Functional Variants in MBL2 Are Associated With Type 2 Diabetes and Pre-Diabetes Traits in Pima Indians and the Old Order Amish

Abstract Objective- MBL2 encodes the mannose-binding lectin which is a key player in the innate immune system, and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population which has a high prevalence of type 2 diabetes. Research design and methods- Nineteen tag Single Nucleotide Polymorphisms (SNPs) were genotyped in a population-based sample of 3501 full-heritage Pima Indians and selected SNPs were further genotyped in independent samples of Native Americans (n=3723) and the Old Order Amish (n=486) subjects. Results- Two variants, a promoter SNP (rs11003125) at -550bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83 were associated with type 2 diabetes in the full-heritage Pima Indians [odds ratio (OR)=1.30 per copy of the G allele for rs1103125, P=0.0007; OR=1.30 per copy of the glycine allele for rs1800450, P=0.002, adjusted for age, sex, birth-year and family membership]. These associations replicated in an independent Native American sample (OR=1.19, P=0.04 for rs11003125) and a Caucasian sample, the Old Order Amish (OR=1.51, P=0.004 for rs1103125; OR=2.38, P=0.003 for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P=0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation and family membership). Conclusions- Our data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.