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A Genome-Wide Search for Genes Involved in Type 2 Diabetes in a Recently Genetically Isolated Population From the Netherlands

Yurii S. Aulchenko^1,2, Norbert Vaessen¹, Peter Heutink³, Jan Pullen⁴, Pieter J.L.M. Snijders¹, Albert Hofman¹, Lodewijk A. Sandkuijl^5,6,, Jeanine J. Houwing-Duistermaat¹, Mark Edwards⁴, Simon Bennett⁴, Ben A. Oostra³, and Cornelia M. van Duijn¹

¹ Genetic Epidemiology Unit, Department of Epidemiology & Biostatistics, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
² Institute of Cytology and Genetics SD RAS, Novosibirsk, Russia
³ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
⁴ Oxagen Limited, Abingdon, U.K
⁵ Leiden University Medical Center, Leiden, the Netherlands

Multiple genes, interacting with the environment, contribute to the susceptibility to type 2 diabetes. We performed a genome-wide search to localize type 2 diabetes susceptibility genes in a recently genetically isolated population in the Netherlands. We identified 79 nuclear families with type 2 diabetes who were related within 13 generations and performed a 770-marker genome-wide scan search for shared founder alleles. Twenty-six markers yielded a logarithm of odds (LOD) score >0.59 (nominal P < 0.05), of which 7 reached LOD scores >1.17 (nominal P < 0.01). The strongest evidence for a type 2 diabetes locus was at marker D18S63 on chromosome 18p (LOD 2.3, P = 0.0006). This region was investigated further using additional markers. For one of these markers (D18S1105), we found a significant association with type 2 diabetes (odds ratio 6.7 [95% CI 1.5–30.7], P = 0.005 for the 97-bp allele, assuming a dominant model), which increased when limiting the analysis to patients with high BMI (12.25 [2.1–71], P = 0.003). A locus on chromosome 18p in patients with high BMI was suggested earlier by Parker et al. Our study is the first to confirm this locus.

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