A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.
BACKGROUND
Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones.


METHODS
We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation.


RESULTS
A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels.


CONCLUSIONS
This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.
Panicker
Vijay
V
Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, United Kingdom.
Cluett
Christie
C
Shields
Beverley
B
Murray
Anna
A
Parnell
Kirstie S
KS
Perry
John R B
JR
Weedon
Michael N
MN
Singleton
Andrew
A
Hernandez
Dena
D
Evans
Jonathan
J
Durant
Claire
C
Ferrucci
Luigi
L
Melzer
David
D
Saravanan
Ponnusamy
P
Visser
Theo J
TJ
Ceresini
Graziano
G
Hattersley
Andrew T
AT
Vaidya
Bijay
B
Dayan
Colin M
CM
Frayling
Timothy M
TM
D000328:Adult; D000368:Aged; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood*; D014284:Triiodothyronine / Q000097:blood*
D014284:Triiodothyronine; D013972:Thyrotropin; D007453:Iodide Peroxidase; D013974:Thyroxine