This document summarizes recent advances in understanding the genetic basis of systemic sclerosis (SSc). Genome-wide association studies and other large genetic studies have identified 30 genes associated with SSc, mostly related to immunity. Three recent large studies identified additional genetic loci associated with SSc and helped clarify associations within the HLA region. However, genetics only explains part of SSc risk and heterogeneity remains poorly understood. Future research needs to address heterogeneity to improve understanding and treatment of this complex disease.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
This document discusses the need for a high-throughput method to discover environmental influences on phenotypes, analogous to genome-wide association studies for genes. It notes that current estimates from twin studies attribute on average 49% of phenotypic variation to genetic factors, leaving 51% unexplained. Developing methods to systematically measure and analyze the "exposome" of environmental exposures each person experiences could help discover environmental factors influencing health and disease.
Big data exposome and pediatric outcomesChirag Patel
The document discusses the need for a new data-driven approach to discover the role of environmental factors (E) in disease, similar to how genome-wide association studies (GWAS) have elucidated genetic factors (G). It notes that phenotypes are influenced by both G and E, but current heritability estimates indicate G accounts for less than 50% of many complex traits, leaving much of the influence of E unknown. The document proposes developing methods to characterize individuals' "exposomes" - the totality of their environmental exposures - using high-throughput techniques to measure biomarkers of exposure in blood and linking exposomes to health outcomes in large studies. This could help uncover how environmental chemicals, lifestyle factors and other external influences
Big data and the exposome, Oregon State 040616Chirag Patel
This document describes the National Health and Nutrition Examination Survey (NHANES), which since the 1960s has collected extensive exposure and health data on approximately 10,000 US participants biannually. NHANES oversamples older adults, African Americans, and Hispanics to represent the US population. It includes health interviews, physical exams, laboratory tests, and medical/dietary assessments to characterize participants' exposures and health status. NHANES provides a gold standard for comprehensively assessing the US population's exposome through its breadth of exposure data collection.
1) The document discusses the need for large-scale studies of environmental exposures, known as environment-wide association studies (EWAS), to discover environmental factors associated with disease and address issues with past fragmented studies of single exposures.
2) EWAS can systematically analyze multiple personal exposures simultaneously and adjust for multiple testing to identify strongest associations, which can then be validated in independent data sets.
3) However, establishing causal inferences from observational EWAS data remains challenging due to complex correlations between many environmental factors.
Informatics and data analytics to support for exposome-based discoveryChirag Patel
The document discusses the need for informatics methods, databases, and standards to support exposome-driven discovery research in a similar way that informatics has supported genomic research. Specifically, it notes that estimates of heritability from twin studies indicate that environmental factors likely play an equally important role as genetics in many traits/diseases. However, the chemical space of the exposome is large and heterogeneous, posing challenges to integrate exposome, genome, and phenome data through approaches like exposome-wide association studies.
This document summarizes research on genetic and environmental risk factors for multiple sclerosis (MS). It finds that MS is influenced by both hereditary and non-hereditary factors. Major genetic risk factors identified include the HLA-DRB1*1501 locus, the interleukin 7 receptor gene, and the interleukin 2 receptor gene, which together account for about 50% of MS's hereditability. Environmental factors associated with increased risk include Epstein-Barr virus, human herpesvirus 6, low vitamin D levels, and smoking.
This document provides an introduction to genome-wide association studies (GWAS) and their role in discovering the genetic basis of complex traits and diseases. It explains that GWAS are a hypothesis-free approach to searching the entire human genome for genetic variants associated with a trait using common single nucleotide polymorphisms. Over 2,000 traits and diseases have been studied through GWAS, identifying over 15,000 genetic associations. The document traces the development of GWAS from early human genome sequencing and projects to characterize human genetic variation to the availability of high-throughput genotyping arrays that enabled widespread application of GWAS in disease research.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
This document discusses the need for a high-throughput method to discover environmental influences on phenotypes, analogous to genome-wide association studies for genes. It notes that current estimates from twin studies attribute on average 49% of phenotypic variation to genetic factors, leaving 51% unexplained. Developing methods to systematically measure and analyze the "exposome" of environmental exposures each person experiences could help discover environmental factors influencing health and disease.
Big data exposome and pediatric outcomesChirag Patel
The document discusses the need for a new data-driven approach to discover the role of environmental factors (E) in disease, similar to how genome-wide association studies (GWAS) have elucidated genetic factors (G). It notes that phenotypes are influenced by both G and E, but current heritability estimates indicate G accounts for less than 50% of many complex traits, leaving much of the influence of E unknown. The document proposes developing methods to characterize individuals' "exposomes" - the totality of their environmental exposures - using high-throughput techniques to measure biomarkers of exposure in blood and linking exposomes to health outcomes in large studies. This could help uncover how environmental chemicals, lifestyle factors and other external influences
Big data and the exposome, Oregon State 040616Chirag Patel
This document describes the National Health and Nutrition Examination Survey (NHANES), which since the 1960s has collected extensive exposure and health data on approximately 10,000 US participants biannually. NHANES oversamples older adults, African Americans, and Hispanics to represent the US population. It includes health interviews, physical exams, laboratory tests, and medical/dietary assessments to characterize participants' exposures and health status. NHANES provides a gold standard for comprehensively assessing the US population's exposome through its breadth of exposure data collection.
1) The document discusses the need for large-scale studies of environmental exposures, known as environment-wide association studies (EWAS), to discover environmental factors associated with disease and address issues with past fragmented studies of single exposures.
2) EWAS can systematically analyze multiple personal exposures simultaneously and adjust for multiple testing to identify strongest associations, which can then be validated in independent data sets.
3) However, establishing causal inferences from observational EWAS data remains challenging due to complex correlations between many environmental factors.
Informatics and data analytics to support for exposome-based discoveryChirag Patel
The document discusses the need for informatics methods, databases, and standards to support exposome-driven discovery research in a similar way that informatics has supported genomic research. Specifically, it notes that estimates of heritability from twin studies indicate that environmental factors likely play an equally important role as genetics in many traits/diseases. However, the chemical space of the exposome is large and heterogeneous, posing challenges to integrate exposome, genome, and phenome data through approaches like exposome-wide association studies.
This document summarizes research on genetic and environmental risk factors for multiple sclerosis (MS). It finds that MS is influenced by both hereditary and non-hereditary factors. Major genetic risk factors identified include the HLA-DRB1*1501 locus, the interleukin 7 receptor gene, and the interleukin 2 receptor gene, which together account for about 50% of MS's hereditability. Environmental factors associated with increased risk include Epstein-Barr virus, human herpesvirus 6, low vitamin D levels, and smoking.
This document provides an introduction to genome-wide association studies (GWAS) and their role in discovering the genetic basis of complex traits and diseases. It explains that GWAS are a hypothesis-free approach to searching the entire human genome for genetic variants associated with a trait using common single nucleotide polymorphisms. Over 2,000 traits and diseases have been studied through GWAS, identifying over 15,000 genetic associations. The document traces the development of GWAS from early human genome sequencing and projects to characterize human genetic variation to the availability of high-throughput genotyping arrays that enabled widespread application of GWAS in disease research.
Genetics of gene expression explores how genetic variation impacts transcriptome diversity and gene regulation. Studying the genetics of gene expression through expression quantitative trait locus (eQTL) mapping can identify genetic variants that influence gene expression levels. eQTL discovery depends on biological factors like cell/tissue type, development, population, and environment, as well as technological factors like sample size and genotyping/gene expression platforms. RNA sequencing has increased the resolution of eQTL mapping by allowing the detection of splicing QTLs, rare eQTLs, and allele-specific expression effects. Understanding the functional consequences of eQTLs and their relationship to disease can provide insights into disease mechanisms and improve disease risk prediction.
This document summarizes recent updates on lupus nephritis (LN), a form of kidney disease caused by systemic lupus erythematosus (SLE) that can lead to kidney failure. It discusses the epidemiology of SLE and LN, noting higher rates in women and certain racial groups. Genetic factors that may influence susceptibility and disease course are also reviewed. The pathogenesis of LN is complex and involves interferon response, neutrophil activation, and impaired clearance of cellular debris. Timely diagnosis via urine testing and kidney biopsy is important for treatment and preventing long-term kidney damage.
