Abstract
Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.S. participants from six diverse background groups (Mainland groups: Mexican, Central American, and South American; and Caribbean groups: Puerto Rican, Cuban, and Dominican). We estimated the SNP-diabetes association in the six groups and in the combined sample. We found that the risk alleles occur in two non-reference haplotypes in HCHS/SOL, as in the SIGMA Mexicans. The haplotype frequencies were very similar between SIGMA Mexicans and the HCHS/SOL Mainland groups, but different in the Caribbean groups. The SLC16A11 sequence variants were significantly associated with risk for diabetes in the Mexican origin group (P = 0.025), replicating the SIGMA findings. However, these variants were not significantly associated with diabetes in a combined analysis of all groups, although the power to detect such effects was 85% (assuming homogeneity of effects among the groups). Additional analyses performed separately in each of the five non-Mexican origin groups were not significant. We also analyzed (1) exclusion of young controls and, (2) SNP by BMI interactions, but neither was significant in the HCHS/SOL data. The previously reported effects of SLC16A11 variants on diabetes in Mexican samples was replicated in a large Mexican-American sample, but these effects were not significant in five non-Mexican Hispanic/Latino groups sampled from U.S. populations. Lack of replication in the HCHS/SOL non-Mexicans, and in the entire HCHS/SOL sample combined may represent underlying genetic heterogeneity. These results indicate a need for future genetic research to consider heterogeneity of the Hispanic/Latino population in the assessment of disease risk, but add to the evidence suggesting SLC16A11 as a potential therapeutic target for type 2 diabetes.
Highlights
Hispanics/Latinos represent the largest ethnic minority population in the United States[1]
We examined the single nucleotide polymorphisms (SNPs) associations with diabetes reported by Williams et al, in U.S Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes individuals who self-identified as having Mexican, Central American, South American, Puerto Rican, Dominican or Cuban background or heritage (Table 1)
Genotypes for the five SNPs constituting the risk haplotype defined by the SIGMA consortium are either assayed on the array or very well imputed in HCHS/SOL (Table 2). We performed both a Spearman correlation analysis as well as a genotype comparison between the data used in this analysis and the HCHS/SOL whole genome sequence (WGS) data, wherein we found that the concordance between the two platforms was high – all SNPS had a correlation coefficient greater than 0.99
Summary
Hispanics/Latinos represent the largest ethnic minority population in the United States[1]. They are a diverse group of individuals, varying greatly from one another genetically, socially, economically, and culturally, despite usually being classified as a single ethnic group. Williams et al reported an SLC16A11 haplotype, defined by 5 single nucleotide polymorphisms (SNPs), as a common risk factor for diabetes in Mexican and Mexican-American populations studied by the SIGMA consortium[3]. We examined the SNP associations with diabetes reported by Williams et al, in U.S Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes individuals who self-identified as having Mexican, Central American, South American, Puerto Rican, Dominican or Cuban background or heritage (Table 1). We tested these five SNPs for interaction with obesity in their effects on diabetes to test associations described by Traurig et al.[4], as described below
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