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

Vinicius M Fava, Jeremy Manry, Aurélie Cobat, Marianna Orlova, Nguyen Van Thuc, Milton O Moraes, Carolinne Sales-Marques, Mariane M A Stefani, Ana Carla P Latini, Andrea F Belone, Vu Hong Thai, Laurent Abel, Alexandre Alcaïs and Erwin Schurr

PLOS Genetics, 2017, vol. 13, issue 2, 1-16

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.Author summary: Leprosy still affects approximately 200,000 new victims each year. A major challenge of leprosy control is the prevention of permanent disability due to nerve damage. Nerve damage occurs if leprosy remains undiagnosed for extended periods or when patients undergo pathological inflammatory responses termed Type-1 Reactions (T1R). T1R is a rare example where beneficial inflammatory responses are temporal separated from host pathological responses. There is strong experimental evidence that supports a role of host genetic factors in T1R susceptibility. Here, we employed a genome-wide association study (GWAS) to investigate susceptibility factors for T1R in Vietnamese families. We followed up the initial GWAS findings in independent population samples from Vietnam and Brazil and identified a set of cis-eQTL genetic variants for the ENSG00000235140 lncRNA as global risk factors for T1R. 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. We observed that more than 10% of IBD-risk loci were nominally associated with risk for T1R suggesting a shared mechanism of excessive inflammatory response in the both disease etiologies.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1006637

DOI: 10.1371/journal.pgen.1006637

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