Biomedical Informatics 706: Precision Medicine with exposuresChirag Patel
This document discusses the need for a more comprehensive approach to understanding disease etiology by investigating environmental exposures, or the "exposome", in addition to genetic factors. It notes that genome-wide association studies have been successful in identifying genetic risk factors, but genetics alone explains only a portion of disease risk. Large studies like the National Health and Nutrition Examination Survey collect extensive exposure and health data that could be leveraged to discover environmental risk factors through an "exposome-wide association study" approach analogous to GWAS. Characterizing both genetic and environmental contributions is crucial for advancing precision medicine.
Repurposing large datasets to dissect exposomic (and genomic) contributions i...Chirag Patel
This document discusses the need for a new paradigm to discover environmental influences on health and disease through high-throughput exposome-wide association studies (EWAS) in a similar manner to genome-wide association studies (GWAS) for genetic influences. It notes that while GWAS have identified many genetic variants associated with traits, they only explain a small portion of heritability, suggesting an important role for environmental factors. The document advocates for developing methods to robustly characterize exposures through the exposome and relate them to health outcomes at a large scale through EWAS. This would help discover major environmental causes of diseases and help explain the "missing heritability".
Transcriptional signaling pathways inversely regulated in alzheimer's disease...Elsa von Licy
This document summarizes a study that analyzed gene expression data from patients with Alzheimer's disease and glioblastoma multiforme to identify signaling pathways that are inversely regulated between the two diseases. The study found that the ERK/MAPK pathway is upregulated in glioblastoma but downregulated in Alzheimer's disease. Additionally, the angiopoietin signaling pathway is upregulated in Alzheimer's disease but downregulated in glioblastoma. Conditioned media containing amyloid-beta peptide suppressed glioblastoma cell growth and ERK/MAPK signaling, suggesting amyloid-beta may contribute to the inverse relationship between the diseases by inhibiting glioblastoma signaling pathways.
Search engine for E NEU network science 080817Chirag Patel
The document describes building a search engine to discover environmental factors associated with disease and health outcomes using large epidemiological datasets like the National Health and Nutrition Examination Survey. It outlines how existing genome-wide association studies were used to discover genetic factors but similar approaches are lacking for environmental exposures. The author advocates developing high-throughput environmental exposure assessment methods and conducting environmental-wide association studies to discover environmental influences in a systematic and reproducible way.
EWAS and the exposome: Mt Sinai in Brescia 052119Chirag Patel
The document summarizes a presentation given by Chirag Patel on estimating the genetic (h2) and shared environmental (c2) contributions to phenotypic variation using a large health insurance claims dataset of over 56,000 twin pairs and 700,000 siblings in the US. The analysis of 560 phenotypes across different disease categories found significant heritable and shared environmental components for many traits, with average h2 of 0.32 and c2 of 0.09. However, factors like air pollution, climate, and socioeconomic status explained only a modest portion of the overall shared environmental variation. This highlights the complex and elusive nature of phenotypic variation that remains unexplained. The presentation emphasizes the need to leverage exposome data to better characterize
This paper discusses Tay-Sachs disease (TSD), a rare genetic lysosomal storage disorder. TSD is caused by mutations in the HEXA gene resulting in a deficiency of the enzyme beta-hexosaminidase A. This causes a toxic buildup of gangliosides that damage nerve cells. While the underlying genetic cause is known, the exact pathogenesis remains unclear. Research using cell models and animal models like sheep aim to further understand TSD at the cellular level to develop improved treatments beyond just carrier screening.
This document discusses the FOXP3 gene as a promising candidate gene in susceptibility to generalized vitiligo. It summarizes that FOXP3 is the master transcription factor that regulates regulatory T cells, which play an important role in preventing autoimmunity. Studies have found associations between polymorphisms in the FOXP3 gene and an increased risk of vitiligo. The document argues that further investigation of FOXP3 genetic variants and their effects on regulatory T cell development and function could provide insights into vitiligo pathogenesis and potential new therapeutic approaches targeting the FOXP3 gene/regulatory T cell network.
Salon b 18 kasim 2011 11.30 11.50 benan bayrakcityfngnc
1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression.
2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown.
3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.
Correlation globes of the exposome 2016Chirag Patel
This document discusses developing exposome correlation globes to map associations between exposures and phenotypes. It summarizes work analyzing replicated correlations between over 250 quantitative exposures measured in NHANES participants to create a globe visualization. The analysis found that while the exposome correlations were dense, with around 3% of pair-wise correlations replicated between cohorts, the correlations were modest in absolute size. The exposome globes could help contextualize exposome-wide association studies and identify co-occurring exposures.
The document describes the design of a customized genome-wide genotyping array ("TxArray") for transplantation studies. It includes approximately 782,000 markers focused on loci related to HLA, KIR, pharmacogenomics, and metabolism that are important for transplantation. Testing on 85 HapMap samples showed high concordance (0.996) and low error rates, and genotype imputation was highly accurate (over 0.962). The array was designed to improve coverage of regions like KIR compared to other platforms and enable large-scale genetic studies in transplant cohorts.
This study aims to search for genetic and proteomic risk factors and protective factors associated with coronary heart disease (CHD) in order to develop new diagnostic techniques and therapies. The study will analyze gene expression patterns in peripheral blood monocytes and perform proteomics analysis of blood serum from five patient groups: 1) those with heart attack and risk factors, 2) those with heart attack without risk factors, 3) young individuals with risk factors but no heart attack, 4) elderly individuals with risk factors but no heart attack, and 5) healthy elderly individuals without risk factors. Gene expression profiles will be obtained using microarray analysis and validated with real-time PCR. Differentially expressed genes and proteins may help identify new targets for preventing and
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
This document provides an introduction to network medicine and discusses its application to chronic obstructive pulmonary disease (COPD). It defines network medicine as studying cellular, disease, and social networks to quantify factors contributing to individual diseases. For COPD, network approaches are being used to build disease networks, define molecular pathways, identify optimal disease phenotypes, develop new classifications, and integrate multi-omics data. Genome-wide association studies have identified risk loci for COPD, which are now being functionally validated in cellular and animal models. Network medicine aims to take a holistic rather than reductionist approach to complex diseases like COPD.
BRN Seminar 12/06/14 Introduction to Network Medicine brnmomentum
This document provides an introduction to network medicine and discusses its application to chronic obstructive pulmonary disease (COPD). It defines network medicine as studying cellular, disease, and social networks to quantify factors contributing to individual diseases. For COPD, network approaches are being used to build disease networks, define molecular pathways, identify optimal disease phenotypes, develop new classifications, and integrate multi-omics data. Genome-wide association studies have identified risk loci for COPD, which are now being functionally validated in cellular and animal models. Network medicine aims to take a holistic rather than reductionist approach to complex diseases like COPD.
This document summarizes a review article on the genetic, autoimmune, and environmental factors involved in rheumatoid arthritis (RA). It discusses how RA results from an interplay between these factors. Genetically, the HLA-DRB1 gene is a major determinant of RA risk. Over 30 non-MHC genes have also been associated with RA through genome-wide association studies and studies of specific populations, including STAT4, PADI4, and PTPN22. Environmental risks like smoking may interact with genetic susceptibility to increase RA risk. Understanding the roles of disease-associated genes and gene-environment interactions could lead to improved RA treatments and prevention strategies.
Repurposing large datasets for exposomic discovery in diseaseChirag Patel
This document discusses the need for large-scale studies of environmental exposures (the exposome) analogous to genome-wide association studies (GWAS) to better understand environmental contributions to health and disease. It notes that while genetics research has made great strides with GWAS, understanding of environmental influences lacks comparable methods and data. The author argues that characterizing the exposome through high-throughput methods could discover new environmental factors in phenotypes, as GWAS did for genetics. National Health and Nutrition Examination Survey is presented as a model for collecting comprehensive human exposure data on a large scale.
