Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes.

CONTEXT

Epidemiological data suggest a common genetic susceptibility to type 1 diabetes (T1D) and autoimmune thyroid disease (AITD).

OBJECTIVE

Our objective was to identify the joint susceptibility genes for T1D and AITD.

DESIGN

We conducted a family-based linkage and association study.

SETTING

The study took place at an academic medical center.

PARTICIPANTS

Participants included 55 multiplex families (290 individuals) in which T1D and AITD clustered (T1D-AITD families).

MAIN OUTCOME MEASURES

We conducted tests for linkage and family-based associations (transmission disequilibrium test) with four candidate genes: human leukocyte antigen (HLA), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), insulin variable number of tandem repeats (VNTR), and thyroglobulin.

RESULTS

Linkage evidence to HLA appeared when subjects with either T1D or AITD were considered affected [maximum LOD score (MLS), 2.2]. The major HLA haplotype contributing to the shared susceptibility was DR3-DQB1*0201, with DR3 conferring most of the shared risk. The CTLA-4 gene showed evidence for linkage only when individuals with both T1D and AITD were considered affected (MLS, 1.7), and the insulin VNTR showed evidence for linkage when individuals with either T1D or AITD were considered affected (MLS, 1.9); i.e. it may contribute to the familial aggregation of T1D and AITD.

CONCLUSIONS

The HLA class II locus contributes to the shared risk for T1D and AITD, and the major HLA haplotype contributing to this association is DR3-DQB1*0201. Additional non-HLA loci contribute to the joint susceptibility to T1D and AITD, and two potential candidates include the CTLA-4 and insulin VNTR loci.