identified a signature of 10 cytokines and chemokines that can correctly identify patients with chronic fatigue syndrome (CFS) associated with xenotropic murine leukemia virus-related virus (XMRV) infection. The study used Luminex multi-analyte profiling to measure cytokine and chemokine levels in the plasma of 118 CFS patients who tested positive for XMRV, compared to 138 healthy controls. Analysis identified a cytokine/chemokine signature that diagnosed XMRV-associated CFS with 93% specificity and 96% sensitivity. This signature provides immunological evidence for the role of XMRV in CFS pathology and the associated inflammatory response.
1) A couple underwent preimplantation genetic diagnosis (PGD) for Dyskeratosis Congenita caused by a mutation in the RTEL1 gene, as they previously had an affected child.
2) Conventional PGD using short tandem repeat (STR) markers near the gene found high rates of allele drop out and no results for some embryos.
3) Reanalysis using quantitative PCR of single nucleotide polymorphisms (SNPs) closer to the mutation found the STR-based method misdiagnosed 3 of 14 embryos due to undetected recombinations between the STR and mutation.
4) The improved resolution of SNPs near the mutation detected recombinations and corrected misdiagnoses, demonstrating
frequency of cryptococcus species and varieties in méxicoIPN
This study analyzed 211 Cryptococcus strains isolated from patients in Mexico City hospitals between 1989-1998. C. neoformans was the dominant species isolated (97.15%), followed by C. albidus and C. uniguttulatus. Most strains were isolated from cerebral spinal fluid (92.5%) and AIDS was the main predisposing factor (85%). The disease was found to predominantly affect males (87.3%) in their third (33.8%) and fourth (37.5%) decades of life. When compared to other Latin American countries, the isolation frequency of C. neoformans var. neoformans and var. gattii in Mexico was most similar to Brazil.
Infective endocarditis is a life-threatening disease caused by bacterial infection of the endothelium and cardiac valves, either native or prosthetic. In the present work the role of the new microbiological techniques (techniques of detection and amplification of the subunit 16 ribosomal sRNA by means of the chain reaction of the polymerase in blood or tissue, fluorescent in situ hybridization, and matrix-assisted laser is reviewed desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS) in the diagnosis of infective endocarditis.
This study evaluated the use of quantitative PCR (qPCR) to genotype single nucleotide polymorphisms (SNPs) near a mutation in the RTEL1 gene for preimplantation genetic diagnosis of Dyskeratosis Congenita, compared to the standard method using short tandem repeats (STRs). The standard STR method misdiagnosed 3 of 14 embryos due to recombination between the distant STR marker and mutation. In contrast, qPCR of closely linked SNPs identified recombination in 9 of 17 embryos and correctly diagnosed all embryos. This case demonstrates that qPCR of SNPs provides improved sensitivity over STRs for detecting recombination near telomeric mutations.
https://www.creative-bioarray.com/support/resazurin-cell-viability-assay.htm
Resazurin cell viability assay is a simple, rapid, reliable, sensitive, safe and cost-effective measurement of cell viability.
This study investigated the relationship between variants of the glycophorin B (GPB) gene and susceptibility to Plasmodium falciparum infection in the Brazilian Amazon. The researchers found that individuals carrying the GYPB*S allele were more likely to be infected with P. falciparum than those without this allele. Sequence analysis of GYPB also suggested it has been under natural selection due to malaria. This study provides evidence that genetic variation in GPB receptor influences the ability of P. falciparum to invade red blood cells in this population.
This study investigated the relationship between variants of the glycophorin B (GPB) gene and susceptibility to Plasmodium falciparum infection in the Brazilian Amazon. The researchers found that individuals carrying the GYPB*S allele were more likely to be infected with P. falciparum than those without this allele. Additionally, population genetics analysis suggested that natural selection has shaped patterns of genetic diversity at the GYPB locus. This study provides evidence that genetic variation in GPB influences susceptibility to P. falciparum infection in this population.
This study investigated the frequencies of ABO blood group genotypes and alleles in Plasmodium falciparum malaria patients and blood donors from the Brazilian Amazon region. The researchers found that over half of individuals had the ABO*O01O01 genotype. The ABO*AO01 genotype was the second most common. No significant differences were detected in genotype or allele frequencies between the malaria patients and blood donors. Analysis of O alleles found the O1 variant allele to be most frequent in both groups, with no evidence of the homozygous O2 allele.
This study analyzed genetic diversity and population structure of Plasmodium falciparum in 5 populations in the Brazilian Amazon region. Microsatellite markers were analyzed in 196 parasite isolates. There was significant multilocus linkage disequificance within populations, particularly those with fewer mixed infections. However, most isolates had unique multilocus genotypes, indicating genetic diversity. Genetic divergence between populations was substantial but did not correlate simply with geographical distance. The findings suggest distinct population structures and minimal gene flow between foci in the region.
1) The study analyzed HIV-1 sequences from 37 patients with high numbers (34 or more) of degenerate base codes in their protease/reverse transcriptase sequences, which can indicate either extensive viral evolution or dual infection. 2) Phylogenetic analysis of envelope and gag sequences from these patients found that 16 (43%) had dual HIV-1 infections, representing 1% of all sequences analyzed. 3) Patients with the highest numbers of degenerate base codes were more likely to have dual infections with different HIV-1 subtypes. The study demonstrates that routine HIV genotyping can help detect undiagnosed dual infections.
This study identified a novel single base deletion mutation in the BBS9 gene in a consanguineous Pakistani family with Bardet-Biedl syndrome (BBS). Whole genome SNP analysis identified a homozygous region linked to BBS on chromosome 7, within which Sanger sequencing revealed a c.299delC mutation in BBS9. This frameshift mutation is predicted to result in a truncated BBS9 protein lacking the C-terminal domain. BBS9 encodes a component of the BBSome protein complex involved in ciliogenesis. The mutation found in this family expands knowledge of the genetic causes of BBS and the mutational spectrum of BBS9.
Ong et al_The M694V mutation in Armenian-Americans_a 10-year retrospective st...Frank Ong, MD, CPI
This study retrospectively analyzed MEFV gene mutation testing results from 476 patients seen at UCLA between 2002-2012 to correlate genotypes with clinical phenotypes in different populations. They found:
1. The M694V mutation was significantly associated with Armenian ethnicity, seen in 35.3% of Armenian patients as a homozygous mutation and 77.3% of Armenian compound heterozygotes, compared to only 2.9% and 47.1% in non-Armenians respectively.
2. Armenian patients had a significant trend of increasing genetic contribution of the M694V mutation, while non-Armenians showed a decreasing trend.
3. The M694V mutation was also more prevalent in single mutation Armenian patients
1) The study found that the Plasmodium yoelii malaria parasite preferentially infects young red blood cells (RBCs) that express high levels of CD47.
