Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXBFKBPLNOTCH4 region of chromosome 6p21.3
Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXBFKBPLNOTCH4 region of chromosome 6p21.3
复制标题
DOI：
10.1093/hmg/dds225
复制
发表时间：
2012-09-15
影响因子：
3.5
通讯作者：
Yates, John R. W.
中科院分区：
文献类型：
--
作者：
Cipriani, Valentina;Leung, Hin-Tak;Yates, John R. W.
视网膜相关性黄斑变性（AMD）是西方人群视力丧失的主要原因。易感性受年龄、环境和遗传因素的影响。已知的遗传风险位点并不能解释所有的遗传性。因此，我们在英国人群中进行了AMD的全基因组关联研究，其中包括893例晚期AMD病例和2199例对照。这表明与成熟的AMD风险位点ARMS 2相关，（年龄相关性黄斑病变易感性2）HTRA 1（HtrA丝氨酸肽酶1）（临2.7 10（72）），（补体因子H）（临2.3 10（47））、C2（补体成分2）CFB（补体因子B）（临5.2 10（9）），C3（补体成分3）（P 2.2 10（3））和CFI（P 3.6 10（3））以及最近报告的VEGFA（P 1.2 10（3））和LIPC（肝脂肪酶）（P 0.04）风险位点。使用1411例晚期AMD病例和1431例对照的重复样本，我们证实了AMD与染色体6p21.3上TNXB单核苷酸多态性之间的新关联（tenascin XB）FKBPL（FK 506结合蛋白样）[rs 12153855/rs 9391734;发现P 4.3 10（7），复制P 3.0 10（4），联合P 1.3 10（9），比值比（OR）1.4，95置信区间（CI）1.31.6]和相邻基因NOTCH 4（Notch 4）（rs 2071277;发现P 3.2 10（8），复制P 3.8 10（5），组合P 2.0 10（11），OR 1.3，95 CI 1.21.4）。这些协会仍然显着的条件分析，其中包括相邻的C2CFB基因座。TNXB、FKBPL和NOTCH 4都是可能的AMD易感基因，但还需要进一步的研究来鉴定致病变异，并确定这些基因中是否有任何一个参与了AMD的发病机制。
Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)HTRA1 (HtrA serine peptidase 1) (P 2.7 10(72)), CFH (complement factor H) (P 2.3 10(47)), C2 (complement component 2)CFB (complement factor B) (P 5.2 10(9)), C3 (complement component 3) (P 2.2 10(3)) and CFI (P 3.6 10(3)) and with more recently reported risk loci at VEGFA (P 1.2 10(3)) and LIPC (hepatic lipase) (P 0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P 4.3 10(7), replication P 3.0 10(4), combined P 1.3 10(9), odds ratio (OR) 1.4, 95 confidence interval (CI) 1.31.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P 3.2 10(8), replication P 3.8 10(5), combined P 2.0 10(11), OR 1.3, 95 CI 1.21.4). These associations remained significant in conditional analyses which included the adjacent C2CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.