Title : A multicenter genome-wide association study of leprosy in Brazil
Abstract:
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Despite substantial progress in controlling its transmission, leprosy continues to affect a considerable number of individuals worldwide. The disease is characterized by a broad clinical spectrum associated with distinct patterns of immune response. The World Health Organization (WHO) classifies leprosy into two main clinical categories based primarily on the number of skin lesions: multibacillary (MB), defined as five or more lesions, and paucibacillary (PB), defined as fewer than five lesions. The regulation of the immune response involves a complex interplay of cellular and tissue processes, among which the control of gene expression plays a fundamental role. Given the multifactorial nature of immune responses and the potential contribution of genetic variation within populations to disease outcomes, this study aimed to characterize the genetic profile of a multicenter Brazilian cohort and investigate the contribution of genetic variants to the modulation of host immune responses and their association with leprosy.
To achieve this objective, samples were collected from patients and household contacts from three Brazilian states: Minas Gerais (21 contacts, 29 PB, and 40 MB), Sergipe (148 contacts, 60 PB, and 55 MB), and Rio de Janeiro (107 contacts, 114 PB, and 90 MB). First, an ancestry analysis was performed, demonstrating a homogeneous genetic composition across the three populations, with approximately 60% European, 10% Native American, and 30% African ancestry. This homogeneous ancestry profile supported the combined analysis of the three populations in subsequent association studies.
A genome-wide association study (GWAS) was subsequently conducted, identifying 40 suggestively associated single nucleotide polymorphisms (SNPs) in the comparison between leprosy cases and healthy household contacts, and 17 SNPs in the comparison between the tuberculoid and lepromatous clinical forms. Following functional annotation of these variants, several were found to be located within or near genes involved in immune response pathways. A fine-mapping analysis was then performed using FUMA, Haploview, Genome Browser, and RegulomeDB. These analyses identified highly regulatory genomic regions containing genes associated with immune responses, including CAPN3, PIK3CB, SP3, and RUNX1, which colocalized with the suggestive SNPs rs28364393, rs13061496, rs76486292, and rs928283, respectively. Haploview and RegulomeDB analyses further indicated that several SNPs in linkage disequilibrium with the suggestive variants may exert regulatory effects on the identified genes.
These preliminary findings indicate that both the comparison between individuals with leprosy and healthy household contacts and the comparison between different clinical forms of the disease identified genetic variants potentially involved in the immunological mechanisms underlying leprosy. Therefore, these SNPs represent potential markers of susceptibility to leprosy and may contribute to a better understanding of the genetic and immunological mechanisms underlying disease pathogenesis.
Keywords: Leprosy; SNPs; immunology; genetic variants; genes.
