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.
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.
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.
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.
Analysis of the HLA allelic and haplotype frequency data in different populations helps to shed light on the evolutionary factors that result in genetic polymorphism and the biological relationships among different ethnic groups. It is important to analyse HLA allele and haplotype frequencies in different populations to find compatible marrow transplantation donors from unrelated individuals. The aim of this study was to investigate the distribution of HLA-A, -C, -B and DRB1 alleles and haplotypes in Northern Portugal. The HLA-A, -C, -B, and -DRB1 allele frequencies were determined by direct counting. The haplotype frequencies were calculated using the expectation-maximisation algorithm in Arlequin v3 software. The Hardy-Weinberg equilibrium was verified using the Guo and Thompson method. The most frequent (> 10%) HLA-A alleles (A*02, A*01, A*03, and A*24), HLA-B alleles (B*44, and B*35) and HLA-C alleles (C*07, and C*04) found in this study frequently occur in many other Caucasian populations. Of the class II HLA alleles at the HLA-DRB1* locus, the allelic groups HLA-DRB1*07 and -DRB1*13 occur most frequently (> 15%) in the Portuguese population, as previously reported by others. The HLA-A*01-C*07-B*08-DRB1*03 and HLA-A*29-C*16-B*44-DRB1*07 haplotypes, described as being of Pan European and western European origin, respectively, were the most frequent haplotypes found in our sample, and they are very frequent in Caucasian Brazilian, German, Italian, Spanish and the previously described Portuguese populations. These data represent an important contribution to future anthropological and disease association studies involving the Portuguese population.
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.
Analysis of the HLA allelic and haplotype frequency data in different populations helps to shed light on the evolutionary factors that result in genetic polymorphism and the biological relationships among different ethnic groups. It is important to analyse HLA allele and haplotype frequencies in different populations to find compatible marrow transplantation donors from unrelated individuals. The aim of this study was to investigate the distribution of HLA-A, -C, -B and DRB1 alleles and haplotypes in Northern Portugal. The HLA-A, -C, -B, and -DRB1 allele frequencies were determined by direct counting. The haplotype frequencies were calculated using the expectation-maximisation algorithm in Arlequin v3 software. The Hardy-Weinberg equilibrium was verified using the Guo and Thompson method. The most frequent (> 10%) HLA-A alleles (A*02, A*01, A*03, and A*24), HLA-B alleles (B*44, and B*35) and HLA-C alleles (C*07, and C*04) found in this study frequently occur in many other Caucasian populations. Of the class II HLA alleles at the HLA-DRB1* locus, the allelic groups HLA-DRB1*07 and -DRB1*13 occur most frequently (> 15%) in the Portuguese population, as previously reported by others. The HLA-A*01-C*07-B*08-DRB1*03 and HLA-A*29-C*16-B*44-DRB1*07 haplotypes, described as being of Pan European and western European origin, respectively, were the most frequent haplotypes found in our sample, and they are very frequent in Caucasian Brazilian, German, Italian, Spanish and the previously described Portuguese populations. These data represent an important contribution to future anthropological and disease association studies involving the Portuguese population.
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.
ABSTRACT- Introduction: Blood group antigens have been reported to be associated with many diseased conditions
severally. Studies have suggested that ABO blood groups have an impact on infection status of the individuals
possessing a particular blood group due to the significant associations observed when analyzed. However there is
limited information on the relationship between these blood group antigens with haemoglobin genotype and CD4 cell
count in Human Immunodeficiency Virus (HIV) infection, hence the need for this study.
Materials and Method: Exactly 240 newly enrolled seropositive patients attending the HIV Clinic of LAUTECH
Teaching Hospital, Osogbo, Nigeria and 120 healthy blood donors were recruited for this study. Antibodies to HIV
were determined using determine rapid HIV 1/HIV 2 test kit (Abbott), enzyme linked immunosorbent assay (ELISA)
(GenScreen plus HIV Ag-Ab test kit, Paris) and Western blot (New-LAV Blot 1, BioRad, France) for confirmatory test.
ABO and Rhesus blood grouping was determined by standard tile and tube techniques. Haemoglobin genotype
determined by alkaline cellulose acetate haemoglobin electrophoresis while CD4 cell count was estimated with Partec
Cyflow analyser.
