Association of TNFSF8 Regulatory Variants With Excessive Inflammatory Responses but not Leprosy Per Se

Abstract

Twin and family studies indicate that host genetic factors influence susceptibility to leprosy and, possibly , leprosy type. Murine studies have suggested a role for the natural resistance-associated macrophage protein 1 (Nramp1) gene, which can influence cellular immune responses to intracellular pathogens. We evaluated a variation in the human homolog, NRAMP1, recently associated with tuberculosis susceptibility in West Africa. A total of 273 patients with leprosy and 201 controls from Mali were genotyped for NRAMP1 polymorphisms previously associated with tuberculosis. No association was found with leprosy per se (P 0.83), but the NRAMP1 3-untranslated region 4-bp insertion/deletion polymorphism was associated with leprosy type (P 0.007). Heterozygotes were more frequent among multibacillary than paucibacillary leprosy cases. Thus, variation in or near the NRAMP1 gene may exert an influence on the clinical presentation of leprosy, possibly by influencing cellular immune response type.

A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy

“…For example, we have previously shown for variants of the TNFSF15/TNFSF8 genes that leprosy patients with the T1R endophenotype are largely the cause of association with the leprosy exophenotype [16, 17] . Consequently, the replication of the TNFSF15/TNFSF8 association in samples of leprosy patients with a low proportion of T1R is expected to display low power.…”

“…The replication sample was of Vietnamese ethnicity and encompassed 253 T1R-affected and 563 T1R-free leprosy patients. The validation sample comprised 471 T1R-affected subjects and 446 T1R-free leprosy patients as controls from the Central-west and South-east regions of Brazil as described previously [16, 37, 38]. In both replication and validation samples, cases and controls were matched for leprosy subtype.…”

The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator

“…Despite the increased TL1A expression in RA, genetic variants near TNFSF15 have not been found to contribute to RA risk. Interestingly, studies in Vietnamese [120], Indian, and West African [121] leprosy cohorts have been unable to replicate genetic association with the TNFSF15 locus, suggesting population-specific effects or disease heterogeneity among the cohorts included [122]. Interestingly, the TNFSF15 locus was also found to be associated with leprosy in a GWAS of Chinese individuals [118,119], adding to the list of IBDassociated loci that are shared with mycobacterial diseases.…”

“…Along with evidence from mouse models of bacterial [25] and viral infection [33], this genetic association raises the possibility of TL1A having a positive role in protection from pathogens. Interestingly, studies in Vietnamese [120], Indian, and West African [121] leprosy cohorts have been unable to replicate genetic association with the TNFSF15 locus, suggesting population-specific effects or disease heterogeneity among the cohorts included [122].…”

Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

“…A prospective study of host responses to M. leprae antigen identified a gene-set signature that predisposed to T1R 12 . In addition, candidate gene approaches identified six protein coding genes in association with T1R [13][14][15][16][17][18][19] . More recently a genome-wide association study (GWAS) identified a long noncoding RNA in chromosome 10 as T1R risk factor in independent populations and also provided suggestive evidence for the PRKN (formerly PARK2) as T1R susceptibility gene 18 .…”