Brief Genetics Report The Variable Number of Tandem Repeats Upstream of the Insulin Gene Is a Susceptibility Locus for Latent Autoimmune Diabetes in Adults

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at 23HphI (odds ratio [OR] 0.42 [95% CI 0.31–0.58], P 2.4 10 ), A allele at 1,404Fnu4HI (0.50 [0.36–0.70], P 3.2 10 ), and C allele at 3,580MspI (0.55 [0.35–0.85], P 0.0046). As with type 1 diabetes, the 23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA. Diabetes 55:1890–1894, 2006 Latent autoimmune diabetes in adults (LADA) and type 1 (insulin dependent) diabetes are both characterized by islet autoimmunity, indicated by the presence of circulating islet autoantibodies. However, the later age of onset (after the peak of type 1 diabetes incidence) and less aggressive clinical course (no immediate requirement for insulin therapy) of LADA result in substantial clinical overlap with type 2 diabetes (non– insulin dependent) (1–3). Qualitative or quantitative differences in genetic susceptibility may underlie the marked variation in disease course and clinical presentation between LADA and type 1 diabetes. The insulin gene region (IDDM2) accounts for 10% of familial risk for type 1 diabetes (4). Most evidence indicates that the variable number of tandem repeats (VNTR) minisatellite (which maps upstream of the translation initiation site) is the probable etiological variant, though certain flanking single nucleotide polymorphisms (SNPs) that are highly correlated with VNTR variation may also play a role (5,6). In non-African populations, much of the variation in VNTR length (repeat unit number) and composition (repeat element sequence) can be captured by dichotomizing VNTR alleles into two classes: the short class I alleles (26–63 repeats) and longer class III alleles (141–209 repeats) (7). In type 1 diabetes, class I alleles confer susceptibility to disease and class III, protection (8). Because of strong linkage disequilibrium (LD) between VNTR allele structure and haplotypes spanning the insulin gene, this major division in VNTR structure can be assayed using the 23HphI SNP (9). Further refinement of type 1 diabetes susceptibility is possible by examining the finer structure within major VNTR classes. A discrete subgroup of class I alleles, termed “ID ,” has been reported to confer protection rather than susceptibility (7). Additionally, class IIIA and IIIB alleles may differ in the degree of protection they offer, an observation reflected in the designation of the extended haplotypes on which these alleles lie as the protective haplotypes (PHs) and very protective haplotypes (VPHs), respectively (9). However, recent reexamination of these subclass associations in additional samples has cast significant doubt on these latter observations (5). It is unclear whether these susceptibility effects of the insulin gene are evident in LADA and/or whether differences in VNTR-encoded susceptibility contribute to the clinical differences between LADA and type 1 diabetes. From Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.; the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.; the Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K.; the Centre for Diabetes and Metabolic Medicine, Bart’s and The London Queen Mary’s School of Medicine and Dentistry, London, U.K.; the School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K.; and the Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. Address correspondence and reprint requests to Anne Clark, Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7L J, U.K. E-mail: [email protected]. Received for publication 19 January 2006 and accepted in revised form 6 March 2006. HWE, Hardy-Weinburg equilibrium; LADA, latent autoimmune diabetes in adults; LD, linkage disequilibrium; PH, protective haplotype; SNP, single nucleotide polymorphism; UKPDS, U.K. Prospective Diabetes Study; VNTR, variable number of tandem repeats; VPH, very protective haplotype; W2 Repository, Warren 2 Repository; Exeter YT2D, Exeter Young-Onset type 2 Diabetes study. DOI: 10.2337/db06-0089 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.