Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy

Abstract

Seven new risk coding variants have been identified through an exome-wide association study (EWAS), which studied the contributions of protein-coding variants to leprosy susceptibility. But some potential susceptibility loci were not studied in the previous EWAS study because of the project consideration. Seventeen unstudied potential susceptibility loci of the previous EWAS were validated in 3169 cases and 9814 controls in this study. Four disease-associated exonic loci were identified: rs671 in ALDH2 (P = 2.0 × 10 , odds ratio [OR] = 1.35), rs13259978 in SLC7A2 (P = 1.74 × 10 , OR = 1.28), rs925368 in GIT2 (P = 9.18 × 10 , OR = 1.44), and rs75680863 in TCN2 (P = 8.37 × 10 , OR = 0.74). Potentially implicating ZFP36L1 as a new susceptibility gene, 1 intergenic single nucleotide polymorphism (SNP), rs1465788 (P = 7.81 × 10 , OR = 0.88), was also suggested to be associated with leprosy. A luciferase reporter assay showed that the rs1465788 risk allele notably decreased the transcription activity of the flanking sequence. These findings suggest the possible involvement of lipid metabolism, NF-κB homeostasis and macrophage antimicrobial pathways in leprosy pathogenesis.

Advances in the Immunology and Genetics of Leprosy

“…Several genes related to microbicidal functions have been identified as leprosy susceptibility genes. The exonic variant rs13259978 in SLC7A2 was found to be associated with leprosy (112). Since SLC7A2 is an important component of the classic nitric oxide antimicrobial pathway in macrophages, this finding suggested the involvement of the nitric oxide microbicidal pathway in leprosy.…”

“…Genetic studies have also discovered other leprosy-associated genes, such as genes related to lipid metabolism, nerve damage, oxidative stress, and ubiquitin-mediated proteolysis. The accumulation of lipids in macrophages is thought to be beneficial for mycobacterium survival, and variants of two lipid metabolism related-genes, ALDH2 and APOE, were shown to confer risk for leprosy (112,157). Although nerve damage is frequently observed in leprosy patients, the association between leprosy and nerve-related genes has rarely been reported.…”

Family-based genome-wide association study of leprosy in Vietnam

“…From the early observations of familial clusters of leprosy cases to recent whole-exome sequencing studies identifying genetic variants associated with leprosy, there is strong evidence to suggest that the development of this disease is under tight human genetic control [2,5]. Genetic studies, including positional cloning analyses [6][7][8], genomewide association studies [9][10][11][12][13][14][15], and, more recently, whole-exome sequencing [16] have identified several susceptibility loci for leprosy (reviewed in [17] and [5]), and have demonstrated the involvement of both innate and adaptive immune responses in this disease [18]. Almost all the susceptibility loci identified in genome-wide studies to date were found in the Chinese population.…”

Family-based genome-wide association study of leprosy in Vietnam

“…From the early observations of familial clusters of leprosy cases to recent whole-exome sequencing studies identifying genetic variants associated with leprosy, there is strong evidence to suggest that the development of this disease is under tight human genetic control (2, 5). Genetic studies, including positional cloning analyses (6-8), genome-wide association studies (9-15), and, more recently, whole-exome sequencing (16) have identified several susceptibility loci for leprosy (reviewed in (17) and (5)), and have demonstrated the involvement of both innate and adaptive immune responses in this disease (18). Almost all the susceptibility loci identified in genome-wide studies to date were found in the Chinese population.…”