Diabetologia (1996) 39:594-599 Diabetologia 9Springer-Verlag 1996 Diabetes susceptibility at IDDM2cannot be positively mapped to the VNTR locus of the insulin gene A. Doria, J. Lee, J.H. Warram, A. S. Krolewski Section on Epidemiology and Genetics, Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Summary An inconsistency has come to light be- tween the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin- dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM pa- tients and 107 non-diabetic control subjects that also show significant association with a marker 5 ' of the INS locus. Patients and control subjects were geno- typed at INS~ + 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS5OO- RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS~ + 1140 allele' +' were significantly more fre- quent among IDDM patients than among control subjects (73 vs 45 %, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele' +' (53 vs 31%, p < 0.001) giv- ing an odds ratio of 2.6 (95 %CI 1.6-4.2). By multilo- cus analysis, the TH/RsaI allele ' +' identified a sub- set of INS~ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ra- tio = 5.4, 95 %CI 2.9-10.4) than allele + 1140 ' +' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymor- phism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM. [Diabetologia (1996) 39: 594-599] Reywords Insulin-dependent diabetes mellitus, insu- lin gene, tyrosine hydroxylase gene, VNTR, linkage disequilibrium. Two years ago, a paper was published by Lucassen et al. [1] reporting that the insulin-dependent diabe- tes mellitus (IDDM) susceptibility locus on chromo- some 11p15.5 (IDDM2) is restricted to a 4.1 kilobase (kb) region corresponding to the insulin (INS) locus Received: 21 July 1995 and in revised form: 21 November 1995 Corresponding author." Dr. A. Doria, Section on Epidemiology and Genetics, Joslin Diabetes Center, One Joslin Place, Bos- ton, MA 02215, USA Abbreviations: IDDM, Insulin-dependent diabetes mellitus; INS, insulin locus; VNTR, variable number of tandem repeats; TH, tyrosine hydroxylase; IGF-2, insulin-like growth factor-2; DGGE, denaturing gradient gel electrophoresis. and a 5' adjacent VNTR (variable number of tandem repeats) polymorphism. Based on this report, more recent papers [2-5] have further argued that the VNTR polymorphism is the IDDM2 susceptibility lo- cus, since any other polymorphism in the INS gene can be excluded as a primary determinant of IDDM by 'cross-match haplotype' analysis [6, 7]. We have re-examined the data published by Lucassen et al. [1] and found that the restriction of IDDM2 to a 4.1- kb region is inconsistent with their own data, so the conclusions of the subsequent reports may be errone- ous. Lucassen et al. [1] examined the risk of IDDM ac- cording to allelic variation at several polymorphisms which are located in the tyrosine hydroxylase