Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches

Abstract

Genetics plays a crucial role in controlling susceptibility to infectious diseases by modulating the interplay between humans and pathogens. This is particularly evident in leprosy, since the etiological agent, Mycobacterium leprae, displays semiclonal characteristics not compatible with the wide spectrum of disease phenotypes. Over the past decades, genetic studies have unraveled several gene variants as risk factors for leprosy per se, disease clinical forms and the occurrence of leprosy reactions. As expected, several of these genes are immune-related; yet, hypothesis-free approaches have led to genes not classically linked to immune response. The PARK2, originally described as a Parkinson’s disease gene, illustrates the case: Parkin—the protein coded by PARK2—was defined as an important player regulating innate and adaptive immune responses only years after its description as a leprosy susceptibility gene. Interestingly, even with the use of powerful hypothesis-free study designs such as genome-wide association studies, most of the major gene effect controlling leprosy susceptibility remains elusive. One hypothesis to explain this “hidden heritability” is that rare variants not captured by classic association studies are of critical importance. To address this question, massively parallel sequencing of large segments of the human genome—even whole exomes/genomes—is an alternative to properly identify rare, disease-causing mutations. These mutations may then be investigated through sophisticated approaches such as cell reprogramming and genome editing applied to create in vitro models for functional leprosy studies.

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

“…population. Several studies have consistently reported the involvement of HLA class II alleles, mostly HLA-DRB1 alleles, as key genetic factors controlling susceptibility to various forms of leprosy [11,18,[39][40][41]. A recent HLA imputation-based meta-analysis in the Chinese population identified HLA-DRB1 and HLA-DQA1 alleles and specific amino acids of HLA-DRβ1 as independent protective factors for leprosy [39].…”

“…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.…”

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

“…However, investigating the immune response elicited by M. leprae remains a particular challenge, due to its extreme dependence on the human host. Genetic disease association studies shed light on a wide range of aspects from the onset of infection to disease cornification, by uncovering genes whose protein products may play pivotal roles in this pathology (48). This has been the case for several genes of the lectin pathway of complement; those encoding PRMs, MBL2 (3) (4) (14), FCN1 (5), FCN2 (4) and FCN3 (9) and the serine protease MASP2 (6) and the possible receptor for MBL encoded by CR1 (10).…”