Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.
We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.
Helgason
Agnar
A
deCODE genetics, 101 Reykjavik, Iceland. agnar@decode.is
Pálsson
Snaebjörn
S
Thorleifsson
Gudmar
G
Grant
Struan F A
SF
Emilsson
Valur
V
Gunnarsdottir
Steinunn
S
Adeyemo
Adebowale
A
Chen
Yuanxiu
Y
Chen
Guanjie
G
Reynisdottir
Inga
I
Benediktsson
Rafn
R
Hinney
Anke
A
Hansen
Torben
T
Andersen
Gitte
G
Borch-Johnsen
Knut
K
Jorgensen
Torben
T
Schäfer
Helmut
H
Faruque
Mezbah
M
Doumatey
Ayo
A
Zhou
Jie
J
Wilensky
Robert L
RL
Reilly
Muredach P
MP
Rader
Daniel J
DJ
Bagger
Yu
Y
Christiansen
Claus
C
Sigurdsson
Gunnar
G
Hebebrand
Johannes
J
Pedersen
Oluf
O
Thorsteinsdottir
Unnur
U
Gulcher
Jeffrey R
JR
Kong
Augustine
A
Rotimi
Charles
C
Stefánsson
Kári
K
D044466:Asian People; D005075:Biological Evolution; D044383:Black People; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007055:Iceland; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012641:Selection, Genetic; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D044465:White People
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein