Interaction and Association Analysis of a Type 1 Diabetes Susceptibility Locus on Chromosome 5q11-q13 and the 7q32 Chromosomal Region in Scandinavian Families

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Abstract
We have previously reported suggestive linkage to chromosome 5p13-q13 in type 1 diabetic families. ISL1, a transcription factor involved in pancreas development, maps to this region. Sequencing of the ISL1 gene in patients and control subjects identified seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families (P < 0.04). To identify possible interactions with the 5q11-q13 region, we applied pathway-restricted linkage analysis by analyzing for effects from regions encoding other transcription factors that are active during pancreas development and maintenance of insulin production. Linkage analysis allowing for interaction between 5q11-q13 and 7q32 resulted in an increase of logarithm of odds from 2.2 to 5.3. This increase was estimated to correspond to a P value P < 0.05). We conclude that pathway-restricted linkage analysis assists in the identification of possible gene-gene interactions and that 5q11-q13 and 7q32 together constitute a significant susceptibility factor for type 1 diabetes.