88 24-1853 051.812.955.17 folder to Tax ReturnSandro Suzart
This study examined the association between genetic polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) genes and the risk of developing asbestos-related pulmonary disorders in Finnish construction workers with high asbestos exposure. The risk of developing malignant mesothelioma or nonmalignant pulmonary disorders was not significantly associated with GSTM1 or GSTT1 genotypes. However, individuals with the NAT2 slow acetylator genotype had over a two-fold increased risk of developing asbestos-related pulmonary disorders compared to those with the fast acetylator genotype. Those with both the GSTM1 null genotype and NAT2 slow acetyl
Ritchie Bros. is a global asset management company that helps clients sell billions of dollars worth of used equipment annually through various disposition solutions. These include unreserved public auctions with on-site and online bidding from buyers around the world, online auctions, private treaty sales, and salvage sales. The document provides examples of large equipment packages and sales totals that Ritchie Bros. has helped facilitate for mining companies and others. It promotes Ritchie Bros.' full-service offerings to customize a sales program tailored to a client's specific objectives and get maximum returns from selling surplus mining equipment through their global network.
This document summarizes a systematic review and meta-analysis of adjunctive diagnostic techniques for oral lesions of unknown malignant potential. 48 articles were identified that evaluated diagnostic methods like oral cytology, toluidine blue staining, and specialist examination, compared to tissue biopsy as the gold standard. 25 articles were included in quantitative analysis. The analysis found that oral cytology has higher diagnostic value than specialist examination, which is better than toluidine blue staining. Future studies directly comparing multiple techniques in the same patients are needed.
Genetics of gene expression explores how genetic variation impacts transcriptome diversity and gene regulation. Studying the genetics of gene expression through expression quantitative trait locus (eQTL) mapping can identify genetic variants that influence gene expression levels. eQTL discovery depends on biological factors like cell/tissue type, development, population, and environment, as well as technological factors like sample size and genotyping/gene expression platforms. RNA sequencing has increased the resolution of eQTL mapping by allowing the detection of splicing QTLs, rare eQTLs, and allele-specific expression effects. Understanding the functional consequences of eQTLs and their relationship to disease can provide insights into disease mechanisms and improve disease risk prediction.
This document summarizes recent updates on lupus nephritis (LN), a form of kidney disease caused by systemic lupus erythematosus (SLE) that can lead to kidney failure. It discusses the epidemiology of SLE and LN, noting higher rates in women and certain racial groups. Genetic factors that may influence susceptibility and disease course are also reviewed. The pathogenesis of LN is complex and involves interferon response, neutrophil activation, and impaired clearance of cellular debris. Timely diagnosis via urine testing and kidney biopsy is important for treatment and preventing long-term kidney damage.
Biomedical Informatics 706: Precision Medicine with exposuresChirag Patel
This document discusses the need for a more comprehensive approach to understanding disease etiology by investigating environmental exposures, or the "exposome", in addition to genetic factors. It notes that genome-wide association studies have been successful in identifying genetic risk factors, but genetics alone explains only a portion of disease risk. Large studies like the National Health and Nutrition Examination Survey collect extensive exposure and health data that could be leveraged to discover environmental risk factors through an "exposome-wide association study" approach analogous to GWAS. Characterizing both genetic and environmental contributions is crucial for advancing precision medicine.
Repurposing large datasets to dissect exposomic (and genomic) contributions i...Chirag Patel
This document discusses the need for a new paradigm to discover environmental influences on health and disease through high-throughput exposome-wide association studies (EWAS) in a similar manner to genome-wide association studies (GWAS) for genetic influences. It notes that while GWAS have identified many genetic variants associated with traits, they only explain a small portion of heritability, suggesting an important role for environmental factors. The document advocates for developing methods to robustly characterize exposures through the exposome and relate them to health outcomes at a large scale through EWAS. This would help discover major environmental causes of diseases and help explain the "missing heritability".
Transcriptional signaling pathways inversely regulated in alzheimer's disease...Elsa von Licy
This document summarizes a study that analyzed gene expression data from patients with Alzheimer's disease and glioblastoma multiforme to identify signaling pathways that are inversely regulated between the two diseases. The study found that the ERK/MAPK pathway is upregulated in glioblastoma but downregulated in Alzheimer's disease. Additionally, the angiopoietin signaling pathway is upregulated in Alzheimer's disease but downregulated in glioblastoma. Conditioned media containing amyloid-beta peptide suppressed glioblastoma cell growth and ERK/MAPK signaling, suggesting amyloid-beta may contribute to the inverse relationship between the diseases by inhibiting glioblastoma signaling pathways.
Search engine for E NEU network science 080817Chirag Patel
The document describes building a search engine to discover environmental factors associated with disease and health outcomes using large epidemiological datasets like the National Health and Nutrition Examination Survey. It outlines how existing genome-wide association studies were used to discover genetic factors but similar approaches are lacking for environmental exposures. The author advocates developing high-throughput environmental exposure assessment methods and conducting environmental-wide association studies to discover environmental influences in a systematic and reproducible way.
EWAS and the exposome: Mt Sinai in Brescia 052119Chirag Patel
The document summarizes a presentation given by Chirag Patel on estimating the genetic (h2) and shared environmental (c2) contributions to phenotypic variation using a large health insurance claims dataset of over 56,000 twin pairs and 700,000 siblings in the US. The analysis of 560 phenotypes across different disease categories found significant heritable and shared environmental components for many traits, with average h2 of 0.32 and c2 of 0.09. However, factors like air pollution, climate, and socioeconomic status explained only a modest portion of the overall shared environmental variation. This highlights the complex and elusive nature of phenotypic variation that remains unexplained. The presentation emphasizes the need to leverage exposome data to better characterize
This paper discusses Tay-Sachs disease (TSD), a rare genetic lysosomal storage disorder. TSD is caused by mutations in the HEXA gene resulting in a deficiency of the enzyme beta-hexosaminidase A. This causes a toxic buildup of gangliosides that damage nerve cells. While the underlying genetic cause is known, the exact pathogenesis remains unclear. Research using cell models and animal models like sheep aim to further understand TSD at the cellular level to develop improved treatments beyond just carrier screening.
This document discusses the FOXP3 gene as a promising candidate gene in susceptibility to generalized vitiligo. It summarizes that FOXP3 is the master transcription factor that regulates regulatory T cells, which play an important role in preventing autoimmunity. Studies have found associations between polymorphisms in the FOXP3 gene and an increased risk of vitiligo. The document argues that further investigation of FOXP3 genetic variants and their effects on regulatory T cell development and function could provide insights into vitiligo pathogenesis and potential new therapeutic approaches targeting the FOXP3 gene/regulatory T cell network.
Salon b 18 kasim 2011 11.30 11.50 benan bayrakcityfngnc
1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression.
2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown.
3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.
Correlation globes of the exposome 2016Chirag Patel
This document discusses developing exposome correlation globes to map associations between exposures and phenotypes. It summarizes work analyzing replicated correlations between over 250 quantitative exposures measured in NHANES participants to create a globe visualization. The analysis found that while the exposome correlations were dense, with around 3% of pair-wise correlations replicated between cohorts, the correlations were modest in absolute size. The exposome globes could help contextualize exposome-wide association studies and identify co-occurring exposures.
The document describes the design of a customized genome-wide genotyping array ("TxArray") for transplantation studies. It includes approximately 782,000 markers focused on loci related to HLA, KIR, pharmacogenomics, and metabolism that are important for transplantation. Testing on 85 HapMap samples showed high concordance (0.996) and low error rates, and genotype imputation was highly accurate (over 0.962). The array was designed to improve coverage of regions like KIR compared to other platforms and enable large-scale genetic studies in transplant cohorts.
