Development of an SNP map in the peri-MHC region on the human chromosome 6 as a tool to identify candidate genes for inflammatory bowel disease
Many genes of the MHC region, located on the human chromosome 6p21, encode proteins with high relevance in immune response and regulation. Linkage to chromosome 6p21 had been established for several inflammatory and autoimmune diseases, one is inflammatory bowel disease (IBD). IBD is a relapsing chronic inflammatory disorder of the gastrointestinal tract influenced by complex genetic, immunological and environmental factors. In this study a single nucleotide polymorphism (SNP) based map, consisting of 142 SNPs and covering about 20 Mb, was developed in the MHC linkage region of IBD with the aim to identify disease susceptibility genes. Association using case control study design and family based transmission distortion technique (TDT) was analysed in a population of 847 IBD affected individuals, their healthy parents and 550 unrelated blood donors. Five candidate genes were analysed in more detail (HLA-DPA1, MAPK14, MAKP13, BRPF3 and TREM1). The results suggest that the observed associations might be caused through linkage disequilibrium (LD) with other candidate genes. Extent and structure of LD in the region was screened in a 10 Mb region with 920 SNPs in 45 US-Americans of European ancestry, followed by a detailed investigation in 3.53 Mb of the MHC, with 320 SNPs in 550 German, 78 British, 93 Norwegian, and 45 US-Americans of African ancestry. Clustering of Lewontin's D' between SNPs and correlation of LD between populations were implemented. High LD levels and clear haplotype block structures were found to intermingle with areas of low or medium LD, and with areas of high LD without clear structure. The data provide a basis for analysis and set-up of further association studies in the MHC region, and show the importance of a thorough investigation of LD structures in a region of interest for disease gene detection with association methods.
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