Jacob L. McCauley, Ph.D. - US grants

PROJECT SUMMARY This application proposes to address the critical need to include underrepresented populations in genomic research, with the purpose of enhancing our understanding of the genetic and phenotypic landscape of multiple sclerosis in the Hispanic population. Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease of the central nervous system affecting more than 400,000 individuals in the United States. MS is characterized by chronic inflammation, myelin loss, gliosis, and varying degrees of axonal pathology which impair saltatory conduction along axons that is necessary for normal functioning of nerve impulses. MS has an undetermined etiology and results in episodic or progressive neurological dysfunction. Although life span is modestly shortened, most patients experience increasing disability and consequent deterioration in quality of life. MS thus carries a significant morbidity that takes an immeasurable toll on the patients and their family members. The involvement of genetic factors in MS has long been appreciated. However, the clinical heterogeneity and complex etiology of MS have been confounding factors for genetic studies. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, further gene discoveries were limited until late 2007. At that time, we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. This result was confirmed in the first genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC). These breakthroughs, along with both statistical and technological advances, have led to the identification and confirmed association of >190 genetic variants for MS susceptibility. Despite these advances, we have only uncovered a relatively small proportion of the genetic influences in MS. Much is yet to be understood regarding the role of these and other genes in MS. We must explore how these known genetic factors influence not only disease susceptibility, but disease outcomes, therapeutics, and responses to environmental exposures. While current research findings are unraveling the genetic underpinnings of individuals with Northern European genetic ancestry, large genetic studies of MS in Hispanics have yet to be realized. Moreover, the generalization of current findings to individuals of different genetic ancestry is a significant and unanswered question, especially in light of the reported differences in prevalence, clinical course, and progression of MS across various ancestral populations. We hypothesize that observed phenotypic differences between racial/ethnic populations are influenced by population-specific genetic factors. Our proposal seeks to broaden our understanding of the genetic etiology of multiple sclerosis, with a specific focus on performing the first battery of comprehensive analyses to elucidate the genetic and phenotypic manifestations of MS in the diverse Hispanic population, an understudied group that represents a rapidly growing percentage of the US population. To achieve this, we propose three specific aims: 1) Characterize established MS risk loci within a Hispanic patient cohort; 2) Perform genome-wide scans to identify novel genetic loci for MS susceptibility; 3) Explore genotype-phenotype correlations across racial/ethnic populations.

? DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a common and devastating immune-mediated disease in which the mucosal immune system abnormally recognizes the intestinal bacterial flora leading to chronic inflammation. The causes of IBD may lie in the interplay between host response genes and a microbiome with pathogenic properties. Most IBD studies have focused on Caucasian populations in North America and Europe. In the US, the population of Hispanics is rising rapidly as is the incidence of IBD in this group-yet litte is known about the genes that may confer susceptibility or factors such as the microbiome that may be promoting disease expression. The most recent meta-analysis of IBD susceptibility, using genome-wide data, identified 140 CD specific loci in studies of European descent populations. We have a unique opportunity to study the interface of genetics, immunology, and the microbiome in South Florida Hispanic patients with CD. A preliminary analysis shows that although the genetic burden is similar between Hispanics and NHWs, the frequency of specific IBD variants is not. We have found that the microbiota of foreign-born Hispanic patients differs from US-born Hispanic IBD patients. Based on these observations, we hypothesize that distinct innate immune pathways are altered in Hispanics with IBD shaped by their underlying admixed genetic ancestry. We further hypothesize that the mucosal microbiome of Hispanic immigrants compared with US-born Hispanics or NHWs will demonstrate a shift towards increasingly dysbiotic microbiota that will be reflected in gene expression changes in the mucosa. To test this hypothesis, we will pursue three related but independently-relevant Specifc Aims. In Aim 1, we will Explore IBD risk alleles and genetic structure in Hispanic patients with CD and its relationship to phenotypic outcomes. We plan to increase our collection to 1000 Hispanic patients with IBD which has never been done before. We will look at the relationship of known and novel Hispanic-specific genes and phenotype. Aim 2 will examine microbiome changes in Hispanic immigrants compared with first-generation Hispanic-Americans or non-Hispanic whites with CD. We have developed an innovative strategy involving deep sequencing of the microbiota in lamina propria phagocytes. Aim 3, will analyze innate immune responses in the mucosa of Hispanic immigrants compared with first-generation Hispanic-Americans and non-Hispanic whites with CD. We will collaborate with Dr. Eric Schadt to integrate the data gathered in the three aims to identify pathways that have not been previously explored in such a comprehensive, layered fashion. By focusing on targeted genomic, transcriptomic, and microbiome differences between immigrant and first-generation Hispanic-Americans with CD, we hope to edify how genes and microbes interact to result in diverse phenotypic manifestations of CD. We will use this as a platform to leverage the ongoing efforts of the NIDDK IBD Genetics Consortium (IBDGC) in Caucasian-Americans.