Abstract 5094: OSBPL10 is Identified as a Novel Susceptible Gene for Peripheral Arterial Disease by Genome-Wide Association Study in Japan
As our society is rapidly aging, diabetes are widely spreading and the massive loss caused by peripheral arterial disease (PAD) is becoming a serious social issue. Neither the mechanism of the generation of PAD nor the determinant factors of its responsiveness to treatment is clear yet. To clarify the genetic basis of PAD, we have carried out genome-wide association study among the Japanese people. About 250,000 single-nucleotide polymorphisms (SNPs) out of each Japanese case-control sample were tested. According to the result of the first screening of 200 PAD cases and 1,600 controls, 4,000 out of 250,000 SNPs were found significantly associated. Then these 4,000 SNPs of 713 PAD cases and new 1600 controls were tried for the second screening, revealing 160 SNPs identified were significantly associated. For validation, we performed age and sex matched re-analysis and discarded false positive SNPs. As a result, several candidate genes that may affect PAD susceptibility were identified. Interestingly, the three SNPs (rs1902341, rs2168422, rs6779621) with the smallest P values (P=5.1×10−6, P=3.9×10−5, P=5.5×10−6, respectively) all located in the 5th intron of the oxysterol binding protein like 10 (OSBPL10) gene. The result of the haplotype analysis of this gene based on the information from HapMap, a coding SNP (cSNP, rs2290532) belonging to the same linkage disequiliblium block as the three SNPs above were found in the neighboring 6th exon. For further investigation of the associations, we genotyped these 3 iSNPs and 1 cSNP out of the samples from public medical examinations (n=2,900). This analysis showed that the risk allele of this cSNP had significant correlation to both the high serum LDL cholesterol and total cholesterol level. The expression of human OSBPL10 was observed by the northern blot analysis. OSBPL10 is expressed in kidney, lung, heart (especially in aorta), placenta and spleen as well as in vascular EC and SMC. Overexpressed OSBPL10 is localized mainly in the endoplasmic reticulum. These results suggest that OSBPL10 may contribute to the regulation of cholesterol homeostasis in the vasculature system. In conclusion, our SNPs analysis indicates the possibility of OSBLP10 being associated with atherosclerosis or PAD.