2) Mice lacking CD47 (CD47-/- mice) were highly resistant to P. yoelii infection and developed a 9.3-fold lower peak parasitemia compared to wild-type mice.
3) Macrophages from CD47-/- mice were more effective at phagocytizing parasitized RBCs during acute infection, when parasitemia was rapidly rising, suggesting CD47 helps the parasite evade immune clearance.
Plasma levels of circulating nucleic acids (CNAs) were significantly higher in patients with Plasmodium vivax malaria compared to healthy donors. CNAs levels strongly correlated with clinical markers of malaria morbidity, including fever and thrombocytopenia. Higher CNAs levels were also associated with a more severe clinical presentation based on a scoring system. These findings suggest that CNAs have potential as sensitive biomarkers for assessing severity of P. vivax malaria infections.
This document summarizes a study that evaluated the Exome Aggregation Consortium (ExAC) database as a control cohort for classifying genetic variants. The researchers analyzed variants from 19 genes related to dominant and recessive disorders. They found:
1) The carrier frequencies and ethnic distributions of pathogenic variants in ExAC were generally consistent with published estimates, indicating ExAC is not overrepresented for pathogenic variants.
2) Only 3 of 871 pathogenic variants exceeded the estimated maximal pathogenic allele frequency for each gene.
3) Variants with frequencies above estimated thresholds were often reclassified as benign or uncertain significance.
A Retrospective Analysis of Exome Sequencing Cases Using the GenePool™ Genomi...Antoaneta Vladimirova
- GenePool, a cloud-based genomics software platform, was used to retrospectively analyze exome sequencing data from over two dozen probands and their families to help diagnose various medical conditions.
- For each proband, GenePool identified one or more likely causative gene variants that matched the family's inheritance pattern and the proband's clinical presentation.
- GenePool's integrated analysis workflows and ability to combine genomic and clinical data helped efficiently analyze each family and prioritize candidate variants and genes.
- This study demonstrates GenePool's utility as a tool for precision diagnosis and its high level of concordance with the Clinic for Special Children's own analysis results.
Karyotypic complexity and multiclonality: Two cytogenetic parameters to be co...Georgia Bardi
Karyotypic complexity and multiclonality (either cytogenetically unrelated clones or cytogenetically related clones) represent two parameters of prognostic significance in management of patients with Myelodysplastic syndromes.
Presented by Georgia Bardi, PhD at MDS workshop in Perugia 2008. Cytogenetic data produced by Eugenia Gourgouveli and Despina Iakovaki.
Whole-exome sequencing of three affected family members identified a frameshift mutation in LAMB3 as the cause of dominant hypoplastic amelogenesis imperfecta in the family. The mutation was a single base pair insertion that caused a premature stop codon and co-segregated with the disease phenotype in the family. This is the first report of dominant AI caused by a heterozygous LAMB3 mutation, as LAMB3 mutations typically cause the skin blistering disorder junctional epidermolysis bullosa in a recessive manner. Identification of the pathogenic variant was achieved without prior linkage analysis through filtering of variants shared between the affected individuals sequenced.
This study evaluated the use of targeted next-generation sequencing (NGS) for preimplantation genetic diagnosis (PGD) of single-gene disorders. The study compared NGS results from embryo biopsies to results from two established PGD methods. NGS provided 100% consistency with the established methods in diagnosing point mutations and small insertions/deletions in six couples at risk of transmitting single-gene disorders. Additionally, NGS allowed for parallel single-gene disorder screening and comprehensive chromosome screening from the same biopsy sample. The study demonstrates NGS can provide accurate and consistent PGD results and could serve as a model for further development of this emerging technology in PGD.
Ebola Associated Genes in the Human Genome Implications for Novel TargetsMedCrave
Ramaswamy Narayanan, Ph.D., professor in the Charles E. Schmidt College of Science at Florida Atlantic University, is working to blend the power of computers with biology to use the human genome to remove much of the guesswork involved in discovering cures for diseases.
Lombardi et al: XMRV/CFS Inflammatory Signaturedegarden
This document summarizes a study that identified a signature of 10 cytokines and chemokines that can correctly identify patients with chronic fatigue syndrome (CFS) associated with xenotropic murine leukemia virus-related virus (XMRV) infection. The study used Luminex multi-analyte profiling to measure cytokine and chemokine levels in the plasma of 118 CFS patients who tested positive for XMRV, compared to 138 healthy controls. Analysis identified a cytokine/chemokine signature that diagnosed XMRV-associated CFS with 93% specificity and 96% sensitivity. This signature provides immunological evidence for the role of XMRV in CFS pathology and the associated inflammatory response.
1) A couple underwent preimplantation genetic diagnosis (PGD) for Dyskeratosis Congenita caused by a mutation in the RTEL1 gene, as they previously had an affected child.
2) Conventional PGD using short tandem repeat (STR) markers near the gene found high rates of allele drop out and no results for some embryos.
3) Reanalysis using quantitative PCR of single nucleotide polymorphisms (SNPs) closer to the mutation found the STR-based method misdiagnosed 3 of 14 embryos due to undetected recombinations between the STR and mutation.
4) The improved resolution of SNPs near the mutation detected recombinations and corrected misdiagnoses, demonstrating
frequency of cryptococcus species and varieties in méxicoIPN
This study analyzed 211 Cryptococcus strains isolated from patients in Mexico City hospitals between 1989-1998. C. neoformans was the dominant species isolated (97.15%), followed by C. albidus and C. uniguttulatus. Most strains were isolated from cerebral spinal fluid (92.5%) and AIDS was the main predisposing factor (85%). The disease was found to predominantly affect males (87.3%) in their third (33.8%) and fourth (37.5%) decades of life. When compared to other Latin American countries, the isolation frequency of C. neoformans var. neoformans and var. gattii in Mexico was most similar to Brazil.
Infective endocarditis is a life-threatening disease caused by bacterial infection of the endothelium and cardiac valves, either native or prosthetic. In the present work the role of the new microbiological techniques (techniques of detection and amplification of the subunit 16 ribosomal sRNA by means of the chain reaction of the polymerase in blood or tissue, fluorescent in situ hybridization, and matrix-assisted laser is reviewed desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS) in the diagnosis of infective endocarditis.
This study evaluated the use of quantitative PCR (qPCR) to genotype single nucleotide polymorphisms (SNPs) near a mutation in the RTEL1 gene for preimplantation genetic diagnosis of Dyskeratosis Congenita, compared to the standard method using short tandem repeats (STRs). The standard STR method misdiagnosed 3 of 14 embryos due to recombination between the distant STR marker and mutation. In contrast, qPCR of closely linked SNPs identified recombination in 9 of 17 embryos and correctly diagnosed all embryos. This case demonstrates that qPCR of SNPs provides improved sensitivity over STRs for detecting recombination near telomeric mutations.
https://www.creative-bioarray.com/support/resazurin-cell-viability-assay.htm
Resazurin cell viability assay is a simple, rapid, reliable, sensitive, safe and cost-effective measurement of cell viability.
