Identifications Of IL18RAP/UK18R1and IL12B As Novel Leprosy Risk Genes Demonstrated Shared Pathogenesis Between Inflammation And Infectious Diseases

Background: It has been established that there are common histologic characteristicsbetween leprosy and inflammatory bowel disease (IBD). In our genome-wideassociation study (GWAS) of leprosy and the study that will be published, we totallyidentified ten susceptibility variants. Among them NOD2, TNFSF15, LRRK2, IL23Rand C13orf31/CCDC122at13q14.11were not only been associated with leprosy butCrohn’s disease (CD). While recent GWAS have corroborated nearly one-third ofsusceptibility loci were shared between CD and UC. So we hypothesized that thereare additional shared susceptibility loci between leprosy and IBD.Objective: By carrying out a comprehensive association study of IBDsusceptibility loci in multiple independent leprosy samples of Chinese population, wehypothesized that there are additional shared susceptibility loci between leprosy andIBD and searched for novel leprosy susceptibi lity genes.Methods: We reviewed the findings from the12GWAS of CD and7GWAS ofUC through the Catalog of Published Genome-Wide Association Studies(http://www.genome.gov/26525384) and identified a total of118genes that showedgenome-wide significant associations with either CD or UC or both. After excluding7SNPs that are located within the MHC region and15SNPs located within the5known leprosy susceptibility genes, we do a two-stage association study in the four independent leprosy samples of Chinese population. In the Stage1, all the133selected SNPs were genotyped in1,504leprosy cases and1,502healthy controls ofnorthern Chinese Han. Of119SNPs that were successfully designed and genotyped,19SNPs showed suggestive association (P <0.05) in the Stage1sample, including9CD SNPs,8UC SNPs and2IBD SNPs (Supplementary table1). In the Stage2, the19SNPs were further genotyped in additional three independent leprosy cohorts ofChinese population:1)1,154cases and2,605controls of northern Chinese Han;2)1,165cases and648controls of southern Chinese Han; and3)1,148cases and748controls of southern Chinese minorities.Results: Two novel associations were discovered at rs2058660(P=1.60×10-17,OR=1.30) on2q12.1and rs6871626(P=3.95×10-18, OR=0.75) on5q33.3.Conclusion: We discovered two novel susceptibility loci for leprosy by carryingout a comprehensive association study of IBD susceptibility loci in leprosy samples ofChinese population. The discovery of the two novel susceptibility loci has implicatedIL18RAP/IL18R1and IL12B as new susceptibility genes for leprosy.