Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; College of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China.
Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
Am J Hum Genet. 2018 May 3;102(5):794-805. doi: 10.1016/j.ajhg.2018.03.006. Epub 2018 Apr 26.
Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis.
全基因组关联研究（GWASs）和全基因组连锁研究（GWLSs）已经确定了许多影响麻风病易感性的风险基因。然而，大多数报道的 GWAS 命中是非编码变体，仅占该疾病估计遗传率的一部分。为了鉴定额外的风险基因，并在 GWAS 位点内定位潜在功能变体，我们在中国西南部云南省的 1433 名麻风病患者和 1625 名健康对照个体中进行了一项三阶段研究，该研究结合了全外显子组测序（WES；发现阶段）、靶向下一代测序（NGS；筛选阶段）和对风险错义变体的精细验证。我们鉴定并验证了 HIF1A 中的一个罕见的有害变体 rs142179458（c.1045G>A [p.Asp349Asn]），该变体导致麻风病风险增加（p = 4.95×10，优势比[OR] = 2.266）。我们能够表明，携带风险等位基因的受影响个体在更年轻时表现为多菌型麻风病（p = 0.025）。我们还证实了 GWAS 命中 LACC1（以前称为 C13orf31）中错义变体 rs3764147（c.760A>G [p.Ile254Val]）与麻风病之间的关联（p = 6.11×10，OR = 1.605）。通过使用人群归因分数，我们表明 HIF1A 和 LACC1 是主要基因，其携带错义变体导致我们研究组中的麻风病风险增加。一致地，麻风病患者的皮肤损伤和分枝杆菌刺激的细胞中 HIF1A 和 LACC1 的 mRNA 表达水平均上调，表明 HIF1A 和 LACC1 在麻风病发病机制中起积极作用。