This study investigated the relationship between variants of the glycophorin B (GPB) gene and susceptibility to Plasmodium falciparum infection in the Brazilian Amazon. The researchers found that individuals carrying the GYPB*S allele were more likely to be infected with P. falciparum than those without this allele. Sequence analysis of GYPB also suggested it has been under natural selection due to malaria. This study provides evidence that genetic variation in GPB receptor influences the ability of P. falciparum to invade red blood cells in this population.
This study investigated the relationship between variants of the glycophorin B (GPB) gene and susceptibility to Plasmodium falciparum infection in the Brazilian Amazon. The researchers found that individuals carrying the GYPB*S allele were more likely to be infected with P. falciparum than those without this allele. Additionally, population genetics analysis suggested that natural selection has shaped patterns of genetic diversity at the GYPB locus. This study provides evidence that genetic variation in GPB influences susceptibility to P. falciparum infection in this population.
This study investigated the frequencies of ABO blood group genotypes and alleles in Plasmodium falciparum malaria patients and blood donors from the Brazilian Amazon region. The researchers found that over half of individuals had the ABO*O01O01 genotype. The ABO*AO01 genotype was the second most common. No significant differences were detected in genotype or allele frequencies between the malaria patients and blood donors. Analysis of O alleles found the O1 variant allele to be most frequent in both groups, with no evidence of the homozygous O2 allele.
This study analyzed genetic diversity and population structure of Plasmodium falciparum in 5 populations in the Brazilian Amazon region. Microsatellite markers were analyzed in 196 parasite isolates. There was significant multilocus linkage disequificance within populations, particularly those with fewer mixed infections. However, most isolates had unique multilocus genotypes, indicating genetic diversity. Genetic divergence between populations was substantial but did not correlate simply with geographical distance. The findings suggest distinct population structures and minimal gene flow between foci in the region.
1. Researchers studied Plasmodium falciparum field isolates from Colombia, Peru, and Brazil to determine the invasion pathways and ligand polymorphisms used.
2. They found that most isolates from Colombia and Peru invade red blood cells through an atypical pathway that is resistant to all enzyme treatments, unlike known pathways.
3. This unusual pathway was associated with specific variants of PfRh2a, PfRh5, and EBA-181 ligands, suggesting these proteins play a major role in this pathway. The study demonstrates diversity in invasion mechanisms between regions.
This research article characterized the genetic diversity of Plasmodium vivax and P. falciparum populations from pregnant women in four malaria-endemic countries. Between 2008-2011, nearly 2000 pregnant women were recruited from Brazil, Colombia, India, and Papua New Guinea and followed until delivery, collecting blood samples. Seven P. vivax microsatellite markers were used to genotype 229 P. vivax isolates. P. vivax populations showed moderate to high genetic differentiation between countries and higher diversity than P. falciparum populations from the same areas. Diversity of P. vivax was very high in some settings compared to transmission levels, suggesting stable demographic histories.
1. The study characterized antibody responses to Plasmodium falciparum invasion ligands EBA-140 and EBA-181 in individuals from malaria-endemic areas of Brazil and Cameroon.
2. Responses differed between populations, with African individuals strongly reacting to most EBA fragments while Brazilian individuals from Mato Grosso reacted weakly and those from the Amazon had elevated but lower responses than Africans.
3. When compared to responses against other malaria proteins, the Brazilian population appeared to have more variable ability to recognize P. falciparum invasion ligands, distinct from the African population.
Presentation 6: Vibrio parahaemolyticus: genome plasticity, mobile genetic el...ExternalEvents
http://www.fao.org/documents/card/en/c/28b6bd62-5433-4fad-b5a1-8ac61eb671b1/
International Technical Seminar/Workshops on Acute hepatopancreatic necrosis disease (AHPND)
Mixed Plasmodium falciparum infections were common in four areas of the Brazilian Amazon region. Molecular diagnosis found 73% of infections were single P. falciparum infections, while 27% were mixed infections, mostly double infections. Mixed infections were associated with weaker clinical malaria symptoms like lower rates of fever and headache compared to single P. falciparum infections. The study highlights the need for improved malaria diagnosis to better understand mixed infections and their impact on disease severity.
This document analyzes genetic variation at the Pfs48/45 gene and microsatellite loci in 255 Plasmodium falciparum isolates from 5 populations. It finds:
1) Alleles and haplotypes of 5 SNPs in the Pfs48/45 gene varied extremely between populations, much more so than alleles at 11 neutral microsatellite loci.
2) Measurements of between-population allele frequency variation (FST) were 4-7 times higher for Pfs48/45 than microsatellites, both within and between continents.
3) The highly skewed Pfs48/45 patterns suggest divergent selection on the protein's amino acid sequence between populations, indicating it may determine game
Malaria in pregnancy is a major global problem, infecting 30.6 million pregnant women annually. Plasmodium falciparum-infected erythrocytes are able to adhere to the placenta via variant surface antigens (VSA) such as VAR2CSA, which binds to chondroitin sulfate A in the placenta. This can cause maternal anemia and mortality as well as low birth weight and fetal retardation. Diagnosis involves blood smears, antigen detection, and PCR assays. Further research focuses on VAR2CSA as a potential vaccine candidate since antibodies to it are associated with reduced risk of low birthweight.
This article summarizes a study of 785 Tanzanian children living in an area with intense malaria transmission. The study found that iron deficiency (ID), as measured by ferritin levels in blood samples taken at routine visits, significantly decreased the odds of subsequent malaria parasitemia, severe malaria, and all-cause mortality in children. When samples from sick visits were also included, ID was associated with significantly lower prevalence of parasitemia, hyperparasitemia (very high parasite levels), and severe malaria at the time of sample collection. The results suggest that naturally occurring ID protects against severe malaria and death in young children, and that iron supplementation may increase malaria risk even in children with ID. Future studies are needed to determine
This study examined the relationship between iron deficiency and malaria risk in 785 Tanzanian children from birth to 3 years of age. The key findings were:
1. Iron deficiency was found to be protective against malaria, with children who had iron deficiency having lower odds of parasitemia, hyperparasitemia, severe malaria, and all-cause mortality compared to children who were iron-replete.
2. Iron deficiency was associated with a 6.6-fold lower odds of concurrent parasitemia and a 24.0-fold lower odds of concurrent hyperparasitemia. It also reduced the odds of severe malaria by 4.0-fold.
3. Prospective analyses found that iron deficiency
This document compares the allele frequencies of 15 Plasmodium falciparum merozoite antigen genes in malaria infections sampled in Kenya in 2007 and 2008. It finds fluctuating allele frequencies in codons 147 and 148 of the reticulocyte-binding homologue 5 (Rh5) gene over this period in uncomplicated malaria infections. However, the dominant YH haplotype was stable over multiple years in asymptomatic and complicated infections. A regression analysis found the chance of the less common HD haplotype decreased over time from 2007 to 2009 in uncomplicated and asymptomatic infections.