Result: There is no significant association between the ABO/Rh antigens and haemoglobin genotypes of the test and
control groups (P<0.05). All participants in the control group had CD4 count >200cells/mm3 while 198 (55%) HIV
infected subjects had CD4 count ≥200cells/mm3 and 42 (11.7%) had CD4 count <200cells/mm3. A significant
association was observed between the CD4 cell count of the patients and their ABO blood group antigens (P<0.05) with
blood group A and AB having the highest CD4count.
Conclusion: The outcome of this study reiterates the fact that blood group antigens are involved in immune protection
against infectious disease. Blood group A which has been implicated to confer susceptibility in some diseased condition
has been observed to confer immunity in this study.
Key-words- CD4 cells, Blood Group Antigens, HIV and Haemoglobin Genotype
Professor Michael Levin's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicaemia in Children & Adults www.meningitis.org/conference2013
Mecanismos inmunologicos del reconocimiento y como el cancer presenta sus autoantigenos, ausencia de estimulacion frente a tumores y las vacunas y extrategias.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
3. 1926
MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
FIGURE 1. This figure presents the
alignments of the genes in the HLA
region.
extension of our previous studies and the analysis of ancestral haplotypes. The haplotypes have been imputed by the presence of haplotypic allele markers, because it was not possible to strictly prove their
segregation from family studies. The investigation presented in this
study allows the delineation of specific MHC regions likely to be
functionally involved in the different patterns of disease progression.
Materials and Methods
Subjects
The GRIV cohort was established in 1995 in France to generate a large
collection of DNA samples for genetic studies of candidate human polymorphisms associated with rapid and slow progression to AIDS (3). To
avoid confounding effects associated with racial/ethnic differences in the
genetic analysis, only Caucasians of European descent were recruited from
hospital-based AIDS units throughout France. Slow progressors (SP) were
defined as asymptomatic individuals who had tested seropositive for HIV-1
for Ն8 years with a CD4ϩ cell count of Ͼ500/mm3 in the absence of
antiretroviral therapy. A seropositive test result for Ͼ8 years was necessary
for inclusion in the study. Rapid progressors (RP) were defined by a CD4
count of Ͻ300/mm3 in a period of time of Ͻ3 years after the last seronegative testing. We selected for the study individuals with complete intermediate to high resolution typings for HLA-A, -C, -B, -DRB1, and
-DQB1 loci. Seventy-four RP and 198 SP to AIDS were included in the
study.
Ancestral haplotypes frequencies for a population of 65,700 French subjects (control French population (CFP)) were previously published by Lonjou et al. (16).
Genetic typings and reconstruction of the MHC ancestral
haplotypes
The methodology for HLA class I and II, and MHC class I chain-related
gene A (MICA) DNA typings was previously described (3, 17). The ancestral haplotypes were reconstructed by imputation of haplotypic allele
markers as previously described (11, 12, 18) and are putative, because it
was not possible to strictly prove their segregation from family studies. The
most frequent ancestral haplotypes found in the GRIV cohort (frequency
Ͼ1%), studied in the present investigation, were the following: 7.1 (HLAA*0301, C*07, B*07, DRB1*1301, and DQB1*0603); 8.1 (HLA-A*01,
C*07, B*08, DRB1*0301, and DQB1*0201); 35.1 (C*04, B*35, DRB1*11,
and DQB1*0301); 35.2 (HLA-A*11, C*04, B*35, DRB1*0101, and
DQB1*0501); 44.1 (HLA-A*02, C*05, B*4402, DRB1*04, and DQB1*03);
44.2 (HLA-A*2902, C*16, B*4403, DRB1*07, and DQB1*0201), and 57.1
(HLA-A*01, C*06, B*5701, DRB1*07, and DQB1*0303). Of note, the haplotype 35.1 definition does not include an HLA-A allele.
Statistical analysis
The analysis of statistical significance was done by using Pearson’s 2 and
Fisher’s exact tests, 2 ϫ 2 contingency tables, and the aid of the INSTAT
2.01 computer program (GraphPad, San Diego, CA).
Table I. Comparative frequencies of ancestral haplotypesa
Frequency ϫ 100
Ancestral
Haplotypes
7.1
8.1
35.1
35.2
44.1
44.2
57.1
SP vs CFP
RP vs CFP
SP (n ϭ 198)
RP (n ϭ 74)
CFP
p value
OR
95% C.I.
p value
O.R.
95% C.I.
