크론병과 나병의 유전적 구조 비교 연구

Abstract

Background Genome-wide association studies (GWAS) of Crohn’s disease (CD) in European and leprosy in Chinese population suggested that CD and leprosy might share genetic risk loci related to nonspecific innate immunity. Pleiotropic variants within these loci showed opposite allelic effects between CD and leprosy.

Methods Using CD meta-analysis of 2,354 CD patients and 4,907 healthy controls in Korean and leprosy meta-analysis of 2,960 leprosy patients and 3,747 healthy controls in Chinese, we compared the genetic architecture of CD and leprosy using linkage disequilibrium score regression analysis (LDSC) and polygenic risk score (PRS) analysis.

Results Most of the shared loci between CD and leprosy showed an opposite allelic effect except the RIPK2 and LACC1 loci. Investigation of the genetic correlation using cross-trait LDSC showed a significant negative genetic correlation between CD and leprosy (rg[SE] = -0.30 [0.12], p = 1.5 x 10-2). Phenotype variance explained by the polygenic risk score derived from Chinese leprosy data explained up to 5.27 % of variance of Korean CD. When the directions of the effects of the LACC1 and RIPK2 loci were flipped to account for the original directions between CD and leprosy, the explained variance increased up to 8.21 %. After removing both the MHC and TNFSF15 regions, the most significant signals in CD, genetic correlation and overlap between the two diseases were decreased.

Conclusions Our study represented the first systemic effort to compare the genetic basis of CD and leprosy in samples of East Asian origin. Our findings showed that CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians with risk allele effects in the opposite directions. In addition, out data suggest that the most significant CD susceptibility loci, MHC and TNFSF15, may be the main driver of higher overlap between CD and leprosy.