Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.
Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C>T) and rs12255372 (IVS4G>T)] which showed strong linkage disequilibrium (D' = 0.88, p<0.001; R(2)=0.76, p<0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p<0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=<0.0001. A similar effect was observed in 919 T2D Indian Asians [OR=1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G>T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.
Department of Medicine, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College Medical School, London, WC1E 6JF, UK. rmhaseh@ucl.ac.uk
Steve E
SE
Humphries
David
D
Gable
Jackie A
JA
Cooper
Helen
H
Ireland
Jeffrey W
JW
Stephens
Steven J
SJ
Hurel
Ka Wah
KW
Li
Jutta
J
Palmen
Michelle A
MA
Miller
Francesco P
FP
Cappuccio
Robert
R
Elkeles
Ian
I
Godsland
George J
GJ
Miller
Philippa J
PJ
Talmud
D000483:Alleles; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044469:Racial Groups / Q000235:genetics*; D012307:Risk Factors; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D006113:United Kingdom; D044465:White People / Q000235:genetics
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein