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

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.麻风病1型反应（Leprosy Type-1 Reactions, T1Rs）是一类累及部分麻风病患者的病理性炎症反应，可导致周围神经损伤。本研究针对221个家系、共计229名罹患T1R的后代开展基于家系的全基因组关联研究（family-based GWAS），并通过逐步重复验证来挖掘T1R的风险因素。我们发现并经重复验证确认了位于10号染色体p21.2区域的单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）与T1R存在特异性关联。对三个独立样本的联合分析显示，rs1875147位点与T1R存在强关联证据（P = 4.5×10^-8；比值比（Odds Ratio, OR）= 1.54，95%置信区间（Confidence Interval, CI）= 1.32–1.80）。该T1R风险位点被限定在一个编码长链非编码RNA（long non-coding RNA, lncRNA）的基因组区间内，且rs1875147是该lncRNA的表达数量性状位点（expression Quantitative Trait Locus, eQTL）。鉴于已有研究发现麻风病与炎症性肠病（inflammatory bowel disease, IBD）之间存在遗传重叠，我们评估了二者共有的遗传调控机制是否可追溯至T1R这一内表型。借助近期一项IBD全基因组关联研究荟萃分析的结果，我们发现本数据集内10.6%的IBD相关SNPs与T1R共享共同的风险等位基因（P = 2.4×10^-4）。该发现表明，临床表现各异的炎症性疾病在遗传调控层面存在广泛的重叠。