This study aimed to identify risk factors for death in children under 15 years old admitted for treatment of visceral leishmaniasis (VL) in northeast Brazil. The researchers reviewed records of 546 patients and found that 57 died, giving a case fatality rate of 10%. Multivariate analysis identified several independent risk factors for death: presence of mucosal bleeding increased the risk 4 times, jaundice 4 times, dyspnea (fast breathing) 3 times, suspected bacterial infections 3 times, and very low neutrophil and platelet counts 3 times and 12 times, respectively. Based on these factors, the researchers created a prognostic score that classified patients as high or low risk, with 88% sensitivity and 79% specificity.
This document summarizes information about malaria vaccines. It discusses how malaria is caused by Plasmodium parasites and transmitted by mosquitoes. Four species can infect humans. Current vaccines target different stages of the parasite's life cycle, including pre-erythrocytic, blood, and sexual stages. Challenges to vaccine development include the parasite's ability to evade the immune system through antigenic variation. Several candidate vaccines are discussed that target different stages, but none have achieved high levels of efficacy and durability.
Epidemiologic Classification of Human Papillomavirus Types Associated with Ce...Alberto Cuadrado
background
Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but
the risk associated with the various HPV types has not been adequately assessed.
methods
We pooled data from 11 case–control studies from nine countries involving 1918 women
with histologically confirmed squamous-cell cervical cancer and 1928 control women.
A common protocol and questionnaire were used. Information on risk factors was
obtained by personal interviews, and cervical cells were collected for detection of HPV
DNA and typing in a central laboratory by polymerase-chain-reaction–based assays
(with MY09/MY11 and GP5+/6+ primers).
results
HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent)
and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV
DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The
most common HPV types in patients, in descending order of frequency, were types 16,
18, 45, 31, 33, 52, 58, and 35. Among control women, types 16, 18, 45, 31, 6, 58, 35, and
33 were the most common. For studies using the GP5+/6+ primer, the pooled odds ratio
for cervical cancer associated with the presence of any HPV was 158.2 (95 percent
confidence interval, 113.4 to 220.6). The odds ratios were over 45 for the most common
and least common HPV types. Fifteen HPV types were classified as high-risk types
(16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82); 3 were classified as probable
high-risk types (26, 53, and 66); and 12 were classified as low-risk types (6, 11, 40,
42, 43, 44, 54, 61, 70, 72, 81, and CP6108). There was good agreement between our epidemiologic
classification and the classification based on phylogenetic grouping.
conclusions
In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73,
and 82 should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66
should be considered probably carcinogenic.
1. The study developed a new PCR/RFLP technique to identify the 3 genotypes of Plasmodium vivax circumsporozoite protein (VK210, VK247, and P. vivax-like) using DNA extracted from blood samples.
2. The technique uses PCR amplification of the central immunodominant region of the CSP gene followed by restriction enzyme digestion and fragment analysis to distinguish the genotypes.
3. Testing demonstrated the technique could accurately identify the genotypes using plasmid controls for each variant, and that it had high sensitivity detecting parasitemia levels as low as 0.0069 parasites per microliter.
Malaria due to Plasmodium falciparum is a major public health concern in Cameroon and Africa, responsible for high rates of morbidity and mortality. While control measures have been effective, an effective vaccine is needed to achieve global malaria elimination goals. This study analyzed genetic diversity in the merozoite surface protein 1 (msp1) gene of P. falciparum isolates from Mount Cameroon. It found 45 distinct DNA fragments in samples from 81 of 173 infected individuals, indicating significant intragenic recombination contributing to parasite diversity. Understanding this diversity is important for vaccine development against P. falciparum.
Genetic polymorphisms of HLA-DP and isolated anti-HBc are important subsets o...UniversitasGadjahMada
Occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the serum and/or liver in HBsAg-negative individuals. OBI is associated with the risk of viral transmission, especially in developing countries, and with progressive liver disease and reactivation in immunosuppressive patients. The objective of this study was to evaluate the relation of OBI to HLA-DP single nucleotide polymorphisms (SNPs) encoding antigen-binding sites for the immune response to HBV infection. As HLA-DP variants affect the mRNA expression of HLA-DPA1 and HLA-DPB1 in the liver, we hypothesised that high levels of HLA-DPA1 and HLA-DPB1 expression favour OBI development. This study enrolled 456 Indonesian healthy blood donors (HBsAg negative). OBI was defined as the presence of HBV-DNA in at least two of four open reading frames (ORFs) of the HBV genome detected by nested PCR. SNPs in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs2281388) were genotyped using real-time Taqman® genotyping assays. Of 122 samples positive for anti-HBs and/or anti-HBc, 17 were determined as OBI. The minor allele in rs3077 was significantly correlated with OBI [odds ratio (OR) = 3.87, 95% confidence interval (CI) = 1.58–9.49, p = 0.0015]. The
prevalence of the minor allele (T) was significantly higher in subjects with OBI than in those without (59% and 33%, respectively). The combination of haplotype markers (TGA for rs3077–rs3135021–rs9277535) was associated with increased risk of OBI (OR = 4.90, 95%CI = 1.12–21.52 p = 0.038). The prevalence of OBI was highest in the isolated anti-HBc group among the three seropositive categories: anti-HBs <500 mIU/ml, anti-HBs ≥500 mIU/ml, and isolated anti-HBc (29.41%, p = 0.014).In conclusion, genetic variants of HLA-DP and the presence of anti-HBc are important predictors of OBI in Indonesian blood donors.
Similar to 2007 genotipagem de duffy em pvivax patients (20)
This document summarizes a study that investigated the influence of HLA-DRB1 alleles on the production of antibodies against malaria antigens in individuals naturally infected with Plasmodium vivax in Brazil. The study found an association between HLA-DR3 and HLA-DR5 alleles and lack of antibody response to the amino terminal region of the circumsporozoite protein (CSP). It also found an association between HLA-DR3 and higher antibody response to merozoite surface protein 1 (MSP1). No significant associations were found between HLA-DRB1 alleles and antibody responses to other malaria antigens tested.
This study examined 51 Brazilian Plasmodium falciparum isolates for polymorphisms in the Pfmdr1 gene thought to be associated with chloroquine resistance. 49 of the isolates were found to be resistant to chloroquine in vitro, while all were sensitive to mefloquine, amodiaquine, and quinine. The isolates were analyzed for three Pfmdr1 polymorphisms: Asn86Tyr, Asn1042Asp, and Asp1246Tyr. Asn86Tyr was not detected in any isolates, while Asn1042Asp was found in 50 isolates and Asp1246Tyr was found in all 51 isolates. This provides support that As
This study evaluated the distribution of Plasmodium vivax variants (VK210, VK247, and P. vivax-like) in three areas of Brazil using a new GFM-PCR-ELISA technique. All variants were found in all three areas. VK210 was most commonly found as a single infection while the others occurred in mixed infections. VK210 was associated with the highest parasitemia levels while P. vivax-like had the lowest. Parasitemia clearance times did not differ based on variant or treatment schedule. The new technique was accurate for epidemiological surveys of the vivax complex.
