Evidence for association of the TCF7 locus with type I diabetes.
The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have been genotyped for the HLA class I and class II loci and, recently, for a genome-wide panel of single-nucleotide polymorphisms (SNPs). In addition, multiple SNPs in specific candidate genes have been genotyped in these families in an attempt to evaluate previously reported T1D associations, including the C883A (Pro-Thr) polymorphism in exon 2 of TCF7, a T-cell transcription factor. The TCF7 883A allele was associated with T1D in subjects with T1D not carrying the high-risk HLA genotype DR3/DR4. A panel of 11 SNPs in TCF7 was genotyped in 2092 families from 9 cohorts of the T1DGC. SNPs at two positions in TCF7 were associated with T1D. One associated SNP, C883A (rs5742913), was reported earlier to have a T1D association. A second SNP, rs17653687, represents a novel T1D susceptibility allele in TCF7. After stratification on the high T1D risk DR3/DR4 genotype, the variant (A) allele of C883A was significantly associated with T1D among non-DR3/DR4 cases (transmission=55.8%, P=0.004; OR=1.26) but was not significantly associated in the DR3/DR4 patient subgroup, replicating the earlier report. The reference A allele of intronic SNP rs17653687 was modestly associated with T1D in both DR3/DR4 strata (transmission=54.4% in DR3/DR4; P=0.03; transmission=52.9% in non-DR3/DR4; P=0.03). These results support the previously reported association of the non-synonymous Pro-Thr SNP in TCF7 with T1D, and suggest that other alleles at this locus may also confer risk.
Erlich
H A
HA
Department of Human Genetics, Discovery Research, Roche Molecular Systems Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, USA. Henry.Erlich@roche.com
Valdes
A M
AM
Julier
C
C
Mirel
D
D
Noble
J A
JA
D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051822:T Cell Transcription Factor 1 / Q000235:genetics* / Q000276:immunology
D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human