Diabetes Mellitus, Insulin-Dependent, 20

A number sign (#) is used with this entry because a form of insulin-dependent diabetes mellitus can be caused by heterozygous mutation in the HNF1A gene (142410) on chromosome 12q24.2.

For a phenotypic description and a discussion of genetic heterogeneity of insulin-dependent diabetes mellitus, see IDDM (222100).

Mapping

The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. Case-control comparisons identified an independent association signal for type 1 diabetes at rs17696736 in the C12ORF30 gene on chromosome 12q24 (p = 1.51 x 10(-14)).

In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the Wellcome Trust Case Control Consortium (2007) study, Todd et al. (2007) confirmed the previously reported association of rs17696736 on chromosome 12q24 (p = 1.35 x 10(-9); combined with WTCCC, p = 2.31 x 10(-16)). The association with rs17696736 led to the identification of a nonsynonymous SNP (rs3184504) in exon 3 of the SH2B3 gene (605093) that was sufficient to model the association of the entire region (p = 1.73 x 10(-21)).

In 8,064 patients with type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and 9,339 controls, Smyth et al. (2008) confirmed association with rs3184504 in the SH2B3 gene (combined p = 5.62 x 10(-31)).

Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs3184504 at 12q24.12 (p = 2.8 x 10(-27)).

Molecular Genetics

Yamada et al. (1997) screened the HNF1A gene for mutations in Japanese subjects with IDDM. Mutations were identified in 3 (5.5%) of the 55 unrelated subjects with IDDM (e.g., 142410.0001, 142410.0005, and 142410.0006). None of these mutations was found in 200 normal chromosomes from nondiabetic subjects. The results indicated that mutation in the HNF1A gene can lead to development not only of early-onset NIDDM (see 142410.0008) but also of IDDM. In a subclassification of IDDM, the HNF1A-deficient type should be distinguished from the classic type of autoimmune-based IDDM in Japanese. All of these mutations were heterozygous.

Yoshiuchi et al. (2001) identified a frameshift mutation in the HNF1A gene (142410.0012) in a family with a strong history of type 1 diabetes.