2.5
6.6
0.5
3.5
8.5
4
5.1
0
10.8
5.4
1.4
4
8.1
2.7
2.4
3.9
1
Ͻ1
1.7
2.5
0.9
0.90
0.08
0.73
0.001
<0.0001
0.24
<0.0001
1.1
1.7
0.5
3.6
5.4
1.6
5.9
0.4–2.6
1–3
0.07–3.6
1.7–7.7
3.3–9
0.8–3.3
3.1–11.1
0.33
0.006
0.001
0.72
0.26
0.007
0.31
0.3
3
5.7
1.4
2.4
3.4
3.1
0.02–4.4
1.4–6.2
2.1–15.5
0.2–9.8
0.8–7.8
1.5–7.9
0.7–12.5
a
Information about the frequencies of ancestral haplotypes in the French population was obtained from a previously published database of 65,700 individuals (16). A
two-tailed Pearson’s 2 test was used to analyze the data as indicated in Materials and Methods. C.I., Confidence interval.
4. The Journal of Immunology
1927
a
Table II. Recombinant fragments between SPs and RPs
a
Cobigram presenting the recombinant fragments among the SP and RP populations. A one-tailed Fisher’s
exact test was used to analyze the data as indicated in Materials and Methods. C.I., Confidence interval.
The recombinant fragments of the ancestral haplotypes were analyzed in the SP and RP populations, as shown
in color. Yellow, OR within 0.5 and 2 (no association); red, OR Ͼ2 (rapid progression); green, OR Ͻ0.5 (slow
progression). Haplotype 7.1 is not shown, because it does not exist in the RP group.
Results
The 35.2, 44.1, and 57.1, and the 8.1, 35.1, and 44.2 ancestral
haplotypes are associated with slow and rapid progression to
AIDS, respectively
To identify associations of ancestral haplotypes with slow or rapid
progression to AIDS we compared the frequencies of haplotypes
found in the GRIV cohort with the frequencies of haplotypes previously published in a normal French population (16). Among the
ancestral haplotypes previously described (13, 14), seven had a
frequency Ͼ1% in the GRIV cohort: 7.1, 8.1, 35.1, 35.2, 44.1,
44.2, and 57.1 (see Material and Methods). Significant associations with slow progression were obtained for the 35.2 (odds ratio
(OR) ϭ 3.6, p ϭ 0.001), 44.1 (OR ϭ 5.4, p Ͻ 0.0001), and 57.1
(OR ϭ 5.8, p Ͻ 0.0001) ancestral haplotypes (Table I). We also
found an increased frequency of the 8.1 (OR ϭ 3, p ϭ 0.0057), of
the 35.1 (OR ϭ 5.7, p ϭ 0.001), and of the 44.2 ancestral haplotypes (OR ϭ 3.4, p ϭ 0.007) in RP as compared with that in the
normal French population (Table I). No association was identified
with the 7.1 haplotype (Table I).
Because the 8.1 haplotype has previously been associated with
increased TNF-␣ production due to an LD with the Ϫ308 G/A
single nucleotide polymorphism (SNP) in the TNF-␣ promoter
(19), we have genotyped the GRIV cohort for the Ϫ308 G/A SNP.
We retrieve the LD between the rare A allele of that SNP and the
8.1 ancestral haplotype, which could give an explanation of the
observed association of this haplotype with rapid progression
to AIDS.
Identification of candidate regions associated with slow
progression and rapid progression to AIDS in the GRIV cohort.
To identify regions within the HLA locus associated with slow or
rapid progression, we used recombinant mapping methodology
(20) and compared the frequency of haplotype fragments found in
SP with that in RP in the GRIV cohort (Table II).
5. 1928
MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
The 8.1 haplotype was fixed from the HLA-A loci to the HLADQB1 loci in the majority of RP to AIDS, making it impossible to
map a region specifically associated with that trait by comparison
with SP to AIDS (Table II). The haplotype 35.1 exhibited a striking association with rapid progression for all fragments within the
C/DQB1 interval. The peak was obtained for the B/DQB1 interval
with an OR value of 14.3 ( p ϭ 0.006). For the haplotype 35.2, a
peak association with rapid progression was observed for the interval C/B with an OR of 2.3 and a p value of 0.02. Thus, carrying
the whole 35.2 haplotype resulted in the expression of the SP phenotype (Table I), while carrying the HLA-C/B interval of this haplotype resulted in the expression of the RP phenotype (Table II).