This study compared ELISA and PCR-ELISA techniques for detecting human Plasmodium parasites in Anopheles mosquitoes from the Amazon region of Brazil. The PCR-ELISA technique confirmed all positive and negative ELISA results but detected additional Plasmodium species in 5 of the 32 positive mosquitoes that were not detected by ELISA alone. The PCR-ELISA is more sensitive than ELISA for detecting human malaria parasites in mosquitoes.
1) O documento analisa os casos de malária no estado de Santa Catarina entre 1996-2001, com 5,5% das 4.707 amostras sendo positivas.
2) Plasmodium vivax causou 69% dos casos, Plasmodium falciparum 25,6%, infecções mistas 5% e Plasmodium malariae 0,4%.
3) 67,4% dos casos foram importados e 32,6% autóctones, com aumento de casos importados nos anos subsequentes.
1) The study evaluated the performance of the OptiMal malaria rapid diagnostic test under different storage conditions of 25°C, 30°C, and 39°C for 24, 48, and 72 hours.
2) The test detected all 111 positive blood samples except for 2 low parasitemia Plasmodium malariae samples.
3) The study suggests that the OptiMal test can be used for malaria diagnosis in Brazilian regions, though further research is needed to evaluate its performance under different environmental conditions like humidity.
This study investigated genetic mutations associated with chloroquine resistance in Plasmodium falciparum samples from the Brazilian Amazon region. The study analyzed 40 samples from 4 localities for mutations in the pfmdr1, cg2, and pfcrt genes. It found 100% of samples contained mutations in pfmdr1 codons 184, 1042, and the cg2 gamma region associated with chloroquine resistance. Most samples also contained the pfcrt K76T mutation, except some from Porto Velho which matched a Thai resistant genotype. This research contributes to understanding the molecular basis of widespread chloroquine resistance in this region.
This study aimed to investigate the presence of arboviruses like dengue virus in clinical samples from 111 malaria patients in the Amazon region of Brazil.
Dengue virus serotype 2 was detected in two patients from Novo Repartimento, Pará who also had active Plasmodium vivax malaria infections. Despite limited data, concurrent dengue and malaria infections are likely more common in the Amazon region than detected, as both diseases co-circulate and have similar transmission vectors and clinical presentations, making dual diagnosis possible. Further research is needed to better understand the frequency of co-infection in this region.
This document describes the development of a PCR-RFLP assay to identify Plasmodium species and variants of P. vivax infecting Anopheles mosquitoes. Specific primers were designed that target regions of the circumsporozoite gene to distinguish P. falciparum, P. malariae, and P. vivax variants VK210, VK247, and P. vivax-like. The assay was tested on artificially infected mosquitoes and showed good agreement with nested PCR. The PCR-RFLP method provides a sensitive way to detect Plasmodium species and variants, which can help understand malaria transmission dynamics.
This study evaluated antibody responses to the Pv200L fragment of Plasmodium vivax merozoite surface protein-1 (PvMSP-1) in individuals from 4 malaria-endemic regions in Brazil. Plasma samples from 261 P. vivax infected individuals were tested for antibodies to Pv200L by ELISA. The frequency of antibody responders ranged from 71.9-98.7% between regions and correlated with malaria transmission intensity. Higher antibody levels were also associated with greater past exposure to malaria parasites. Results provide evidence that Pv200L elicits naturally acquired antibodies and could be a potential vaccine candidate.
This document summarizes a study that investigated the influence of HLA-DRB1 alleles on the production of antibodies against malaria antigens in individuals naturally infected with Plasmodium vivax in Brazil. The study found an association between HLA-DR3 and HLA-DR5 alleles and lack of antibody response to the amino terminal region of the circumsporozoite protein (CSP). It also found an association between HLA-DR3 and higher antibody response to merozoite surface protein 1 (MSP1). No significant associations were found between HLA-DRB1 alleles and antibody responses to other malaria antigens tested.
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2. Malaria Journal 2007, 6:167 http://www.malariajournal.com/content/6/1/167
Background did not correlate Fy heterozygosity with protection against
Plasmodium vivax has been the most common cause of the P. vivax [17]. The present study reports the Duffy blood
human malaria parasite in the Brazilian Amazon region group genotyping in P. vivax malaria patients from four
over the last seven years [1]. Innate resistance to malaria different Brazilian endemic areas, exploring these signifi-
infections in humans is conferred by different blood cant phenotypic associations between blood group vari-
group polymorphisms. The association of the Duffy ants, as well as polymorphic regions of RBC receptors,
blood group (FY) with P. vivax human malaria has been with susceptibility or resistance to malaria.
well-documented, where Duffy-negative individuals are
naturally resistant to invasion by this parasite [2]. Methods
Study population
The Duffy blood group antigen has been identified as a The study took place from May 2003 to August 2005. The
scavenger on the red blood cell (RBC) surface eliminating vivax malaria patients (n = 312) who were enrolled in this
excesses of circulating toxic chemokines, named Duffy study complied with the following criteria: they sought
antigen/receptor for chemokines (DARC) [3]. The deter- medical assistance presenting clinical malaria symptoms,
minant, a glycoprotein that passes through the membrane were over 18 years old and had positive results for thick
seven times, includes a 35–43 KDa epitope in the extracel- blood film/molecular diagnosis. A control group con-
lular, N-terminal domain that mediates erythrocyte inva- sisted of blood donors (n = 330) and according to the Bra-
sion by P. vivax merozoites [4]. The Fy gene has two exons zilian blood bank policy they complied with the
(Fya and Fyb) that are encoded by the co-dominant alleles following criteria: they were over 18 years old, of both
FYA and FYB, located on chromosome 1 [5,6]. The corre- genders and belonging to all blood groups. Additionally,
sponding anti-Fya and anti-Fyb antibodies define four dif- their place of birth was in the study area, they reported
ferent phenotypes; Fy(a+b+), Fy(a+b-), Fy(a-b+) and Fy(a- never suffering from malaria attacks and had no signs of
b-) [7]. The FYA and FYB alleles differ by a point mutation malaria during the initial interview and had negative
in the major cDNA transcript [8], encoding glycine in Fya results for thick blood film/molecular diagnosis. The con-
or aspartic acid in Fyb at residue 42 of the most important trols were matched to the patients in respect to age (± 5
form of the protein, encoded by the exon 2 [9,8]. The years), gender and ethnicity. All of the control subjects
molecular mechanism that gives rise to the null Duffy were genetically independent. Blood samples were col-
phenotype [Fy(a-b-)] has been classically associated with lected from all participants (Macapá/Amapá State, Belém/
a point mutation in the GATA box of the DARC promoter Pará State, Porto Velho/Rondônia State and Rio Branco/
which silences the gene encoding the Duffy system anti- Acre State), after informed consent.
