Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort

Abstract

BackgroundRecently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).MethodsINVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.ResultsWe observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.ConclusionsOur results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.Trial registrationclinicaltrials.gov (NCT00133692)

The Association between HMGA1 rs146052672 Variant and Type 2 Diabetes: A Transethnic Meta-Analysis

“…The majority of the study populations was Caucasian (n = 3); one involved Han Chinese population, two Hispanic Americans, and one African Americans. In Hispanic Americans, a much lower minor allele frequency for the HMGA1 gene variant rs146052672 was observed by Karnes et al [ 24 ], with respect to that reported later by Pullinger et al [ 25 ]. Hispanic Americans include Mexican Americans, Puerto Ricans, Cubans and several other ethnic backgrounds.…”

“…Genetic diversity in these Hispanic American subgroups has been identified as an important factor explaining the difference in the risk of T2D: higher in Mexican Americans than other US Hispanics [ 44 , 45 ]. Hispanics recruited by Pullinger et al were predominantly of Mexican origin [ 25 ], whereas it is not clear where Hispanic participants were recruited in the other study of Karnes et al [ 24 ]. All studies adjusted for age.…”

“…All studies adjusted for age. Four papers adjusted also for gender and BMI [ 9 , 22 – 24 ]. Four studies employed the TaqMan allelic discrimination technique and one employed the High Resolution Melting (HRM) method.…”

“…The pooled OR estimate for all sensitivity analyses performed did not modify substantially the conclusions of the overall meta-analysis. To determine whether modification of the inclusion criteria affected the results of this meta-analysis, we initially performed sensitivity analysis excluding the study by Karnes et al [ 24 ], given that it was the only study performed in a specific subgroup population (hypertensive and coronary artery disease patients). The corresponding pooled OR did not remarkably change (OR 1.39; 95% CI 1.17, 1.66; P < 0.001), confirming the stability of the results ( Fig 3A ).…”

“…Association of this variant with T2D was not replicated in a subsequent study that involved a heterogeneous French population [ 22 ]. Later, however, it was reported that the HMGA1 rs146052672 variant was significantly associated with T2D in a Chinese population study [ 23 ], whereas non univocal results were obtained among Hispanic-American populations of the US [ 24 , 25 ]. Furthermore, evidence implicating the rs146052672 variant as one conferring cross-ethnicity risk for the development of insulin-resistance-related conditions has been provided more recently, in a case-control study from Italy and Turkey, in which an increased risk of metabolic syndrome was seen among carriers of this variant [ 26 ].…”