For the haplotype 44.1, a nearly significant association with slow
progression is obtained for the DRB1/DQB1 interval (OR ϭ 0.5,
p ϭ 0.06). For the haplotype 44.2, an association is observed with
rapid progression to AIDS with the intervals A/B and C/B with
ORs close to 2.4 and p values close to 0.05 (Table II). The DRB1/
DQB1 interval of the 57.1 haplotype was significantly associated
with slow progression to AIDS (OR ϭ 0.33, p ϭ 0.05); however,
all the fragments between C and DQB1 exhibited similar ORs
close to 0.4 and low p values such as 0.06 for the C/B interval
(Table II).
The associations involving the HLA-B44 allele are of particular
interest, because it is the most prevalent allele in the Caucasian
population (frequency of ϳ34%). The HLA-B gene is very close to
the MICA gene (Fig. 1), and it is known that the HLA-B*4403
allele present in the 44.2 ancestral haplotype is known to be in LD
with the MICA*004 allele, while the HLA-B*4402 allele in the
44.1 ancestral haplotype is in LD with the MICA*008 allele (18).
The MHC class I chain-related gene B (MICB) allele MICB*01021
is found in both the 44.1 and the 44.2 ancestral haplotypes (18). A
preliminary analysis of the GRIV cohort shows that, in fact, most
of the HLA-B44 carriers in our sample of RP are MICA*004, while
most of the HLA-B44 carriers in the SP are MICA*008 (data not
shown).
A recently published study showed an epistatic interaction between the killer Ig-like receptor (KIR) genes and HLA-B genes,
with an impact as strong as the CCR-5 ⌬32 deletion (21). In that
study, an association was observed only when analyzing the KIRs
in combination with their HLA ligands. It is known that the
KIR2DL2 and 2DL3 receptors on NK cells bind a conserved
HLA-C1 group motif (defined by S77 and N80), whereas the
KIR2DL1 receptor binds the HLA-C2 group (N77 and K80). We
tried to compare the RP and SP to AIDS by sorting them in the
HLA-C1 or HLA-C2 group motifs, but we could not see any difference. As described by Martin et al. (21), it might be necessary
to analyze the combination of HLA and KIR gene polymorphisms
to observe an association.
Discussion
Although the frequencies of ancestral haplotypes in all populations
are extremely low (11, 12, 16), we are reporting for the first time
an association of the 35.2, 44.1, and 57.1 ancestral haplotypes, and
of the 35.1 and 44.2 ancestral haplotypes with slow progression
and rapid progression to AIDS, respectively. Previous reports have
also found that the 8.1 ancestral haplotype is associated with rapid
progression to AIDS (22, 23). Of note, these associations between
ancestral haplotypes and AIDS progression withstand Bonferroni
corrections. The OR in this study, comprised between 2.9 and 5.9,
are globally higher than those obtained for single HLA alleles (3–
10). This can be explained by two reasons: a statistical explanation
based on the small number of subjects carrying ancestral haplotypes and a biological explanation based on the importance of the
contextual arrangement of genetic elements for successful immu-
nologic control of HIV-1 infection. For instance, the single allele
HLA-B8 alone is not associated with rapid progression to AIDS
(3); the HLA-B8 allele is associated with rapid progression only in
the full context of the ancestral haplotype 8.1. Our results do not
exclude that ancestral haplotypes are associated with susceptibility
to infection, because they are generally higher in both the SP and
RP populations than in the CFP population. It is unlikely that there
is a bias in the CFP population, because the haplotyping involved
65,700 individuals (16) and the frequencies are very similar to the
ones from other large studies (24).
Until now, the most widely viewed explanation for HLA influence is that class I and class II genes act directly by restricting the
immune response—Ag peptidic presentation—inducing selection
of HIV-1 viral escape mutants: in fact, the direct interaction between HLA and the generation of escape mutants can be analyzed
directly (25). Our approach based on the analysis of recombinant
ancestral haplotypes (fragments of these haplotypes) should permit
further mapping and identification of new disease susceptibility
genes within the HLA locus acting in concert with the classical
MHC class I and II genes (20). Our results suggest that the HLAC/B regions of the 44.2 and 35.2 ancestral haplotypes are associated with rapid progression to AIDS, and that the DRB1/DQB1
regions of the 44.1 and 57.1 ancestral haplotypes are associated
with slow progression to AIDS. For the haplotype 35.1, all intervals were associated with rapid progression to AIDS with a peak
for B/DQB1. It is important to emphasize that these data do not
integrate Bonferroni corrections, and only the associations of the
B/DQB1 and DRB1/DQB1 fragments of the 35.1 haplotype with
rapid progression to AIDS would remain significant if such corrections were applied. It was not possible to determine the effect of
specific recombination events within the 8.1 ancestral haplotype
because the haplotype was totally conserved among RP subjects;
however, we found it in total LD with the previously described
Ϫ308 A allele of TNF-␣ promoter (19).
