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.
Highlights
Leprosy is a chronic infectious disease caused by Mycobacterium leprae and about 200,000 cases were reported each year[1]
We found that five gene variants including gene GAL3ST4, CHGB48, CHGB23, GLT8D2 and ANKRD35 were more frequently reported than the other ten variants among the remaining six patients from two leprosy families by means of gene sequencing
The results showed significant difference for CHGB23 between the patients and controls (Table 5), and, CHGB23 gene polymorphism in male population was found to be different between leprosy patients and healthy controls
Summary
Leprosy is a chronic infectious disease caused by Mycobacterium leprae and about 200,000 cases were reported each year[1]. The clinical features of leprosy differ greatly among individuals, and previous studies showed that the widely different clinical manifestations of leprosy contrast with the low variability of the bacillus[2] This suggests that the host genetic variation may have played a more important role in the pathogenesis of the disease[3,4]. Whole exome sequencing is a new powerful strategy to discover causative genes in rare Mendelian disorders[12]. This technology combined with a filtering methodology was demonstrated as an approach to identify susceptible genes among many genetic diseases[13]. Protein change E661Q I279M A37T G282A R178Q A353G T239M A467V R779H V804L V812M T657I R62G F343L G34LG M845V V174A M110V P109L C537G
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