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

Abstract

Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32–1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.

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

“…Acute episodes of T1R are characterized by a cytokine storm which is indicative of dysregulated inflammatory responses. Prospective transcriptomic analyses of the immune response to M. leprae antigen and a genome-wide association study support the central role of host genetics in the break-down of coordinated gene regulation in the T1R phenotype 12,18 .…”

“…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 .…”

Association of polymorphisms in SLC gene family with risk of leprosy and malformation in Chinese familial and sporadic patients

“…Genetic factors have been recognized as an important contributor of leprosy after infected with leprosy bacillus. Genome wide association studies (GWAS) have identified several susceptibility common variants [24,25,26] and lncRNA [27] associated with leprosy. Meanwhile, immune response genes have been proved to be associated with pathogenesis of different forms of leprosy [28] .…”

Longitudinal IP-10 Serum Levels Are Associated with the Course of Disease Activity and Remission in Patients with Rheumatoid Arthritis

“…The chemokine IP-10 is secreted by various cell types, and through its receptor (CXCR3), it regulates immune responses by activation and recruitment of leukocytes (T cells, monocytes, and NK cells) (10). Leprosy reactions have considerable overlap with acute immunological complications (flares) in other chronic diseases, such as RA (11), Buruli ulcer (12,13), and Crohn's disease (14,15). Flares of these chronic diseases are characterized by a sudden increase in inflammation as well, leading to a deterioration of disease symptoms and often to irreversible tissue damage.…”