This study aims to search for genetic and proteomic risk factors and protective factors associated with coronary heart disease (CHD) in order to develop new diagnostic techniques and therapies. The study will analyze gene expression patterns in peripheral blood monocytes and perform proteomics analysis of blood serum from five patient groups: 1) those with heart attack and risk factors, 2) those with heart attack without risk factors, 3) young individuals with risk factors but no heart attack, 4) elderly individuals with risk factors but no heart attack, and 5) healthy elderly individuals without risk factors. Gene expression profiles will be obtained using microarray analysis and validated with real-time PCR. Differentially expressed genes and proteins may help identify new targets for preventing and
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
This document provides an introduction to network medicine and discusses its application to chronic obstructive pulmonary disease (COPD). It defines network medicine as studying cellular, disease, and social networks to quantify factors contributing to individual diseases. For COPD, network approaches are being used to build disease networks, define molecular pathways, identify optimal disease phenotypes, develop new classifications, and integrate multi-omics data. Genome-wide association studies have identified risk loci for COPD, which are now being functionally validated in cellular and animal models. Network medicine aims to take a holistic rather than reductionist approach to complex diseases like COPD.
BRN Seminar 12/06/14 Introduction to Network Medicine brnmomentum
This document provides an introduction to network medicine and discusses its application to chronic obstructive pulmonary disease (COPD). It defines network medicine as studying cellular, disease, and social networks to quantify factors contributing to individual diseases. For COPD, network approaches are being used to build disease networks, define molecular pathways, identify optimal disease phenotypes, develop new classifications, and integrate multi-omics data. Genome-wide association studies have identified risk loci for COPD, which are now being functionally validated in cellular and animal models. Network medicine aims to take a holistic rather than reductionist approach to complex diseases like COPD.
This document summarizes a review article on the genetic, autoimmune, and environmental factors involved in rheumatoid arthritis (RA). It discusses how RA results from an interplay between these factors. Genetically, the HLA-DRB1 gene is a major determinant of RA risk. Over 30 non-MHC genes have also been associated with RA through genome-wide association studies and studies of specific populations, including STAT4, PADI4, and PTPN22. Environmental risks like smoking may interact with genetic susceptibility to increase RA risk. Understanding the roles of disease-associated genes and gene-environment interactions could lead to improved RA treatments and prevention strategies.
Repurposing large datasets for exposomic discovery in diseaseChirag Patel
This document discusses the need for large-scale studies of environmental exposures (the exposome) analogous to genome-wide association studies (GWAS) to better understand environmental contributions to health and disease. It notes that while genetics research has made great strides with GWAS, understanding of environmental influences lacks comparable methods and data. The author argues that characterizing the exposome through high-throughput methods could discover new environmental factors in phenotypes, as GWAS did for genetics. National Health and Nutrition Examination Survey is presented as a model for collecting comprehensive human exposure data on a large scale.
88 24-1853 051.812.955.17 folder to Tax ReturnSandro Suzart
This study examined the association between genetic polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) genes and the risk of developing asbestos-related pulmonary disorders in Finnish construction workers with high asbestos exposure. The risk of developing malignant mesothelioma or nonmalignant pulmonary disorders was not significantly associated with GSTM1 or GSTT1 genotypes. However, individuals with the NAT2 slow acetylator genotype had over a two-fold increased risk of developing asbestos-related pulmonary disorders compared to those with the fast acetylator genotype. Those with both the GSTM1 null genotype and NAT2 slow acetyl
Ritchie Bros. is a global asset management company that helps clients sell billions of dollars worth of used equipment annually through various disposition solutions. These include unreserved public auctions with on-site and online bidding from buyers around the world, online auctions, private treaty sales, and salvage sales. The document provides examples of large equipment packages and sales totals that Ritchie Bros. has helped facilitate for mining companies and others. It promotes Ritchie Bros.' full-service offerings to customize a sales program tailored to a client's specific objectives and get maximum returns from selling surplus mining equipment through their global network.
This document summarizes a systematic review and meta-analysis of adjunctive diagnostic techniques for oral lesions of unknown malignant potential. 48 articles were identified that evaluated diagnostic methods like oral cytology, toluidine blue staining, and specialist examination, compared to tissue biopsy as the gold standard. 25 articles were included in quantitative analysis. The analysis found that oral cytology has higher diagnostic value than specialist examination, which is better than toluidine blue staining. Future studies directly comparing multiple techniques in the same patients are needed.
Private Treaty Unused Mining Equipment Sales by Ritchie BrosPhillip A. Weston
Unused units of 2010 CATERPILLAR 793D and 2010 BUCYRUS RH340B are located in the Ritchie Bros yard in Dubai, Jebel Ali. You can email me or call me to arrange for a viewing. pweston@rbauction.com
Hazardous Waste Management Training 3-15, GSRMCErin Merrell
Hazardous waste containers must be clearly labeled with the product identification, the words "Hazardous Waste", the date of storage, and the generating department. Containers must be compatible with the waste, in good condition, and stored on an impermeable surface with secondary containment. A hazardous waste manifest must accompany shipments, listing the generator, facility receiving the waste, waste description, and quantity. When signing the manifest, staff should check that quantities and descriptions are correct.
Hazardous Material Spill General Instructions Grid 3-15, GSRMCErin Merrell
This document outlines procedures for handling hazardous materials spills at Good Samaritan Regional Medical Center. It defines incidental spills as small spills that can be cleaned by on-site staff using spill kits. Emergency spills are larger spills that require evacuation and outside contractor assistance. The procedures instruct staff to contain spills, notify managers, don protective equipment, and clean using the appropriate spill kit or contact specialists for emergency spills. Documentation of any spill incident is also required.
Tops Pickle has developed a brand plan to grow its pickle category sales over the next year. The plan includes analyzing the current market size and Tops' market share, profiling target consumers, conducting a SWOT analysis, and examining competitors. The strategies proposed focus on developing regional variants to match local tastes across India, segmenting products based on factors like region, price, and purchasing groups. A detailed activity plan and proposed research will help implement tactics to build the brand nationally.
Gaussian is a computational chemistry software package used to calculate the structures and properties of molecules. It uses quantum mechanics and density functional theory to solve chemical problems without experiments. Gaussian can optimize molecular geometries, calculate vibrational frequencies, and determine properties like infrared spectra. It provides information on molecular energies, structures, reaction pathways and more through simulation.
El documento habla sobre las inteligencias múltiples y cómo el arte puede desarrollarlas. Explica la teoría de las inteligencias múltiples de Howard Gardner y los diferentes tipos de inteligencia. Argumenta que el arte debe incluirse más en la educación porque permite desarrollar las inteligencias lingüística, lógico-matemática, kinestésica, espacial, musical e interpersonal de manera práctica y expresiva.
This document discusses using Facebook's Marketing API and provides examples of how to upload product catalogs and retrieve advertising insights and metrics. It demonstrates Python code samples to upload a product feed, update product availability and pricing, and retrieve advertising insights data. The presentation also covers how to analyze marketing data using the API to identify opportunities such as campaigns with low ROI.
Gene expression signatures in tuberculosis have greater overlap with autoimmune diseases than infectious diseases. The analysis identified 2,468 differentially expressed genes in tuberculosis, 8,134 in infection, and 11,348 in autoimmune disorders. There was more overlap between the tuberculosis and autoimmune signatures, with 810 shared genes, compared to only 96 shared with infection. Additionally, pathways analysis showed the predominant involvement of type I interferon signaling, which is important in autoimmunity. This supports the hypothesis that an autoimmune process contributes to pathology in pulmonary tuberculosis.
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1. SCLERODERMA (J VARGA, SECTION EDITOR)
Recent Advances in the Genetics of Systemic Sclerosis:
Toward Biological and Clinical Significance
Benjamin D. Korman & Lindsey A. Criswell
Published online: 18 March 2015
# The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract Significant advances have been made in under-
standing the genetic basis of systemic sclerosis (SSc) in recent
years. Genomewide association and other large-scale genetic
studies have identified 30 largely immunity-related genes
which are significantly associated with SSc. We review these
studies, along with genomewide expression studies, proteo-
mic studies, genetic mouse models, and insights from rare
sclerodermatous diseases. Collectively, these studies have be-
gun to identify pathways that are relevant to SSc pathogenesis.
The findings presented in this review illustrate how both ge-
netic and genomic aberrations play important roles in the de-
velopment of SSc. However, despite these recent discoveries,
there remain major gaps between current knowledge of SSc, a
unified understanding of pathogenesis, and effective treat-
ment. To this aim, we address the important issue of SSc
heterogeneity and discuss how future research needs to ad-
dress this in order to develop a clearer understanding of this
devastating and complex disease.