gens in the RBCs of these individuals resulting in a FYB
allele [9]. Recently, the FYA allele has been identified [10] Genomic DNA extraction, PCR amplification and RFLP
and a new FYB allele was found with three single nucle- analysis
otide polymorphisms (11). It has been demonstrated in The Duffy blood group genotypes were assessed using
blood donors from Southeast Brazil that Caucasians and PCR/RFLP with modifications as described previously
African descendents were serologically Fy(b-) with the [11]. Briefly, the DNA was extracted from frozen pellets of
majority of the African descendents being FYB with the infected erythrocytes using the Easy-DNA™ extraction kit
GATA single nucleotide polymorphism (SNP), while the (Invitrogen, California – USA). The PCR was performed
majority of Caucasian typing Fy(b-) had FYB with 265T/ with 100 ng of DNA, 50 pmol of each primer, 2 nmol each
298A SNPs [11]. The Fy-negative is common on RBCs of dNTP, 1.0 U Taq DNA polymerase, and buffer, in a total
Negro individuals from ethnic African groups, but it is volume of 50 µL. The promoter region was amplified
rare in many other populations [12]. using the FYN1 and FYN2 primers that flank the GATA
box motif. To determine the Duffy RBC polymorphism,
Previous studies have demonstrated that heterozygous FYAB1 sense, and FYAB2 reverse sense primers were used
Duffy negative malaria individuals remain susceptible to [18]. The amplification conditions were performed as
infections by P. vivax [13,14]. It was demonstrated in indi- described by Castilho et al [11]. PCR products were run on
viduals living in a malaria endemic region of Papua New 1.5% agarose gel, followed by ethidium bromide staining
Guinea that Duffy binding protein adherence to RBCs is and photo-documentation using a Gel Doc 1000 (BioRad,
significantly reduced for erythrocytes of P. vivax malaria Town, USA). The RFPL analysis was digested during three
patients who carry one Duffy-negative allele [15]. In addi- hours with Ban1, MspA1 and Sty1 restriction enzymes as
tion, it was observed that in different areas from the Bra- previously described [11].
zilian Amazon region some of the Duffy phenotypes
showed significant correlation between blood donors and Statistical analysis
malaria patients [16]. On the other hand, a previous study In order to access the significance of the variables and to
in the Western Brazilian Amazon region (Rondônia State) obtain independence among the proportions, the Fisher's
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3. Malaria Journal 2007, 6:167 http://www.malariajournal.com/content/6/1/167
exact test was used. The mean ages of patients and con- The frequency of individuals with the FYB-33 allele
trols were 29 years (± 14 SD) and 28 years (± 8 SD), among blood donors was 35.15% versus 24.36% in
respectively. All the studied groups showed no statistically patients. This difference was statistically significant (P =
significant differences in mean ages or ethnicity, indicat- 0.0033). The prevalence of the FYB allele was significantly
ing well-matched populations. The same results were higher (P = 0.0358) among malaria-infected patients.
obtained when we compared the two different groups However, significant differences were not detected in
from each area. respect to the frequency of individuals with the FYX and
FYA alleles in the two study groups (Table 2).
Results
The genotypic and allelic frequencies of the Duffy blood Discussion
group in the 330 blood donors and 312 patients infected Thus far, innate resistance to malaria infections in
by P. vivax as determined by PCR/RFLP are summarized in humans has been attributed to blood group polymor-
Table 1. The data show a high frequency of the FYA/FYB phisms. Duffy blood group polymorphisms are important
genotype in 199 individuals (31.0%) of the studied pop- in areas where P. vivax predominates, because this mole-
ulation. This is followed by 117 (18.2%) and 94 (14.6%) cule acts as a receptor for this protozoan (but not for the
of homozygotes for the FYB and FYA alleles, respectively. other human malaria parasites) on the surface of RBCs
While the frequencies for heterozygote individuals with [19]. Field observations from West Africa and Ethiopia
FYA/FYB-33 and FYB/FYB-33 were comparable at 14.9% have indeed established a strong correlation between
(96). Low frequencies were detected for the FYA/FYX, FYB/ absence or low endemicity of P. vivax malaria and the high
FYX, FYX/FYX and FYB-33/FYB-33 genotypes. The negative prevalence of the Duffy negative allele [20,21]. Little is
Duffy genotype (FYB-33/FYB-33) was found in both indi- known on the frequency of RBC polymorphisms that con-
viduals infected by P. vivax and unaffected blood donors. fer either partial or complete resistance against malaria.
The data obtained in the present study emphasize the
Table 2 shows a comparison of the results of genotyping importance of the evaluation of Duffy blood group geno-
and inferred phenotypes of FY among blood donors and types in malaria endemic areas of the Brazilian Amazon
patients infected by P. vivax in the Amazon region. In region.
respect to the allelic combinations of FY, there was a sig-
nificant difference between donors and patients only for The Brazilian population has a highly heterogeneous eth-
the FYB-33/FYB-3 genotype (P = 0.0003). As for the heter- nic composition, a result of the hybridization of the
ozygotes, the results demonstrated a significant difference numerous native indigenous populations and immigrants
(P = 0.0404) between those with the FYA/FYB genotype, from Europe, Africa and Asia. The immigration flow was
which was lower for blood donors (90 - 27.27%) than for not uniform in the different regions of the country [22-
patients infected by P. vivax (109 - 34.93%). No individu- 24]. The differential distribution of Duffy antigenic deter-
als were identified with the FYX/FYB-33 genotype. minants among ethnic groups is an aspect characteristic of
this blood system. Hence, this has been used as a marker
Table 1: Genotyping results of the Duffy Blood Group System in 642 individuals (donors and patients infected with Plasmodium vivax)
from Brazilian Amazon region.
Genotype result nt 125 FYA/FYB nt 265 FYBWK or FYX GATA (n) FYBES or FY0 or FYB-33 Predicted Phenotype
Donors/Patients Donors/Patients
FYA/FYA G/G 43/51 C/C T/T
FYA/FYX G/A 03/05 C/T T/T Fy(a+b-) n = 108/90
FYA/FYB-33 G/A 62/34 C/C T/C
FYA/FYB G/A 90/109 C/C T/T Fy(a+b+) n = 90/109
FYB/FYB A/A 54/63 C/C T/T
FYB/FYX A/A 06/04 C/T T/T Fy(a-b+) n = 114/109
FYB/FYB-33 A/A 54/42 C/C T/C
FYX/FYX A/A 00/02 T/T T/T Fy(a-b-) n = 18/04
FYB-33/FYB-33 A/A 18/02 C/C C/C
Total 330/312
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4. Malaria Journal 2007, 6:167 http://www.malariajournal.com/content/6/1/167
Table 2: Comparison of genotyping results and allele frequencies of the Duffy Blood Group System among blood donors and patients
infected with P. vivax from Brazilian Amazon region.
