A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes.
Type 1 diabetes is an autoimmune disease with a Th1 phenotype in which insulin-producing beta-cells in the pancreas are destroyed. The T-cell-specific transcription factor TCF7 activates genes involved in immune regulation and is a candidate locus for genetic susceptibility to type 1 diabetes. A nonsynonymous single nucleotide polymorphism (SNP) (Pro to Thr) in the TCF7 gene, C883A, was examined in samples from 282 Caucasian multiplex type 1 diabetic families. HLA-DRB1 and -DQB1 genotypes were previously determined for these samples, allowing data stratification based on HLA-associated risk. The transmission disequilibrium test showed significant overtransmission of the A allele from fathers (64.1%, P < 0.007) and nonsignificant overtransmission (57.4%, P < 0.06) of the A allele to patients who do not carry the highest-risk HLA-DR3/DR4 genotype. Elliptical sib pair analysis showed significant associations of the A allele with type 1 diabetes in paternal transmissions (P < 0.03), transmissions to male children (P < 0.04), and in the non-DR3/DR4 group (P < 0.04). These data also suggest that TCF7 C883A may affect age of disease onset. Analysis of genotype data from surrounding SNPs suggests that this TCF7 polymorphism may itself represent a risk factor for type 1 diabetes.
Noble
Janelle A
JA
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. jnoble@chori.org
White
Amy M
AM
Lazzeroni
Laura C
LC
Valdes
Ana M
AM
Mirel
Daniel B
DB
Reynolds
Rebecca
R
Grupe
Andrew
A
Aud
Dee
D
Peltz
Gary
G
Erlich
Henry A
HA
D000225:Adenine; D002140:California; D003596:Cytosine; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020224:Expressed Sequence Tags; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D044465:White People / Q000235:genetics
D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D014157:Transcription Factors; D003596:Cytosine; D000225:Adenine