Keywords Scleroderma . Systemic sclerosis . Autoimmune
disease . Genetics . Single nucleotide polymorphisms .
Genomics . Mouse models . Heterogeneity
Introduction
Systemic sclerosis (SSc, the systemic form of scleroderma) is
a complex disease with features that include autoimmunity,
vasculopathy, and fibrosis. The disease is more common in
women (4:1 female to male ratio) [1, 2]. There is significant
clinical heterogeneity between SSc patients which remains
poorly understood [3], and there remain critical gaps in under-
standing of the biologic basis of SSc. The core signs and
symptoms of SSc are Raynaud’s phenomenon, skin thicken-
ing, and serum autoantibody production, but patients have
different patterns of internal organ involvement with variable
presentations and outcomes [4, 5]. SSc patients overall have
an estimated 66 % 10-year survival rate, which decreases to
38 % for those with significant internal organ involvement [6,
7]. Pulmonary fibrosis and pulmonary artery hypertension
(PAH) are leading causes of death and affect approximately
15 % of SSc patients [8]. Cardiac disease including left- and
right-sided heart failure, conduction system abnormalities, ar-
rhythmias, or pericardial disease affects 15–35 % of patients
[9–12]. Skin involvement causes significant disability and al-
so correlates directly with increased mortality [13]. The pres-
ence of cardiac involvement portends a poor prognosis with
70 % 5-year mortality [14] contributing to roughly 25 % of
SSc-related deaths [15].
SSc is a rare disease with an estimated 50 to 300 cases per
million, and while the overall genetic burden is modest (only
2.6 % of SSc patients’ siblings develop SSc), evidence from
familial, twin, and epidemiologic studies has implicated ge-
netic predisposition for disease [16–19]. A positive family
history raises relative risk by 15- to 19-fold in siblings relative
to the general population, and first-degree relatives also have
increased risk for developing Raynaud’s phenomenon and
interstitial lung disease [20, 21]. However, the genomic vari-
ants identified to date only account for approximately half of
the genetic burden of SSc; environmental and epigenetic
This article is part of the Topical Collection on Scleroderma
B. D. Korman
Division of Rheumatology, Feinberg School of Medicine,
Northwestern University, Chicago, IL, USA
e-mail: benjamin-korman@northwestern.edu
L. A. Criswell (*)
Rosalind Russell/Ephraim P. Engleman Rheumatology Research
Center, Division of Rheumatology, University of California, San
Francisco, CA, USA
e-mail: Lindsey.criswell@ucsf.edu
Curr Rheumatol Rep (2015) 17: 21
DOI 10.1007/s11926-014-0484-x
2. factors are thought to play a major role in this Bmissing heri-
tability,^ and recent work has implicated multiple different
epigenetic risk factors [22–24].
Like most autoimmune diseases, the genetic contribution to
scleroderma is not due to a single rare genetic mutation but
rather derives from many common genetic variants which
predispose patients to disease. As an autoimmune disease, it
has been well established that SSc is associated with HLA
loci, and these studies have been recently reviewed elsewhere
[24, 25]. Through the use of high-throughput technologies
including genomewide association studies (GWAS), re-
searchers have identified and confirmed over 25 additional
non-HLA SSc-associated genetic loci. The vast majority of
these regions overlap with those that have been implicated
in other autoimmune diseases. In this review, we will first
briefly review this rapidly expanding area and then discuss
other approaches that have implicated genetic pathways in
SSc in an attempt to better understand disease pathogenesis.
Immune Genes Implicated by Large-Scale Genetic Studies
Prior to the past 10 years, beyond the HLA region, no clear SSc
genetic susceptibility loci had been identified. However, with
the advent of advances in genetic technologies and the devel-
opment of national and multinational case–control cohorts,
there have been an increasing number of studies that have iden-
tified significant genetic associations with systemic sclerosis. In
this review, we will focus on loci that have been identified as
genomewide significant and those that have been replicated.
Using genetic association results obtained for other auto-
immune diseases including systemic lupus erythematosus and
rheumatoid arthritis to identify candidate genes, significant
associations have been identified between SSc and single nu-
cleotide polymorphisms in the BANK1, BLK, CD226, IL2RA,
IL12RB, KCNA5, IRF5, STAT4, TNFAIP3, TNFSF4, and
TLR2 genes [26–40].
The advent of GWAS allowed for confirmation of previ-
ously reported associations with the MHC region, IRF5, and
STAT4 [41–43], and identified CD247 as a disease-associated
locus [44]. Subsequent GWAS and GWA follow-up studies
have identified IRF8 [43, 44], PSORS1C1 [45], IL12RB1 [46,
47], IL12RB2 [35], and CSK [39] loci as genomewide signif-
icant. In addition to these loci, at least two studies have con-
firmed significant association (p<1*10−4
) at the TNFAIP3,
TNFSF4, ATG5, SCHIP1-IL12A, and DNASE1L3 loci
(Table 1). While the evidence confirming their association is
not yet available, studies have now identified an additional 17
loci that have been demonstrated to have associations with
SSc (p*10−4
>p>5*10−8
). These associations are summarized
in Table 2, while Fig. 1 illustrates how many of these poly-
morphisms may contribute to disease pathogenesis.
While most of these studies have been extensively
reviewed elsewhere [48, 49], three new studies in the past year
have shed additional insights into the immunogenetics of SSc.
In one of the largest genetic studies to date, Mayes et al. ge-
notyped 1833 SSc cases and 3466 controls with the
Immunochip, a custom SNP genotyping array that provides
high-density mapping of autoimmune disease-associated loci
[50]. Using this approach, the authors identified novel
Table 1 Confirmed genomewide significant non-HLA associations or studies with two independent replications with p<5*10−4
Symbol Gene name Locus SNP Approach Case/control SSc phenotype OR p value
ATG5 [50] Autophagy-related 5 6q25 rs9373839 Immunochip 1833/3466 SSc 1.19 3.8*10−8
CD247 [44, 45] T cell receptor zeta-chain 1q22 rs2056626 GWAS 2296/5171 SSc 0.82 3.4*10−9
CSK [39] c-src 15q24 rs1378942 GWA FU 5270/8326 SSc 1.20 5.0*10−12
DNASE1L3 [50] Deoxyribonuclease I-like 3 3p14 rs35646470 Immunochip 1833/3466 ACA (and all) 2.03 4.3*10−31
IL12RB1 [47] IL-12 receptor beta-1 19p13 rs2305743 GWA FU 8697/5032 SSc 0.81 4.3*10−10
IL12RB2 [35] IL-12 receptor beta-2 1p31 rs3790567 GWA FU 3344/3848 SSc 1.17 2.8*10−9
IRF5 [44, 45] Interferon response factor 5 7q32 rs10488631 GWAS 2296/5171 SSc 1.49 3.8*10−14
IRF8 [64] Interferon response factor 8 7p12 rs11642873 GWAS 3360/10,143 lcSSc 0.75 2.3*10−12
PSORS1C1 [45] Psoriasis susceptibility 1 candidate 1 6p21 rs3130573 GWAS 564/1776 SSc 1.25 5.7*10−10
SCHIP1-IL12A [50] Schwannomin interacting protein
1/interleukin 12 alpha
3q25 rs77583790 Immunochip 1833/3466 SSc (lcSSc) 2.57 1.2*10−11
STAT4 [44, 45] Signal Transducer and activator
of transcription 4
2q32 rs3821236 GWAS 2296/5171 SSc 1.30 3.9*10−9
TNFAIP3 [28, 37] TNF-associated interacting protein 3 6q23 rs5029939 CG 1202/1196 SSc 2.08 1.2*10−7
TNFSF4 [9, 31, 93] TNF superfamily member 4 1q25 rs2205960 CG 1031/1014 ACA+ 1.33 1.3*10−5
Genes that have been shown to be significant in two or more studies are in italics
lcSSC limited cutaneous systemic sclerosis, SNP single nucleotide polymorphism, OR odds ratio, CG candidate gene, GWAS genomewide association
study, GWA FU GWAS follow-up study, SSc systemic sclerosis, ATA anti-topoisomerase I antibody, ACA anti-centromere antibody, SScPAH SSc-
associated pulmonary arterial hypertension
21 Page 2 of 11 Curr Rheumatol Rep (2015) 17: 21
3. associations at the DNASE1L3, SCHIP1-IL12A, and ATG5
loci [50]. Additionally, this work allowed dense HLA
mapping stratified by antibody status (centromere and
topoisomerase); using this large collection, and employing
imputation and conditional analysis, they were able to
identify a model composed of six polymorphic amino acid
positions and seven SNPs which explains all observed
associations in the HLA region in SSc and its serological
subphenotypes. In a second study by Martin et al., the
authors performed a meta-analysis of previous GWAS in-
cluding both SSc and systemic lupus erythematosus (SLE)
patients for a total of 6835 cases and 14,274 controls [51].
