Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study.
Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study.
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DOI：
10.1016/s0140-6736(08)61348-3
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发表时间：
2008-11-22
期刊：
影响因子：
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通讯作者：
Lotery A
中科院分区：
文献类型：
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作者：
Ennis S;Jomary C;Mullins R;Cree A;Chen X;Macleod A;Jones S;Collins A;Stone E;Lotery A
老年性黄斑变性是发达国家最常见的视力损害和失明形式。遗传学研究在确定该病的分子病因方面取得了进展，发现了补体因子H(CFH)基因的突变和10号染色体上包含HTRA1/LOC387715/ARMS2基因的一个基因座。补体3(C3)和包含B因子和C2基因的一个人类白细胞抗原基因的变异也与此有关。我们的目标是进一步确定这种疾病的遗传风险因素。我们采用病例对照研究设计，在英国老年性黄斑变性患者(n=479)和对照组(n=479)样本中，使用93个单核苷酸多态(SNPs)对32个基因进行低密度筛查。根据与年龄相关性黄斑变性的潜在功能相关性，选择基因作为候选基因。重要的初步发现通过在248名与疾病无关的美国患者和252名对照的独立美国队列中的复制以及关联信号周围的高密度基因分型得到证实。SNP变异rs2511989位于SERPING1SERPING16号内含子，与老年性黄斑变性显著相关(未校正p=4.0×10−5，校正p=0·00372)。我们没有发现疾病与其他31个候选基因之间存在关联的证据。Rs2511989 G/A杂合子与野生型G/G纯合子相比，年龄相关性黄斑变性的优势比为0.63(95%CI为0.47~0.84)。A/A纯合子与野生型的比数比为0·44(0·31-0·)。我们在美国队列中复制了观察到的基因关联(p=0.008)。此外，一项跨越SERPING1基因区域的二次高密度基因分型研究发现了另外五个与年龄相关性黄斑变性相似的SNP变异(rs2244169、rs2511990、rs2509897、rs1005510和rs2511988)。SERPING1基因变异显著改变了老年性黄斑变性的易感性。SERPING1编码C_1抑制因子，它在抑制补体成分1(C_1)中起着至关重要的作用，可能与补体激活的经典途径有关。黄斑视力研究基金会、黄斑疾病协会、惠康信托基金、布莱恩·默瑟信托基金、美国健康援助基金会、美国国立卫生研究院、霍华德·休斯医学研究所。
Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H (CFH) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 (C3) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease. We used a case–control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals. The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4·0×10−5, corrected p=0·00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0·63 (95% CI 0·47–0·84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0·44 (0·31–0·64). We replicated the observed genotypic association in a US cohort (p=0·008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988). Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 (C1) and might implicate the classic pathway of complement activation in this disease. Macula Vision Research Foundation, the Macular Disease Society, the Wellcome Trust, Brian Mercer Trust, the American Health Assistance Foundation, National Institutes of Health, the Howard Hughes Medical Institute.