ABSTRACT: The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians.Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5' flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n=150)/control (n=150) group for early-onset T2DM (onset age <25 years); (ii) a case (n=362)/control (n=127) group for obesity; (iii) a large (n=1,311, cases n=810/controls n=501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping.The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM (p=0.01-0.04) in the case-control study, but were not associated with obesity in the obesity case-control study, nor associated with T2DM (at any age) or body-mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output (p=0.02). rs6574549 was associated with fasting insulin (p=0.02), insulin action (p=0.04), and energy expenditure (p=0.02). None of these nominal associations remained statistically significant after corrections for multiple testing.We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population.