After replication of top hits in an independent SSc case–con-
trol study, this study identified novel SSc associations at
KIAA0319L and the previously described SLE susceptibility
loci PXK and JAZF1. An additional GWA follow-up study
identified a genomewide significant association of SSc with
polymorphism near PPAR-γ [52], a gene implicated in metab-
olism, immunity, and protection from fibrosis [53].
Pathways and Potential Biomarkers Implicated
by Human Transcriptomic and Proteomic Studies
While genomic technologies have yielded major insights into
genetic predisposition, utilization of other Bomics^ ap-
proaches, including transcriptomics and proteomics, has
yielded additional important insights into pathways activated
during SSc and in different patient subsets.
Microarray Intrinsic Subsets
Given the availability of skin as a target tissue in SSc, tran-
scription profiling of skin biopsies from scleroderma patients
has been undertaken and has yielded significant insights into
scleroderma. Microarray studies have identified pathways that
are activated in patients with disease and also identified novel
patient subsets based on molecular expression patterns. Be-
yond the clinical classification of limited and diffuse SSc, the
lack of biomarkers to explain patient heterogeneity has been a
major limitation in identifying patients with different progno-
ses, and skin microarray has identified novel ways of evaluat-
ing SSc patients. Furthermore, the gene expression pattern has
been shown to serve as a genetic biomarker for skin severity as
a 44-gene subset can predict patients’ modified Rodnan skin
score (MRSS), a validated SSc-specific skin disease severity
score [54, 55].
Skin biopsy microarrays are not only able to distinguish
SSc from normal skin but also have proven helpful to classify
SSc patients into fibroproliferative, inflammatory, limited, and
normal-like subsets based on a core set of genes known as an
Bintrinsic subset^ [54]. Michael Whitfield and colleagues
have subsequently confirmed the validity of these subsets
[55–58] and utilized them to better understand molecular strat-
ification of patients.
Table 2 Additional SSc genetic associations with one study with p value between 5*10−4
and 5*10−8
Symbol Gene name Locus SNP Approach Case/control SSc
phenotype
OR p value
BANK1 [27, 94] B cell scaffold protein with ankyrin repeats 1 4q24 rs10516487 CG 1295/1137 dcSSc 1.30 4.0*10−4
BLK/C8orf13 [32, 85] B lymphocyte kinase/chromosome 8
open reading frame 13
8p23 rs2736349 CG 1639/1416 SSc 1.27 6.8*10−5
CD226 [33] Cluster of differentiation 226 18q22 rs763361 CG 1990/1642 SSc 1.22 5.7*10−5
GRB10 [64] Growth factor receptor-bound protein 10 7p12 rs12540874 GWAS 3360/10,143 lcSSc 1.15 1.3*10−6
IL2RA [40] IL-2 receptor alpha 10p15 rs2104286 CG 3023/2735 ACA+ 1.30 2.1*10−4
JAZF1 [51] JAZF zinc finger 1 7p15 rs1685352 GWAS 2761/3720 SSc 1.14 3.6*10−5
KCNA5 [30] Potassium voltage-gated channel,
shaker-related subfamily, member 5
12p13 rs10744676 CG 1576/1033 SScPAH 0.64 3.0*10−4
KIAA0319L [51] KIAA0319L 1p34 rs2275247 GWAS 2761/3720 SSc (lc) 1.46 3.9*10−6
NKFB1 [39] Nuclear factor kappa beta 1 4q24 rs1598859 GWA FU 5270/8326 SSc 1.14 1.0*10−6
PPARG [52] Peroxisome proliferator-activated
receptor gamma
3p25 rs310746 GWA FU 2921/6963 SSc 1.25 5.0*10−7
PSD3 [39] Pleckstrin and Sec7 domain-containing 3 8p22 rs10096702 GWA FU 5270/8326 SSc 1.18 3.0*10−7
PXK [51] PX domain-containing serine/threonine kinase 3p14 rs2176082 GWAS 2761/3720 SSc (ACA) 1.21 4.4*10−7
RHOB1 [45] Ras homolog family B 2p24 rs13021401 GWAS 564/1776 SSc 1.21 3.7*10−6
RPL41 [64] Ribosomal protein L41 12q13 rs11171747 GWAS 1699/10,143 dcSSc 1.23 6.0*10−8
SOX5 [64] Sex-determining region Y-box 5 12p12 rs11047102 GWAS 1791/10,143 ACA+ 1.36 1.4*10−7
TLR2 [36] Toll-like receptor 2 4q32 rs5743704 CG 1622/1462 SSc 2.24 3.0*10−4
TNIP1 [45] TNFAIP3 interacting protein 1 5q32 rs2233287 GWA FU 4389/7611 SSc 1.19 1.9*10−4
Curr Rheumatol Rep (2015) 17: 21 Page 3 of 11 21
4. The inflammatory group, marked by genes from the
immune system response and inflammatory response
Gene Ontology pathways, also includes upregulation of
interferon-inducible genes, genes involved in vasculature
development, and genes associated with fibrosis [54,
55]. This group tends to include patients with aggressive skin
disease but more robust response to immunosuppressive treat-
ment (mycophenolate mofetil) [58]. In contrast, the
fibroproliferative group expresses genes from the mitosis,
chromosome segregation, and DNA metabolic process path-
ways and tends to be more treatment refractory [54, 55, 58].
While initially thought to be intrinsic and identifying sta-
ble disease subsets [55], subsequent studies have shown
that individual patients can change subsets both over time
and in response to treatment with mycophenolate mofetil
[58]. While not the primary pathway identified in unbi-
ased analyses, the TGF-β pathway has been shown to be
activated in patients with a fibroproliferative intrinsic sub-
set; this also correlates with downregulation of the
PPAR-γ pathway [56, 59].
Interferon-Inducible Signature
In peripheral blood and PBMCs, microarray studies have
identified that roughly half of SSc patients possess an inter-
feron signature similar to that seen in SLE and other autoim-
mune diseases [60–62]. Other studies have shown that
plasmacytoid dendritic cells (pDCs) are the primary source
of the interferon [63]. Given this finding, along with the asso-
ciation of SSc with polymorphisms in interferon regulatory
factors IRF5 and IRF8 [44, 64], the interferon pathway may
be playing a critical role in modulating SSc pathogenesis [65].
One study demonstrated that the plasma interferon score was
higher in SSc patients than controls and correlated with
Medsger disease severity index and pulmonary function pa-
rameters [66].
CXCL4
Proteomic analysis is still in its infancy but holds tremendous
promise for the identification of potential biomarkers. In a
Fig. 1 Schematic of cellular roles for molecules genetically implicated in
SSc pathogenesis. Tissue injury leads to release of self antigens and
subsequent cell-mediated (via MHC) and innate (via TLRs) immune ac-
tivation. Cells implicated in SSc and molecules genetically implicated in
SSc (italicized, boxed) are emphasized. Cell interaction and cell products
lead to immune-mediated fibroblast activation and subsequent tissue
fibrosis
21 Page 4 of 11 Curr Rheumatol Rep (2015) 17: 21
5. recent study, proteomewide analysis showed that CXCL4 is
the predominant protein secreted by pDCs in SSc, both in
circulation and in skin [67]. The levels seen in SSc patients
were substantially higher than those seen in other autoimmune
diseases such as SLE and ankylosing spondylitis, higher in
diffuse cutaneous than limited cutaneous disease, and higher
in earlier dcSSc than in long-standing disease. Furthermore,
levels correlated with skin and lung fibrosis and with pulmo-
nary arterial hypertension, indicating that this may represent a
novel disease-specific biomarker with prognostic
significance.
