Identification of novel genetic loci GAL3ST4 and CHGB involved in susceptibility to leprosy

Abstract

Leprosy has long been thought to have a strong genetic component, and so far, only positional cloning and genomewide association studies have been used to study the genetic susceptibility to leprosy,while whole exome sequencing (WES) approach has not yet been applied. In this study, we used WES approach on four leprosy patients and four healthy control relatives from two leprosy families. We found three new susceptible loci of leprosy, one in GAL3ST4 and two in CHGB. We went on to validate the findings of WES using 151 leprosy cases and 226 healthy controls by Sanger sequencing. Stratified by gender, GAL3ST4 was found to be the susceptible gene only for the female population, and CHGB48 and CHGB23 were susceptibile to leprosy for the male population, respectively). Moreover, the gene expression levels of the three susceptible loci were measured by real-time PCR after the stimulation by M. leprae antigens in the PBMC (peripheral blood mononuclear cells) of 69 healthy people. The results showed that the female subjects with high frequent genotype in GAL3ST4 had a fivefold elevated expression. We suggest the polymorphisms in GAL3ST4 in different population are associated with increased risk of leprosy.

Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

“…During the preparation of our work, we noticed two recent publications about exome studies in Chinese individuals with leprosy. 58,82 were said to be associated with leprosy susceptibility in these studies. 58,82 We checked the risk variants in the above genes in our WES data (Table S7) but failed to find any association between these genes and leprosy in our samples.…”

Polymorphisms in mitochondrial ribosomal protein S5 (MRPS5) are associated with leprosy risk in Chinese

“…The TDT was used to evaluate allele transmission from parents to offspring in the 8 leprosy-affected families. Subsequently, 231,176 SNPs were originally obtained and several novel common variants (MAF≥5% in the 1,000 Genomes Project data) were recognized including two novel mutations (rs16991480 and rs76791154) in CHGB [ 29 ] ( S5 Table ), but no rare risk variants significantly associated with leprosy were identified. Moreover, we performed gene-based burden test in the WES samples.…”

“…Over the last decade, a significant number of studies using next-generation sequencing have identified various susceptibility genes and variants associated with leprosy [ 8 , 13 , 21 , 22 , 28 , 29 , 48 , 49 ]. In the present study, WES was performed in 8 families with at least one case of leprosy, and 31 variants shared by affected individuals within at least two families and absent in all the unaffected ones with a MAF ≤ 0.5% in the ExAC were selected for further confirmation.…”

“…In this study, we sequenced only 28 individuals in the WES discovery stage, there must have been additional rare risk mutations missed. When the previously reported WES data of four leprosy patients and four healthy relatives from two leprosy families in Henan and Yunnan Province were included to screen candidate variants [ 29 ], three novel rare nonsynonymous variants which are only present in cases from at least two families but absent in all the controls, i.e. rs746426634 in STYK1 (MIM: 611433), rs75765336 in GBGT1 (MIM: 606074) and rs141225250 in GCC2 (MIM: 612711) were confirmed by Sanger sequencing and further determined in the 55 leprosy cases.…”

“…We first reported three new common genetic susceptible loci, one in GAL3ST4 and two in CHGB identified by whole exome sequencing (WES) on four leprosy patients and four healthy relatives from two leprosy families in Henan and Yunnan Province [ 29 ]. In this study, we intended to identify novel and rare protein-coding variants through bigger-scale WES with more patients.…”