Duffy blood group system Brazilian Amazon Region
Genotypes Predicted Phenotype Donors (n = 330) Patients P. vivax (n = 312) P
FYA/FYA Fy(a+b-) 43 51 0,2644
FYA/FYX Fy(a+b-) 3 5 0,4942
FYA/FYB-33 Fy(a+b-) 62 34 0,0055*
FYA/FYB Fy(a+b+) 90 109 0,0404*
FYB/FYB Fy(a-b+) 54 63 0,2208
FYB/FYX Fy(a-b+) 6 4 0,7530
FYX/FYX Fy(a-b-) - 2 0,2358
FYB/FYB-33 Fy(a-b+) 54 42 0,3205
FYB-33/FYB-33 Fy(a-b-) 18 2 0,0003*
Alelles Alelles Frequencies
FYA 0,365 0,400 0,2896
FYB 0,390 0,450 0,0351
FYX 0,014 0,021 0,5726
FYB-33 0,230 0,128 0,0000
* Fisher's Exact Test.
for the ethnic composition as well as an indicator in the was lower. In fact, with the exception of negroid ethnic
populational evolution. In the current study, significant groups, this genotype is extremely rare [12,30,32,33].
differences in the allelic frequencies of the FY gene were
identified when compared with previous studies of The FYA allele is common in European and Oriental peo-
patients infected with human plasmodium in Brazilian ples but it is rare in African Negroes. Additionally, the FYB
Amazon regions [17,25-27]. However, the FYA, FYB and is more common in populations classified as white than
FYB-33 alleles showed differential distributions compared in asiatic and negroid populations [34,35]. The frequency
to the population of the southeastern region of Brazil of the FYA and FYB alleles in the Brazilian Amazon popu-
[11]. The genotypic compositions obtained in this study lation was higher than those in the Southeastern region
demonstrated significant variations compared to previous [11] probably due to the massive influence of Portuguese
studies performed in the states of Pará and Rio Grande do colonization in the North region of Brazil as well as the
Sul [28,29] and in the cities of São Paulo [30], Campinas presence of Amerindians [36], as recent molecular analy-
[11] and Ribeirão Preto [31] all of which are in the state sis has corroborated that Amerindians have an Asian ori-
of São Paulo, Southeastern region of Brazil. gin [37]. Indeed, in the North region of Brazil, studies
carried out with different tribes of Amerindians have
The currently obtained results showed that the FYA/FYB shown that the FYA allele is the most common [31,38]. As
genotype was the most common, followed by the expected, a lower frequency of the FYB-33 allele was
homozygotes for the FYB and FYA alleles and by the het- observed in the North region (P = 0.0001). Although a
erozygotes FYA/FYB-33 and FYB/FYB-33 (Table 1). The high prevalence of this allele was demonstrated in iso-
FYB-33/FYB-33 genotype, which is classically seen in indi- lated communities in the states of Amapá and Pará, North
viduals unaffected by P. vivax infection, was identified in region of Brazil [39], the introduction of a negroid ethnic
3.2% of the general population and in 5.5% of blood component in the Amazon region is recent [40,41]. In
donors. These numbers differ from previous reports on a respect to the FYX allele, there does not seem to be a differ-
group of malaria patients uninfected by P. vivax in the ential ethnic distribution as, the frequency detected here is
state of Rondônia [17], where the frequency of this geno- similar to those described in other Caucasian-like popula-
type was 12% and also for a mixed sample from the tions in Brazil [11] and also in Europe [42].
Northern and Southeastern regions of Brazil [27]. Some
populations had higher genotypic frequencies for FYA/ The different FY allelic frequencies in individuals from
FYB and FYB/FYB-33 than for a caucasian-like and negroid North compared to Southeastern Brazil, may be due to the
population from the Southeastern of Brazil [11]. On the contribution of the three major ethnic groups (Europeans,
other hand, the frequency of the FYB-33/FYB-33 genotype in particular Portuguese; Blacks and Amerindians) in the
formation of both populations. The Amerindian contri-
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5. Malaria Journal 2007, 6:167 http://www.malariajournal.com/content/6/1/167
bution was higher in the north of the country whereas lizing alternative receptors, apart from Fy, for binding in
European migration took place more in the South and the erythrocyte invasion process. Whether FYB carrying
Southeastern regions [43-45]. In spite of the current the GATA box mutation is the primordial gene that
knowledge of the relationship between structure/function encodes the Duffy system antigens or whether the GATA
and tissue location of DARC, the functional significance box mutation has evolved to escape malaria infection per
of each of the alleles and the different genotypic combina- se is controversial. However, the presence of this allele
tions require further elucidation. The variation in the eth- (FYB-33) may be a demonstration of the selection advan-
nic composition of the urban and rural populations of the tage by mutation in the population. Thus, in the Brazilian
Brazilian Amazon region and of distinct regions in Brazil Amazon, where P. vivax predominates, the frequency of
[26,46], may influence the allelic and genotypic distribu- the FYB-33 allele is higher than expected given the ethnic
tions reflecting in matrixes of genetic mechanisms favora- population, both in terms of heterozygotes and homozy-
ble to the susceptibility to infectious and parasitic gotes. This might, over time, cause an increase in the
diseases, in particular to malaria. number of Duffy-negative individuals in the population
and, as a consequence, a reduction in the rate of infection
The frequency of the allele with the FY GATA mutation by P. vivax in this region.
(FYB-33) was greater in blood donors than in patients
infected with malaria (P = 0.0033), suggesting that there In the group of patients infected by P. vivax, different
is a reduction in the infection rate of carriers of the FYB-33 allelic combinations with FYX were detected, including
allele. These results were recently reinforced by data from five (1.6%)FYA/FYX individuals, four (1.3%) FYB/FYX and
of individuals infected by P. falciparum when compared to two (0.6%) FYX/FYX (Table 2). The frequency of this allele
those infected by P. vivax in Brazilian Amazon regions among patients and blood donors did not show statistical
[27]. The FYB-33 allele is a variant of the FYB allele result- differences (P = 0.3873). Studies carried out in blood sam-
ing from a T → C point mutation in the gene promoter ples from European and American Caucasians and Afro-
region (neucleotide-33), which abolishes its expression American individuals, demonstrated that the C265T (FYX)
[9]. The same occurs in the FYA allele, determining the mutation altered the Duffy protein expression on the RBC
FYAnull allele [10]. The presence of the FYB-33 allele results surface differently, depending on the ethnic group, using
in a 50% reduction in the Duffy protein expression on the at least two mechanisms. One mechanism involves silent
erythrocyte surface [15,47]. This process demonstrates the transcription in one of the FYB alleles and the other affects
action of the dose-related effect of the gene [15,48], which the translation and/or the stability of the protein [47,54].