In another study which used proteomics from pDCs to
identify novel biomarkers, plasma levels of the Toll-like re-
ceptor agonist S100A8/9 were found to be elevated in SSc
patients compared to controls [68].
Insights From Rare Sclerodermatous Diseases
Cancer-Associated RNA Polymerase III Antibody SSc
Anti-RNA polymerase 3 antibodies are observed in roughly
10 % of SSc patients although prevalence is variable based on
genetics and geography [69]. Joseph et al. performed an ele-
gant study to determine whether RNA polymerase III antibod-
ies may derive from cancer among the subset of SSc patients
who develop them [70]. In previous studies, RNA pol III
patients have been identified as being at a significantly in-
creased risk of cancer and also of having a cancer diagnosis
prior to or near the time of SSc diagnosis [71, 72]. Joseph et al.
successfully isolated tumor DNA from histologic slides and
identified mutations in the POLR3 gene or loss of heterozy-
gosity in six of eight patients with cancer and RNA polymer-
ase III antibodies and no patients with SSc and cancer with
other autoantibodies [70]. Furthermore, immunologic charac-
terization of the CD4+ T cells from patients with POLR3 tu-
mor mutations demonstrated the presence of Tcells reactive to
the RPC1 peptide (an RNA polymerase III subunit encoded
by POLR3) that are patient, peptide, and HLA specific.
Stiff Skin Syndrome
The stiff skin syndrome (SSS) is a rare Mendelian disorder
caused by mutations in the fibrillin gene, the same gene re-
sponsible for Marfan syndrome, which is associated with
highly elastic connective tissue. Unlike SSc, SSS does not
portend other internal organ manifestations and is not associ-
ated with autoimmunity or vasculopathy [73]. Gerber et al.
[74] attempted to recapitulate this disease utilizing a knock-
in strategy to create a strain of mice carrying a mutated
fibrillin-1 allele identified in patients with SSS and another
mutant mouse strain (D1545E) harboring an integrin mutation
predicted to disrupt integrin binding to fibrillin-1. Both mutant
mice strains developed dermal fibrosis accompanied by ex-
cess collagen deposition as well as progressive loss of intra-
dermal adipose tissue. In addition to skin fibrosis, the trans-
genic mice spontaneously developed marked cutaneous in-
flammation, with accumulation of pDCs, Th2- and Th17-
skewed T helper cells, and plasma cells. Moreover, these mice
developed circulating anti-topoisomerase I antibodies. Because
fibrillin-1 is known to modulate TGF-β signaling and because
the SSS fibrillin-1 mutations specifically affect the integrin-
binding domain, the authors speculated that the stiff skin phe-
notype might be due to unchecked TGF-β activation and in-
creased TGF-β signaling [74]. Interestingly, treatment of the
mutant mice with a neutralizing antibody to TGF-β, as well
as alpha-1 integrin-activating antibody, was able to reverse the
fibrotic process and mitigate the immune dysregulation.
Insights From Genetic Mouse Models of Scleroderma
The most commonly utilized mouse model of scleroderma
remains the bleomycin model which nicely recapitulates many
of the seminal features of the disease, including fibrosis and
inflammation. However, because this is a chemical injury
model with largely unknown molecular mechanism(s), multi-
ple attempts have been made to engineer or discover genetic
mouse models that may yield important insights into disease
pathogenesis. While none of the genetic models to date ade-
quately recapitulates all disease features, the growing diversity
of models enables researchers to study different aspects of
disease and determine the effects of modulation of multiple
relevant pathways on outcomes important in SSc. In Table 3,
we summarize 11 different genetic models which appear to
recapitulate important aspects of SSc.
Tsk1 and Stiff Skin Syndrome Models: Fibrillin-1
The tight skin mouse, which shows prominent spontaneous
fibrosis of the hypodermis, has been widely used as a genetic
mouse model of SSc, although exactly how this model corre-
sponds with human disease has been difficult to explain. The
Tsk1 mouse has now been shown to be caused by mutations in
the fibrillin gene [75–77]. In the recent model by Gerber et al.
discussed in BStiff Skin Syndrome,^ knock-in human fibrillin-
1 mutations were introduced and the mice demonstrated a
phenotype that included dermal fibrosis, inflammation, and
autoimmunity. It is interesting that previous descriptions of
human SSS have not described either a significant inflamma-
tory component in the skin lesions nor described the autoim-
munity that is seen in the mice. Whether this represents poor
clinical characterization of human SSS due to its rarity or
whether the mouse model more closely resembles SSc than
SSS, the mouse model clearly recapitulates aspects of human
fibrotic skin disease. It is not clear, however, whether it is a
Curr Rheumatol Rep (2015) 17: 21 Page 5 of 11 21
6. model of SSS, SSc, or a unique murine entity that lacks a
human correlate.
Tsk2
The Tsk2 mouse may more closely mimic human disease (it
spontaneously displays fibrosis, inflammation, and autoim-
munity); while the ENU-induced locus is on chromosome 1,
genetic studies are ongoing to elucidate the genetic lesion in
this model [78].
TGF-β pathway
TGF-β is widely cited as the pathogenic molecule in SSc and
other forms of fibrosis. Mice with an inducible constitutively
active TGF-β receptor I (TGF-β RI) mutation driven by a
fibroblast-specific promoter have been generated and demon-
strate fibrosis of the dermis and fibrotic thickening of small
blood vessel walls in the lung and kidney [79]. Primary skin
fibroblasts from these mice showed elevated expression of
downstream TGF-β targets, reproducing the hallmark bio-
chemical phenotype of explanted SSc dermal fibroblasts.
Constitutive activation of TGF-β in fibroblasts is therefore
sufficient to induce a fibrotic phenotype.
Wnt and PPAR-γ pathways
The Wnt pathway is a key developmental and homeostatic
pathway in multiple tissues, and alterations in the pathway
have been shown to be pro-fibrotic. Patients with SSc have
increased fibroblast levels of β-catenin, a key Wnt mediator.
Mice with fibroblast-specific β-catenin ablation rapidly devel-
op skin fibrosis [80], while pharmacologic treatment with Wnt
antagonists can reverse skin fibrosis [81]. Transgenic mice
expressing Wnt-10b in adipose tissue showed not only pro-
gressive loss of subcutaneous adipose tissue but also dermal
fibrosis, increased collagen deposition, fibroblast activation,
and myofibroblast accumulation [82]. Wnt activity correlated
with collagen gene expression in these biopsy specimens. This
suggests that Wnt-10b switches differentiation of mesenchy-
mal cells toward myofibroblasts by inducing a fibrogenic tran-
scriptional program while suppressing adipogenesis.
Fibroblast-specific deletion of PPAR-γ, the master regula-
tor of adipogenesis, results in enhanced susceptibility to
bleomycin-induced skin fibrosis and enhanced sensitivity of
fibroblasts to TGF-β1 in PPAR-γ-deficient mice. These re-
sults indicate that PPAR-γ suppresses fibrogenesis [83].
