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


METHODS
We conducted a family-based linkage and association study.


METHODS
The study took place at an academic medical center.


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


METHODS
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.
Golden
Brian
B
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Levin
Lara
L
Ban
Yoshiyuki
Y
Concepcion
Erlinda
E
Greenberg
David A
DA
Tomer
Yaron
Y
D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D015803:HLA-DR3 Antigen / Q000235:genetics; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D007328:Insulin / Q000235:genetics*; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D020080:Tandem Repeat Sequences; D013954:Thyroglobulin / Q000235:genetics; D013967:Thyroiditis, Autoimmune / Q000235:genetics*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D015803:HLA-DR3 Antigen; D007328:Insulin; D013954:Thyroglobulin