Subscribe to RSS
DOI: 10.1055/s-0030-1269606
Genetic variation in the human interleukin 4 (IL4) gene is associated with gallstone susceptibility
Introduction: Quantitative trait locus mapping in the inbred mouse model of cholesterol cholelithiasis identified a gallstone-susceptibility (Lith) locus on mouse chromosome 11, which co-localizes with the Il4 gene. In addition, ablation of Il4 promoted cholesterol gallstone formation in the mouse model of cholelithiasis rendering IL4 an interesting LITH-candidate gene. Methods: To systematically explore the IL4 gene as a LITH gene in humans, we performed a genetic association study in gallstone carriers (N=184) and control subjects without evidence for gallstones (N=833) from a self-contained population of Sorbs from Saxony. Based on the HapMap database, three haplotype-tagging single nucleotide polymorphisms (SNPs) (rs2243290, rs2227284 and rs2243263) capturing the genetic variation of IL4 (r2 cut-off 0.8; minor allele frequency >0.05) were genotyped in cases and controls employing the TaqMan method. Data were analyzed in the additive model using logistic regression including age, sex and body mass index as covariates. Results: Two of the three SNPs were associated with cholelithiasis, rs2243290 (P=0.06) and rs2227284 (P=0.02). In addition, when only cases with a previous history of a cholecystectomy were considered, both SNPs were significantly associated with symptomatic gallstone disease (rs2243290 (P=0.009); rs2227284 (P=0.002)). For both SNPs, an increase in gallstone susceptibility was associated with the variant minor allele. Conclusion: Our results indicate an increased gallstone risk from frequent variants of IL4. Anti-inflammatory effects might explain a protective effect of IL4 on cholelithiasis by up-regulation of PPARgamma and a reduction of leukotriene production by inhibition of the arachodinate-5-lipoxygenase leading to a diminished production of mucin glycoproteins. Accordingly, our findings suggest that IL4 could be a target for prevention and non-surgical management of cholelithiasis in genetically predisposed patients.