Fra-2 and sUPAR: Models of SSc Vasculopathy
The expression of the transcription factor Fra-2 is upregulated
in SSc patients and in different mouse models of SSc. Fra-2
transgenic mice have been shown to develop spontaneous skin
Table3Geneticmousemodelsofscleroderma
ModelGeneCell-specificablationPathwayOrgansFibrosisVasculopathyInflammationAutoimmunity
TSK1[95]Fibrillin-1–TGF-betaSkin(hypodermis)YYNY
Tsk2[96]Chr1,genenotcurrentlyknown–TGF-betaSkinYYYY
SSSmouse[74]Fibrillin-1–TGF-betaSkinYYYY
TBRICA;Cr-ER[79]TGF-betareceptorFibroblastTGF-betaSkin,lung,kidney,vasculatureYYNN
TBRIIdk[102]TGF-betareceptorFibroblastTGF-betaSkin,lungSomeSomeYN
CTGFTg[97]CTGFFibroblastTGF-betaSkin,lung,kidney,vasculatureYYNN
CaveolinKO[98]CAV1––Lung,heart,pulmonaryarteryYYNN
Fli1[99]FLI1––SkinYYNN
Fra-2[101]Fos-relatedprotein2–PDGFSkin,pulmonaryartery,vasculatureYY––
sUPAR[87]Solubleurokinase-typeplasminogen
activatorreceptor
–UPA/plasminSkin,lungYYN–
Wnt-10b[82]Wnt-10bAdiposeWntSkinYNN–
21 Page 6 of 11 Curr Rheumatol Rep (2015) 17: 21
7. and lung fibrosis and vasculopathy (including skin
microvasculopathy and pulmonary artery enlargement consis-
tent with pulmonary hypertension) which are mediated by
TGF-β and PDGF [84]. This is particularly important because
most other mouse models (both genetic and inducible) do not
demonstrate significant vasculopathy which is a key clinical
feature of SSc [86].
Urokinase-type plasminogen activator receptor (uPAR) has
been implicated in SSc microvasculopathy. Mice deficient in
soluble uPAR demonstrate skin fibrosis as well as decreased
microvessels which were shown to have undergone apoptosis
[87]. While these mice did demonstrate lung disease, it was
more reminiscent of chronic pneumonia than of pulmonary
fibrosis.
SSc Heterogeneity and Genetics
Nearly all of the genetic associations reviewed in BImmune
Genes Implicated by Large-Scale Genetic Studies^ represent
genes involved in immunity, and associations with the same
genes have been reported in multiple other autoimmune dis-
eases. Despite the prominent fibrotic features of SSc, genetic
studies to date have not identified major risk factors related to
genes involved in the process of fibrosis [88]. Interestingly,
recent studies have looked at SSc lung disease and idiopathic
pulmonary fibrosis (IPF) and found little genetic overlap, sug-
gesting that the fibrosis in SSc and ILD may be distinct [89,
90]. One explanation for the lack of fibrotic genes identified
may be that the design of many of the studies, including the
recent Immunochip and SSc–SLE pan-meta-GWAS, was bi-
ased toward identification of immune system loci. Because a
core set of known fibrotic genes has not yet been identified, a
similar strategy to enhance the identification of fibrotic genes
is not as easily achievable. Furthermore, if fibrosis is second-
ary to either epigenetic changes or a process secondary to an
aberrant immune response (see Fig. 1), that could explain the
lack of fibrotic genes identified in otherwise largely agnostic
GWAS.
Identification of genetic variants that contribute to SSc has
been complicated by the complexity and heterogeneity of the
disease. SSc behaves more like a syndrome than a unified
disease as SSc patients can have multiple different clinical
phenotypes and patterns of organ involvement. As personal-
ized medicine advances, we may learn that there are in fact
multiple or even numerous unique disease entities that are all
currently classified as SSc. Cancer-associated RNA polymer-
ase III antibody-associated SSc [70] is probably one example
of molecularly defined disease that has a novel pathogenesis
and may respond differently to treatment. For the purpose of
understanding disease, heterogeneity likely hampers scien-
tists’ ability to identify genetic risk loci because cases repre-
sent patients with a multitude of SSc-related conditions.
The contribution of race/ethnicity represents another com-
plicating factor; there are genetic differences between and
across ethnicities which affect prevalence and relative impor-
tance of genetic susceptibility loci. Furthermore, Caucasian
and Asian populations have been well represented in genetic
studies compared to African-Americans, who have more se-
vere SSc manifestations. Indeed, all of the large-scale genetic
studies reviewed in BImmune Genes Implicated by Large-
Scale Genetic Studies^ have focused on Caucasian popula-
tions, and further analysis of other ethnic groups may yield
new genetic insights, as has been seen in other diseases [91].
Attempts to subclassify patients are frequently made on the
basis of skin disease (limited versus diffuse cutaneous dis-
ease), autoantibodies, and organ involvement (particularly
lung disease [3, 92]). There has already been substantial work
to determine whether genetic associations are present only in
certain SSc subtypes (mostly lcSSc/dcSSc and ATA/ACA).
However, limited clinical phenotyping makes it difficult to
study homogeneous SSc patient groups that represent disease
endophenotypes and may have more distinct and clear-cut
genetic predispositions.
More recently, the use of skin biopsy microarray intrinsic
subsets as a way of classifying disease has been proposed as
identifying disease endophenotypes [92]. Identification of ad-
ditional novel biomarkers may further enable biological clas-
sification into subtypes, and that should hopefully contribute
to better understanding of patients’ genetic susceptibility to
SSc. With functional studies such as gene expression analysis,
another challenge for understanding SSc is studying specific
classes of SSc cells and tissues. Because SSc has multiple
diverse manifestations, it is difficult to determine which cell
type is most appropriate for investigation. A great deal of
focus has been on dermal fibroblasts, but whether these cells
are primary or secondary in disease pathogenesis remains un-
clear. Similarly, while immune cells are clearly relevant, it
remains unclear whether lymphocytes, dendritic cells,
macrophages, or other cell types are most relevant. While
the vasculature and lungs are clearly important, these tis-
sues remain difficult to acquire. Skin biopsy remains an
important tissue which is accessible and is of diagnostic/
prognostic significance, but because skin is very hetero-
geneous (keratinocytes, dermal fibroblasts, immune cells,
adipocytes, vessels), analysis of gene expression may be
obscured by genetic Bnoise^ from multiple cell types. As
cell-based assays and systems biology approaches devel-
op further, it will be increasingly important to identify
which cells to study and to study them in isolation in
order to understand the biological relevance of SSc genet-
ic associations. Figure 1 illustrates which cell types the
identified genetic variants affect and how these may con-
tribute to the pathogenesis of SSc.
With the advent of next-generation sequencing, there
is also a movement toward personalized genomics.
Curr Rheumatol Rep (2015) 17: 21 Page 7 of 11 21
8. Despite the recent identification of a number of suscep-
tibility loci in SSc as reviewed in BImmune Genes Im-
plicated by Large-Scale Genetic Studies,^ other than
HLA, the variants identified are not likely to be the causative
variants. This is because GWAS utilize common (with the
minor allele >5 % in the population) single nucleotide poly-
morphisms that are in linkage disequilibrium with implicated
causative genetic variants. Furthermore, the total contribution
of susceptibility loci discovered by GWA and follow-up stud-
ies explains only a fraction of the Bheritability^ of the disease.
These concepts lead many to believe that there exist many rare
variants with relatively large effects, which, in aggregate, ac-
count for the remaining prevalence of the disorder. These so-
called private mutations can be identified with exome or
whole genome sequencing and may be able to explain indi-
vidual patients’ genetic predisposition for disease. While such
private mutations may be present in only one or very few
affected individuals, identification of multiple private muta-
tions within genes or in common pathways may also help
elucidate disease pathogenesis that is more broadly relevant
and inform the development of therapies that may help classes
of patients.
While genetics clearly contributes importantly to SSc path-
ogenesis, it does not fully explain disease susceptibility. En-
vironmental factors and associated epigenetic changes likely
contribute importantly as well [23]. In addition to better epi-
demiologic studies to identify exposures such as chemicals
and viruses that may influence disease risk, studies of epige-
netic DNA modifications may also be crucial to understanding
the molecular processes central to SSc.
SSc remains one of the most mysterious and difficult to
treat diseases in modern medicine. While many studies have
provided novel insights into genetic risk factors and pathways
that are dysregulated, there remains a huge gap between cur-
rent knowledge, understanding of pathogenesis, and the iden-
tification of effective treatments. The heterogeneity of SSc
complicates its understanding, but modern omics technologies
and better clinical phenotyping are contributing toward the
goal of SSc being a disease that can be understood with sys-
tems biology tools and more effectively treated with a person-
alized medicine approach.
Compliance with Ethics Guidelines
Conflict of Interest Benjamin D. Korman and Lindsey A. Criswell
declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the Creative
Commons Attribution License which permits any use, distribution, and
reproduction in any medium, provided the original author(s) and the
source are credited.
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