may limit the invasion process of red blood cells by the These studies showed that heterozygote individuals for
parasite, although susceptibility to P. vivax may occur in the FYX (FYWK) allele have 50% less of the Duffy protein
heterozygotic Duffy-negative individuals [13,14]. Thus on the surface of the membrane of the erythrocyte. On the
the FY/FYB-33 genotypic combination, with either other hand, individuals homozygotic for the FYX allele
Fy(a+b-) or Fy(b+b-), seems to convey a reduction in the have about one tenth of the antigen expression in the
susceptibility to malaria. In vitro studies [15] support this erythrocytes [47]. However, the information shown by the
hypothesis as RBCs that express these phenotypes have a present study suggest that these polymorphisms do not
significant reduction in cytoadherence of the parasite seem to be associated with susceptibility to malaria.
when compared to RBCs that express Fy(b+b+). Recently,
in Papua New Guinea, a significant reduction in infection As illustrated in Table 2, a higher frequency of the FYA/
by P. vivax was observed in Duffy negative individuals het- FYB genotype in patients compared to blood donors (P =
erozygotic for the FYAnull allele [49]. 0.0404) was detected. In principle, this seems to indicate
that the condition of heterozygosis, resulting from the
In this study a low frequency of the negative Duffy geno- expression of the FYA and FYB genes, favors infection by
type (FYB-33/FYB-33) was detected among uninfected P. vivax. In fact, as has already been demonstrated by us,
subjects. As has previously been demonstrated, the based on a phenotyping study, Fy(a+b+) individuals may
absence of the Fy antigen in many ethnic Negro groups be more susceptible to infection by this species of Plasmo-
and their descendents, does not seem to exert any delete- dium [16]. Although no qualitative or quantitative meas-
rious effect, however it does bestow a natural resistance urements of the Duffy glycoprotein expressions were
against infection by P. vivax [2,9,14,35,50,51]. These indi- made in this study, we saw a larger number of malaria epi-
viduals are homozygotes for the FYB mutation in the sodes among patients with the heterozygote genotype
GATA, that completely abolishes the Fy expression in than the homozygote genotype. The basis of this observa-
erythrocytes but not in cells of other tissues [9]. Recent tion has not been determined yet, but the phenotypic [16]
reports have provided evidence on the transmission and genotypic data presented from the same Brazilian
among Duffy-negative patients in Africa [52] and in Brazil Amazon areas associated with pertinent publications,
[53]. These data suggest the possibility that P. vivax is uti- point to the possibility that heterozygote individuals
Page 5 of 8
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6. Malaria Journal 2007, 6:167 http://www.malariajournal.com/content/6/1/167
modulate the susceptibility to malaria by P. vivax by size involved, and the fact that the control group consisted
means of quantitative and/or qualitative variations that patients infected by P. falciparum.
affect the Duffy antigen expression on erythrocytes. In the
first aspect, in vitro studies demonstrate differences in the Conclusion
levels of the expression of FY glycoprotein on the surface The Brazilian population presents an elevated degree of
of the reticulocytes of Caucasian-like and Afro-American miscegenation which is implicated in variations in the
individuals with the Fy(a+b+) erythrocytic phenotype allelic distribution of FY, which was also found in this
[48]. These authors verified that individuals with FYA and study. Future analyses that consider haplotypic frequen-
FYB alleles expressed a lower quantity of DARC than het- cies of the alleles and quantification of the DARC expres-
erozygotes. Hence, it is possible that heterozygote individ- sion in populational groups in endemic and non-endemic
uals have a greater repertory of receptors for the possible areas, increasing the knowledge on the dynamics of this
variations that occur in the parasite protein binder to the gene and its possible contribution as a modulator in the
human erythrocytes. susceptibility to malaria. The data obtained in the present
study supports the hypothesis that individuals with the
The recent demonstration of polymorphisms in the Duffy FYA/FYB genotype have higher susceptibility to malaria.
binding protein in isolates of P. vivax from the Brazilian The presence of the FYB-33allele may be a selective advan-
Amazon [55] seems to support the observed results. An tage in the population, reducing the rate of infection by P.
association, between human receptor polymorphisms vivax in this region. However, the populational and longi-
and variations in the parasite binders of Plasmodium falci- tudinal studies must be amplified accompanying groups
parum that modulate susceptibility to malaria, was also of individuals with the FYB-33 allele and the FYA/FYB
demonstrated [19,56-60]. Hence, apart from the different genotype, including clinical parameters, as well as the
levels of the expression, the specific conformation of the evaluation of their expressions which may contribute to
Fya and Fyb antigens may determine differences in the better elucidate the physiopathologic differences in this
susceptibility to infection. Nevertheless, one of the possi- parasite/host relationship in regions endemic for P. vivax
ble consequences of differential susceptibility to vivax malaria, in particular the Brazilian Amazon.
malaria could be modifications in allelic frequencies of
FYA and FYB in populations exposed to P. vivax, the most Authors' contributions
prevalent species in the Brazilian Amazon region. If in fact CEC carried out all genotype assay. AADC, VSDC and CEC
this process occurs as a consequence of infection, it seems collected samples from P. vivax malaria individuals and
to be necessary, but not sufficient to eliminate heterozy- blood donors. CEC, LCM, CRBD and LC participated in
gote individuals, even if they are affected by repetitive epi- the design of the study and drafted the manuscript. RLM
sodes of malaria by P. vivax, as the infection is rarely severe and ARBR conceived of the study and participated in all
and occurs in the entire age range with different frequen- aspects of its design, acquisition of funding, execution,
cies for different ages and regions of the Brazilian Amazon coordination and manuscript preparation. All authors
without lethality [61,62]. read and approved the final manuscript.
Based on the significant associations described herein, our Acknowledgements
data differ from previous studies [17] carried out in the To all individuals enrolled in this study and to Blood Bank Managing Direc-
western Brazilian Amazon region as well as recent studies tor of the studied areas for help in blood donor samples collection. We
of patients from the Brazilian Amazon as a whole [27]. In thank Aline Barroso, Maria Cristina Figueredo and Mauro Tada for help in
malaria field work. To Professor Luiz Hildebrando Pereira da Silva for facil-
respect to the first studies, these differences may be a result
ities at CEPEM. Financial support was provided by FAPESP (Process 02/
of the small sample sizes initially evaluated; the control 9546-1), CNPq (Process 302353/2003-8). C.E.C. is a PhD student from Fac-
group of the current study was composed of blood donors uldade de Medicina de São José do Rio Preto. The protocol for this study
who reported never having experienced malaria against was reviewed and approved by the Research Board of the Faculdade de
samples from individuals who had P. falciparum previ- Medicina de São José do Rio Preto.
ously evaluated and the various ethnic groups in the dif-
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