Lack of Association of the Ala ⁴⁵Thr Polymorphism and Other Common Variants of the NeuroD Gene with Type 1 Diabetes

Variation in genes necessary for normal functioning and development of β-cells, e.g., NEUROD1, which encodes a transcription factor for the insulin gene and is important in β-cell development, causes maturity-onset diabetes of the young. Some studies have reported an association between a nonsynonymous Ala⁴⁵Thr (+182G→ A) single nucleotide polymorphism (SNP) in NEUROD1 and type 1 diabetes, but this result has not been consistently found. To clarify this, we genotyped Ala⁴⁵Thr in 2,434 type 1 diabetic families of European descent and Caucasian ethnicity from five different countries. Taking the allele frequency of 36% for Thr⁴⁵ and an odds ratio (OR) of 1.2, this sample provided >99% power to detect an association (P < 0.95). We could not confirm the association (P = 0.77). No evidence of population heterogeneity in the lack of association of Thr ⁴⁵ with type 1 diabetes was observed. To evaluate the possibility that another NEUROD1 variant was associated with type 1 diabetes, we resequenced the gene in 32 U.K. affected individuals and identified and genotyped all common SNPs (minor allele frequency >10%; n = 5) in 786 families. We report no evidence of association of these common variants in NEUROD1 and type 1 diabetes in these samples.