NEW YORK (GenomeWeb) – In Nature Genetics, researchers from China, Singapore, and the US described half a dozen new loci that seem to influence individuals' susceptibility to contracting leprosy, an infection caused by Mycobacterium leprae bacteria.
The team did a three-stage genome-wide association study that involved 8,313 Chinese individuals with leprosy and more than 16,000 without the disease. In addition to known risk variants in known susceptibility genes, the search turned up six sites not identified in the past.
Many of the new and known risk variants also showed apparent pleiotropy with regions implicated in other diseases, the researchers explained, particularly autoimmune and inflammatory conditions. Interestingly, though, some of the variants that seemed to bump up leprosy risk have been suggested as protective variants in conditions such as Crohn's disease or atopic dermatitis, underscoring the distinct immune contributions to the infectious and inflammatory conditions.
"[O]ur analysis … suggests that genes involved in pathogen sensing might have similar pathogenic roles in inflammatory and infections diseases, consistent with previous reports of the involvement of bacterial infection in the development of Crohn's disease," the study's authors wrote, "whereas immune responses have a discordant role in infection and inflammatory diseases."
"[A]lthough molecular sensing of intracellular infection might have similar pathogenic roles in these diseases," they explained, "immune-related pathways have discordant roles, supporting the concept that strong immune and inflammatory responses are advantageous in defending against infection but increase the risk of autoimmunity and inflammatory diseases."
For their multi-stage analysis, the researchers began by comparing genotyping profiles in two cohorts containing healthy Chinese individuals, individuals with leprosy, and/or individuals with other immune-related conditions.
Data for one of the groups — 706 leprosy cases, 1,225 healthy controls, and 4,362 immune disease controls — had been published in a past study, while another 842 leprosy cases and 925 controls from northern China were newly genotyped for the study.
Based on information at nearly 4.6 million genotyped and imputed SNPs in leprosy cases and controls from these two cohorts, the researchers verified associations at sites implicated in leprosy risk in the past and unearthed many more suspicious new loci.
The team narrowed in on the top 16 most promising SNPs at these and other sites through follow-up testing on 2,761 Han Chinese individuals with leprosy and 3,038 without.
With the help of a second round of validation testing that included another 10,471 cases and controls, the researchers eventually narrowed in on six new leprosy-associated loci reaching genome-wide significance.
Three of those fell near BATF3, CCDC88B, and CIITA-SOCS1, they noted, while other associated variants showed potential regulatory roles. Among them: a leprosy-associated variant suspected of mediating expression of the human leukocyte antigen gene HLA-DRB1.
Through fine-mapping in the leprosy cases and healthy control individuals from the original two cohorts, meanwhile, they more clearly defined leprosy-associated HLA alleles within the major histocompatibility (MHC) locus, a region of the genome well known for its role in immune function.
The search also led to new risk variants in two genes already linked to the disease, the team reported, while variants in a third previously identified gene appeared to mediate leprosy susceptibility in individuals from northern China but not in the southern Chinese population analyzed in the current study.