ACTR1Ahas pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

Abstract

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated five risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 (2 independent loci) and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583: combined p=8.81x10-9; OR=0.51 [95% CI 0.40-0.64]). The leprosy risk locus is a determinant of ACTR1A RNA expression in CD4+ T cells (posterior probability of colocalization - PP=0.96). Furthermore, it demonstrates pleiotropy with established risk loci for inflammatory bowel disease and atopic disease. Reduced ACTR1A expression decreases susceptibility to leprosy and atopy but increases risk of inflammatory bowel disease. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the evidence that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

The epidemiology of leprosy in Karonga District, northern Malawi 1973–2023: An analysis of leprosy’s distribution, risk factors, control and decline in rural Africa

“…Most recently, a genome-wide association study (GWAS) was carried out involving 327 cases and 436 controls from Karonga along with 247 cases and 368 controls from Mali. 74 This study replicated five risk loci previously reported in Asia (MHC class I and II, two loci within LACC1 and SLC29A3), and identified a novel leprosy susceptibility locus at 10q24, a determinant of ACTR1A RNA expression in CD4 T cells. Reduced ACTR1A expression appears to decrease susceptibility to leprosy and atopy but increase the risk of inflammatory bowel disease.…”

“…Or chance. We doubt that human genetics plays a major role in determining local heterogeneity, despite the several hints of genetic associations described above, [69][70][71][72][73][74] and the several observations of family clustering, which we are more inclined to attribute to close physical contact and other shared risk factors within the home environment. And we are aware of no behavioural differences which could explain the distribution of the disease.…”

Leprosy: treatment, prevention, immune response and gene function

“…Furthermore, the research group has identified SLC29A3 as a susceptibility gene for leprosy, which encodes equilibrative nucleoside transporter 3 (ENT3). Studies have shown that the lack of ENT3 leads to enlargement and disruption of lysosomal compartments, accumulating residual mitochondria, increased intracellular ROS, and DNA damage in T cells (138). The IRGM gene, which regulates autophagy, has also been confirmed to be associated with leprosy susceptibility; it was demonstrated that only rs13361189 TC and CC genotypes are significantly associated with leprosy (75).…”