Genetic variants associated with circulating liver injury markers in Mexican Americans, a population at risk for non-alcoholic fatty liver disease.

Objective: Mexican Americans are disproportionally affected by non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma. Noninvasive means to identify those in this population at high risk for these diseases are urgently needed. Approach: The Cameron County Hispanic Cohort (CCHC) is a population-based cohort with high rates of obesity (51%), type 2 diabetes (28%) and NAFLD (49%). In a subgroup of 564 CCHC subjects, we evaluated 339 genetic variants previously reported to be associated with liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in United Kingdom and Japanese cohorts. Results: Association was confirmed for 86 variants. Among them, 27 had higher effect allele frequency in the CCHC than in the United Kingdom and Japanese cohorts, and 16 had stronger associations with AST and ALT than rs738409 (PNPLA3). These included rs17710008 (MYCT1), rs2519093 (ABO), rs1801690 (APOH), rs10409243 (S1PR2), rs1800759 (LOC100507053) and rs2491441 (RGL1), which were also associated with steatosis and/or liver fibrosis measured by vibration-controlled transient elastography. Main contributors to advanced fibrosis risk were rs11240351 (CNTN2), rs1800759 (LOC100507053), rs738409 (PNPLA3) and rs1801690 (APOH), with advanced fibrosis detected in 37.5% of subjects with 3 of these 4 variants [AOR = 11.6 (95% CI) = 3.8-35.3]. AST- and ALT-associated variants implicated distinct pathways (ethanol and galactose degradation versus antigen presentation and B cell development). Finally, 8 variants, including rs62292950 (DNAJC13), were associated with gut microbiome changes. Conclusion: These genotype-phenotype findings may have utility in risk modeling and disease prevention in this high-risk population.

Gut Microbiome Alterations Associated with Diabetes in Mexican Americans in South Texas.

Mexican Americans have a high prevalence of diabetes and burden of diabetes-related complications, highlighting the need for novel preventive strategies and noninvasive predictors of diabetes risk tailored to this population. Changes in the gut microbiome have the potential to predict diabetes. Here, we aimed to identify alterations in the gut microbiome associated with diabetes in the high-risk population of Mexican Americans in South Texas. Stool samples were collected from 216 subjects from the population-based Cameron County Hispanic Cohort. Among them, 75 had type 2 diabetes. Taxonomic and functional profiling of the stool samples were assessed by 16S and shotgun metagenomic sequencing, and the influence of genetic factors was explored. The gut microbiome of subjects with diabetes was enriched with proinflammatory Proteobacteria members (Enterobacteriaceae, Escherichia-Shigella) and depleted of butyrate-producing Clostridiales members (Faecalibacterium prausnitzii, Peptostreptococcaceae, and Clostridium sensu stricto 1). The accompanying metagenomic changes in subjects with diabetes suggested dysregulated amino acid metabolism, reduced galacturonate and glucuronate catabolism (correlating with Faecalibacterium prausnitzii abundance), and enriched heme biosynthesis (correlating with Enterobacteriaceae abundance). Polymorphism rs7129790 near MMP27 was strongly associated with high Proteobacteria abundance and was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. In conclusion, Mexican Americans in South Texas with diabetes display distinct gut microbiome and metagenomic signatures. These signatures may have utility in risk modeling and disease prevention in this high-risk population. IMPORTANCE The gut microbiome composition varies across ethnicities and geographical locations, yet studies on diabetes-associated microbiome changes specific to high-risk Mexican Americans are lacking. Here, we aimed to identify specific alterations associated with diabetes in this population, as well as host genetic factors that may explain increased disease susceptibility in this ethnic group. Using samples from a population-based cohort of Mexican Americans with a high prevalence of obesity and diabetes, we confirmed findings from studies on other ethnicities that suggested promotion of a chronic proinflammatory environment, loss of butyrate production, and compromised intestinal barrier integrity. High abundance of proinflammatory Proteobacteria was associated with a polymorphism that was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. Validation of microbiome-based risk models for diabetes should be evaluated in prospective cohort studies.

Admixture mapping in two Mexican samples identifies significant associations of locus ancestry with triglyceride levels in the BUD13/ZNF259/APOA5 region and fine mapping points to rs964184 as the main driver of the association signal.

We carried out an admixture mapping study of lipid traits in two samples from Mexico City. Native American locus ancestry was significantly associated with triglyceride levels in a broad region of chromosome 11 overlapping the BUD13, ZNF259 and APOA5 genes. In our fine-mapping analysis of this region using dense genome-wide data, rs964184 is the only marker included in the 99% credible set of SNPs, providing strong support for rs964184 as the causal variant within this region. The frequency of the allele associated with increased triglyceride concentrations (rs964184-G) is between 30-40% higher in Native American populations from Mexico than in European populations. The evidence currently available for this variant indicates that it may be exerting its effect through three potential mechanisms: 1) modification of enhancer activity, 2) regulation of the expression of several genes in cis and/or trans, or 3) modification of the methylation patterns of the promoter of the APOA5 gene.

Genome-Wide Association Study of Staphylococcus aureus Carriage in a Community-Based Sample of Mexican-Americans in Starr County, Texas.

Staphylococcus aureus is the number one cause of hospital-acquired infections. Understanding host pathogen interactions is paramount to the development of more effective treatment and prevention strategies. Therefore, whole exome sequence and chip-based genotype data were used to conduct rare variant and genome-wide association analyses in a Mexican-American cohort from Starr County, Texas to identify genes and variants associated with S. aureus nasal carriage. Unlike most studies of S. aureus that are based on hospitalized populations, this study used a representative community sample. Two nasal swabs were collected from participants (n = 858) 11-17 days apart between October 2009 and December 2013, screened for the presence of S. aureus, and then classified as either persistent, intermittent, or non-carriers. The chip-based and exome sequence-based single variant association analyses identified 1 genome-wide significant region (KAT2B) for intermittent and 11 regions suggestively associated with persistent or intermittent S. aureus carriage. We also report top findings from gene-based burden analyses of rare functional variation. Notably, we observed marked differences between signals associated with persistent and intermittent carriage. In single variant analyses of persistent carriage, 7 of 9 genes in suggestively associated regions and all 5 top gene-based findings are associated with cell growth or tight junction integrity or are structural constituents of the cytoskeleton, suggesting that variation in genes associated with persistent carriage impact cellular integrity and morphology.