Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects.
BACKGROUND
The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T(4) to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance.


OBJECTIVE
The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a beta-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits.


METHODS
The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients.


RESULTS
We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area under the serum insulin curve during an oral glucose tolerance test (P = 0.03) and elevated fasting plasma glucose (P = 0.02) in homozygous Ala92 allele carriers, the latter strengthened by epistasis with the ADRB2 Gly16Arg variant in a double recessive model (P = 0.004). However, after permutation procedure, performed to correct for multiple hypothesis testing, the associations did not reach study-wide significance.


CONCLUSIONS
The DIO2 Thr92Ala variant does not confer an increased risk of T2D, obesity, or insulin resistance.
Grarup
Niels
N
Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark. ngrp@steno.dk
Andersen
Mette K
MK
Andreasen
Camilla H
CH
Albrechtsen
Anders
A
Borch-Johnsen
Knut
K
Jørgensen
Torben
T
Auwerx
Johan
J
Schmitz
Ole
O
Hansen
Torben
T
Pedersen
Oluf
O
D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000209:etiology / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D044465:White People; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D000097564:Iodothyronine Deiodinase Type II