London School of Hygiene and Tropical Medicine, London University, London, UK.
BMC Med Genet. 2009 Dec 16;10:138. doi: 10.1186/1471-2350-10-138.
Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Blindness is due to progressive scarring of the conjunctiva (trachomatous scarring) leading to in-turning of eyelashes (trichiasis) and corneal opacification. We evaluated the contribution of genetic variation across the chemokine and cytokine clusters in chromosomes 4q and 5q31 respectively to risk of scarring trachoma and trichiasis in a large case-control association study in a Gambian population.
Linkage disequilibrium (LD) mapping was used to investigate risk effects across the 4q and 5q31 cytokine clusters in relation to the risk of scarring sequelae of ocular Ct infection. Disease association and epistatic effects were assessed in a population based study of 651 case-control pairs by conditional logistic regression (CLR) analyses.
LD mapping suggested that genetic effects on risk within these regions mapped to the pro-inflammatory innate immune genes interleukin 8 (IL8) and granulocyte-macrophage colony stimulatory factor (CSF2) loci. The IL8-251 rare allele (IL8-251 TT) was associated with protection from scarring trachoma (OR = 0.29 p = 0.027). The intronic CSF2_27348 A allele in chromosome 5q31 was associated with dose dependent protection from trichiasis, with each copy of the allele reducing risk by 37% (p = 0.005). There was evidence of epistasis, with effects at IL8 and CSF2 loci interacting with those previously reported at the MMP9 locus, a gene acting downstream to IL8 and CSF2 in the inflammatory cascade.
innate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma.
沙眼是由沙眼衣原体引起的慢性结膜炎，是世界上最常见的传染性致盲原因。失明是由于结膜（沙眼性瘢痕）的进行性瘢痕导致睫毛内翻（倒睫）和角膜混浊。我们评估了染色体 4q 和 5q31 上趋化因子和细胞因子簇中的遗传变异对冈比亚人群中大规模病例对照关联研究中瘢痕性沙眼和倒睫风险的贡献。
连锁不平衡（LD）作图用于研究与眼部 Ct 感染的瘢痕后遗症风险相关的 4q 和 5q31 细胞因子簇中的风险效应。通过条件逻辑回归（CLR）分析，在基于人群的 651 对病例对照研究中评估疾病关联和上位效应。
LD 作图表明，这些区域内对风险的遗传影响映射到促炎固有免疫基因白细胞介素 8（IL8）和粒细胞-巨噬细胞集落刺激因子（CSF2）基因座。IL8-251 稀有等位基因（IL8-251 TT）与避免瘢痕性沙眼相关（OR=0.29，p=0.027）。染色体 5q31 中的 CSF2_27348A 等位基因与剂量依赖性预防倒睫相关，每个等位基因的副本可使风险降低 37%（p=0.005）。有上位效应的证据，IL8 和 CSF2 基因座的效应与以前报道的 MMP9 基因座的效应相互作用，该基因位于 IL8 和 CSF2 炎症级联的下游。
固有免疫反应 SNP-单倍型与眼部 Ct 后遗症相关。这项工作说明了两个基因对上的上位效应在沙眼中的第一个例子。
