Examining genetic heterogeneity of type 2 diabetes in obese and normal weight families in the San Luis Valley genetic study

Several investigators have conducted large population based linkage studies to identify a putative genetic etiology for type 2 diabetes, but results have been inconsistent. When genetic heterogeneity is present, pooling these families may actually dilute the power to detect a major type 2 diabetes susceptibility gene. Specifically, genetic heterogeneity may exist if susceptibility genes for the disease differ between obese and normal weight families. In the present study, Hispanic families in the San Luis Valley of Colorado were ascertained when two or more siblings were affected with type 2 diabetes. Siblings, and parents when available, had blood samples collected, genetic markers analyzed, and lifestyle factors assessed.;Results indicated that a few genetic markers were being shared by affected siblings at a higher proportion than expected. Specifically, excess allele sharing was exhibited by single nucleotide polymorphisms for the calpain-10 gene, SNP 43 and 44, cytochrome p450 cyp19 gene, and the protein phosphatase-1 regulatory subunit 3 gene. Significant evidence for linkage was demonstrated by the single nucleotide polymorphisms for the LAMIN A gene after adjusting for age and dietary fat intake, and for the peroxisome proliferator-activated receptor gamma gene after adjusting for age and dietary fat intake, and age and physical inactivity, independently. The finding for the peroxisome proliferator-activated receptor gamma gene became stronger when the analysis was restricted to normal weight families. Further testing, utilizing other statistical models, revealed the presence of a calpain-10 SNP 63 interaction with dietary fat intake.;Given consistent linkage results demonstrated between type 2 diabetes and the peroxisome proliferator-activated receptor gamma gene in both pooled and normal weight families after adjustment for covariates, further studies of the gene in this population are warranted. These studies may lead to the identification of a common genetic susceptibility gene segregating in Hispanic families in Colorado at high risk for type 2 diabetes. While the evidence for a gene environment interaction wasn't overwhelming for the calpain-10 gene, recent publications have elucidated its role and further testing in this population could yield interesting results when enough families can be categorized by both exposure level and weight class.