Genetic analyses of a type 2 diabetes susceptibility locus at chromosome 1Q21-Q24

• Main Author: Duesing, Konsta
• Published: Imperial College London 2008
• Subjects: 572.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485423

Diabetes mellitus is a heterogeneous metabolic disorder characterised by high blood glucose levels. Type 2 diabetes (T2D) is by far the most common form ofdiabetes, accounting for approximately 9095% ofdiabetic cases. Together with its close correlate, obesity, T2D is recognised as a public health problem ofepidemic proportions. ' The aim ofthis thesis was to evaluate the evidence that common polymorphisms in four select positional candidate genes at the chromosome 1q21-q24 T2D susceptibility locus - PBX], LMNA, APOA2 and CRP - show association with T2D in a French Caucasian case-control cohort of over 3,000 individuals. Several PBX] SNPs, including the G21S coding SNP rs2275558 (P = 0.013, OR 1.17 [95% CI 1.031.32]), were nominally associated with T2D, but the strongest result was obtained with the intron 2 variant rs2792248 (P = 0.004, OR 1.21 [95% CI 1.06-1.39]). However, none ofthe associations survived multiple testing adjustment. At the LMNA locus, the synonymous exon 7 SNP rs505058 (D446D) showed the strongest evidence of association with T2D (P = 0.002; OR 1.31 [95% CI 1.111.57]) and this result survived adjustment for multiple testing. A meta-analysis ofrs505053 data from 7,811 participants provided support for a modest association ofrs505058 with TID (P = 0.002; OR 1.20 [95% CI 1.07-1.35]). No evidence for the contribution ofvariation at either the APOA2 or CRP genomic loci to TID susceptibiUty was found. In conclusion, the available data do not support a major effect ofcommon variation at these loci on TID susceptibility in Northern European Caucasians. Further large -scale SNP association studies and meta-analyses, deep resequencing efforts and CNV association studies are all required ifwe are to make progress in identifying the elusive TID susceptibility variants in the lq region.