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.

Beyond type 2 diabetes, obesity and hypertension: an axis including sleep apnea, left ventricular hypertrophy, endothelial dysfunction, and aortic stiffness among Mexican Americans in Starr County, Texas.

BACKGROUND: There is an increasing appreciation for a series of less traditional risk factors that should not be ignored when considering type 2 diabetes, obesity, hypertension, and cardiovascular disease. These include aortic stiffness, cardiac structure, impaired endothelial function and obstructive sleep apnea. They are associated to varying degrees with each disease categorization and with each other. It is not clear whether they represent additional complications, concomitants or antecedents of disease. Starr County, Texas, with its predominantly Mexican American population has been shown previously to bear a disproportionate burden of the major disease categories, but little is known about the distribution of these less traditional factors. METHODS: Type 2 diabetes, obesity and hypertension frequencies were determined through a systematic survey of Starr County conducted from 2002 to 2006. Individuals from this examination and an enriched set with type 2 diabetes were re-examined from 2010 to 2014 including assessment of cardiac structure, sleep apnea, endothelial function and aortic stiffness. Individual and combined frequencies of these inter-related (i.e., axis) conditions were estimated and associations evaluated. RESULTS: Household screening of 5230 individuals aged 20 years and above followed by direct physical assessment of 1610 identified 23.7 % of men and 26.7 % of women with type 2 diabetes, 46.2 and 49.5 % of men and women, respectively with obesity and 32.1 and 32.4 % with hypertension. Evaluation of pulse wave velocity, left ventricular mass, endothelial function and sleep apnea identified 22.3, 12.7, 48.6 and 45.2 % of men as having "at risk" values for each condition, respectively. Corresponding numbers in women were 16.0, 17.9, 23.6 and 28.8 %. Cumulatively, 88 % of the population has one or more of these while 50 % have three or more. CONCLUSIONS: The full axis of conditions is high among Mexican Americans in Starr County, Texas. Individual and joint patterns suggest a genesis well before overt disease. Whether they are all mediated by common underlying factors or whether there exist multiple mechanisms remains to be seen.

Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs.

We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci.

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.

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait.

Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a disproportionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (∼10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index ≥ 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues.

Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies.

OBJECTIVE: The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a Mexican-American population. RESEARCH DESIGN AND METHODS: We genotyped 116,204 single nucleotide polymorphisms (SNPs) in 281 Mexican Americans with type 2 diabetes and 280 random Mexican Americans from Starr County, Texas, using the Affymetrix GeneChip Human Mapping 100K set. Allelic association exact tests were calculated. Our most significant SNPs were compared with results from other type 2 diabetes genome-wide association studies (GWASs). Proportions of African, European, and Asian ancestry were estimated from the HapMap samples using structure for each individual to rule out spurious association due to population substructure. RESULTS: We observed more significant allelic associations than expected genome wide, as empirically assessed by permutation (14 below a P of 1 x 10(-4) [8.7 expected]). No significant differences were observed between the proportion of ancestry estimates in the case and random control sets, suggesting that the association results were not likely confounded by substructure. A query of our top approximately 1% of SNPs (P < 0.01) revealed SNPs in or near four genes that showed evidence for association (P < 0.05) in multiple other GWAS interrogated: rs979752 and rs10500641 near UBQLNL and OR52H1 on chromosome 11, rs2773080 and rs3922812 in or near RALGPS2 on chromosome 1, and rs1509957 near EGR2 on chromosome 10. CONCLUSIONS: We identified several SNPs with suggestive evidence for replicated association with type 2 diabetes that merit further investigation.