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.
Highlights
A clear temporal separation from the different stages of leprosy pathogenesis identifies the endophenotype Type-1 Reactions (T1Rs) as a well-delineated example for host pathological inflammatory responses in humans
To test our proposal that T1R is a strong model for pathological inflammatory responses we evaluated if inflammatory bowel disease (IBD) genetic risk-factors were enriched among T1R risk factors
To contrast the genetic control of leprosy and its clinical subtypes from the genetic control of the pathological immune responses typical for T1R, we designed a genome-wide association scan (GWAS) to identify novel genes or variants associated solely with T1R. This may lead to predictive biomarkers for early recognition of T1R and possibly indicate novel pharmacological interventions that reduce the need for potentially adverse long-term corticoid treatment in T1R
Summary
A clear temporal separation from the different stages of leprosy pathogenesis identifies the endophenotype Type-1 Reactions (T1Rs) as a well-delineated example for host pathological inflammatory responses in humans. Variants in several of these genes had been implicated in susceptibility to leprosy per se raising the possibility of an overlapping genetic control of intensity of pathway activation between protective and pathological host responses [18]. To contrast the genetic control of leprosy and its clinical subtypes from the genetic control of the pathological immune responses typical for T1R, we designed a genome-wide association scan (GWAS) to identify novel genes or variants associated solely with T1R. This may lead to predictive biomarkers for early recognition of T1R and possibly indicate novel pharmacological interventions that reduce the need for potentially adverse long-term corticoid treatment in T1R
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