Genetic and functional studies of lithogenic loci genetic variants in cholesterol gallstone disease

Abstract

newline Worldwide, the gallbladder stone disease is extremely prevalent in adult population. newlineThe broad geographical, ethnic, and cultural unevenness in the incidence of newlinegallbladder stones reflects its multi factorial etiology encompassing both the genetic newlineand the environmental factors. Quite a lot of evidences suggest that genetic factors newlinemight elucidate the inter-individual variability in the susceptibility of cholesterol newlinegallbladder stones. Till date there was no satisfactory research study in Indian newlinepopulation that could elucidate the complex pathophysiology of gallstone disease. newlineConsequently, we have carried out a case control analysis. This study included 610 newlinegallstone patients (USG positive) and 315 healthy controls. On the basis of newlinepathophysiology and epidemiology of gallstone disease, cholesterol metabolism, newlinecholesterol transport, sex steroids and their receptors, bile acid transport mucins, newlinegallbladder motility and adrenergic receptor pathways, we hypothesized that the newlinegenetic variants in genes belonging to these pathways may provide insights into newlinemolecular mechanism of gallstone formation and development. Subsequently, a newlinepanel of 48 SNPs was prepared from 47 candidate genes, using SNP database from newlineHapmap, 1000 genome and Tagger SNPs in Linkage Disequilibrium. Based on newlineAllelic discrimination by Sequenom Mass ARRAY platform iPLEX Gold Reaction, newlinefor genotype association study, differences in genotype distributions were calculated newlineapplying a log additive logistic regression model adjusted for gender and age. All 48 newlineSNPs from 47 candidate genes have been proposed to play a substantial role in the newlinegenetic predisposition of gallbladder stone disease particularly in European newlinepopulations. Eight out of the 48 SNPs did not followed HWE and so were removed newlinefrom further analysis. newlineLogistic regression analysis of the 40 investigated genetic variants with gallstone newlinedisease revealed significant associations (Pandlt;0.05) of following SNPs namely, FGFR4 newliners351855, CYP7A1 rs6471717, APOE rs7412, TM4SF4 rs9843304,