Interestingly, among the seven ancestral haplotypes studied,
four of them involve HLA gene alleles that were previously associated with disease progression (3): HLA-B35 for haplotypes B35.1
and B35.2, HLA-DRB11 for the haplotype 35.1, HLA-A29 for the
haplotype B44.2, and HLAB57 for the haplotype B57.1. Unlike
HLA-B35, the ancestral haplotype B35.2 exhibited an association
with slow progression to AIDS (Table I). However the C/B fragment of this ancestral hapolotype seemed to be associated with
rapid progression to AIDS (Table II) and tends to confirm the
direct role of HLA-B35 allele in AIDS progression. A corrective
effect may occur elsewhere in the haplotype, whether between the
A and C gene, suggesting a possible role for HLA-E, or in the
B/DQB1 region pointing out MICA/B or TNF-␣. The analysis of
the recombinant fragments of 35.1 suggests a strong association
with rapid progression to AIDS for all the recombinant fragments,
highly significant for the B/DQB1 fragment (Table II): the association of the B35.1 haplotype appears bimodal with a peak in the
OR at 14.3 linked with the combined association of the alleles B35
and DR11, and two smaller ORs but very significant ( p ϭ 0.02 and
p ϭ 0.004) at the level of the C/B and DRB1/DQB1 fragments,
respectively, which correspond to the associations of B35 and
DR11 with rapid progression to AIDS we previously described (3).
This could suggest the tracking effect of an association for a gene
located within the B/DRB1 fragment, or a synergistic effect for the
combination of the individual alleles B35 and DR11. A recent
work has shown that the HLA-B35 allele effect was associated with
the subtypes 02, 03, and 04 of B35 (9). It is not known whether the
ancestral haplotypes 35.1 and 35.2 are associated with a given
subtype of B35 and that analysis will need to be performed. Of
interest, the association with rapid progression to AIDS found on
6. The Journal of Immunology
the C/B region for both the 35.1 and 35.2 haplotypes in the recombinant analysis had an OR of 2.3, similar to the one published
for the B35 subtypes 02, 03, and 04 (9). The association of the 44.2
haplotype with rapid progression to AIDS is similar in amplitude
to the one we previously described for A29 (3); however, the recombinant fragment C/B of the 44.2 haplotype appears also sufficient to track that association. Finally, for the HLA-B57 association, the recombinant analysis of the 57.1 haplotype points to the
whole C/DQB1 region: unlike the 35.1 haplotype, the ORs are
similar for all fragments, and all the genes in the C/DQB-1 region
could thus be good candidates to explain the association. In this
study of recombinant fragments, no discrepancy is observed between B and C genes, on the one hand, and DRB1 and DQB1, on
the other hand, reflecting their close proximity on chromosome 6.
In the DR/DQ region, besides the HLA DR/DQ genes themselves, the neighboring genes known as transporter associated with
Ag processing and large multifunctional protease are interesting
candidate genes that are functionally involved in the Ag processing
by class I molecules (26). Around the HLA B/C genes, promising
candidates are the genes of the MICA and MICB, but the HLA-E
locus located in between the HLA-A and HLA-C is also polymorphic (27, 28). MICA and MICB proteins are ligands of the NK
cell-activating receptor NKG2D (29), while HLA-E is the ligand
of the inhibitory NKG2A, -B, and -C receptors (30 –32).
In conclusion, our study confirms that the molecular mechanisms underlying the associations between HLA genes and AIDS
disease progression are not always direct effects of HLA restriction
but can also be indirect effects due to LD, or both. Our analysis
through the ancestral haplotypes has brought some insight into the
possible mechanisms by pointing out class I, II, or III MHC regions linked to various HLA alleles susceptible to being associated
with disease progression. The combined analysis of the TNF-␣,
MICA/B, HLA-E, transporter associated with Ag processing, large
multifunctional protease, and KIR/killer cell-activating receptor
gene polymorphisms as well as of the viral gene sequences (25)
and their interactions (21) should certainly bring a definitive answer to these questions.
1929
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Acknowledgments
We are grateful to all the patients and medical staff who have kindly collaborated with the project.
23.
24.
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