Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals

AIMS/HYPOTHESIS: We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. METHOD: Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. RESULT: The top signals (unadjusted p value <1×10(−5)) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52× 10(−6)) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. CONCLUSIONS/INTERPRETATION: In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues

Characterization of ancestral and derived Y-chromosome haplotypes of New World native populations.

We analyze the allelic polymorphisms in seven Y-specific microsatellite loci and a Y-specific alphoid system with 27 variants (alphah I-XXVII), in a total of 89 Y chromosomes carrying the DYS199T allele and belonging to populations representing Amerindian and Na-Dene linguistic groups. Since there are no indications of recurrence for the DYS199C-->T transition, it is assumed that all DYS199T haplotypes derive from a single individual in whom the C-->T mutation occurred for the first time. We identified both the ancestral founder haplotype, 0A, of the DYS199T lineage and seven derived haplogroups diverging from the ancestral one by one to seven mutational steps. The 0A haplotype (5.7% of Native American chromosomes) had the following constitution: DYS199T, alphah II, DYS19/13, DYS389a/10, DYS389b/27, DYS390/24, DYS391/10, DYS392/14, and DYS393/13 (microsatellite alleles are indicated as number of repeats). We analyzed the Y-specific microsatellite mutation rate in 1,743 father-son transmissions, and we pooled our data with data in the literature, to obtain an average mutation rate of.0012. We estimated that the 0A haplotype has an average age of 22,770 years (minimum 13,500 years, maximum 58,700 years). Since the DYS199T allele is found with high frequency in Native American chromosomes, we propose that 0A is one of the most prevalent founder paternal lineages of New World aborigines

Diabetes Risk in Older Mexican Americans: Effects of Language Acculturation, Generation and Socioeconomic Status

The effect of language acculturation, socioeconomic status (SES), and immigrant generation on development of diabetes among Mexican Americans was evaluated in the Hispanic Established Population for the Epidemiologic Study of the Elderly (HEPESE). HEPESE is a longitudinal cohort study of 3,050 non-institutionalized Mexican Americans aged 65 years at baseline (1993-1994) from 5 Southwestern states. Diabetes incidence was ascertained in 4 follow-up surveys to 2004-05 by respondent self-reported physician-diagnosis of diabetes, high blood glucose, or sugar in the urine. Language of interview, immigrant generation, gender, age, education, family history of diabetes, smoking status, alcohol use, health insurance type and self-reported height and weight were assessed. High socioeconomic status (SES) was defined by high school graduation and non-Medicaid insurance. Cox's proportional hazards models were fit to evaluate the effects of language acculturation, generation and SES on incident diabetes. 845 of 3,050 (27.7%) Mexican Americans had diabetes at baseline and were younger, more educated, and more likely to have health insurance than those without diabetes. Risk of developing diabetes increased for Spanish-speaking respondents with low SES from 1st to 3rd generation (HR = 1.76, 95% CI = 1.02-3.03) and from 2nd to 3rd generation (HR = 2.15, 95% CI = 1.20-3.84). Among English-speaking, high SES participants, generation had a protective effect on developing diabetes: HR = 0.45 (95% CI = 0.22-0.91) when comparing 3rd versus 1st generation. The effect of language acculturation and immigrant generation on incident diabetes is moderated by SES status in HEPESE participants