未经证实:为了选择年龄相关性黄斑变性(AMD)遗传负担较低的个体和家庭,告知黄斑疾病的临床诊断,并发现与黄斑病变相关的新遗传变异。
UNASSIGNED:基于靶向和全外显子组测序的遗传关联研究。
未经评估:共有758名受试者(481名黄斑病变患者和277名对照),包括72个家庭的316人。
未经证实:我们专注于涉及补体的150个基因,凝血,和炎症途径。使用逻辑回归对≥5名受试者共有的7755种变体进行单变体测试。基于基因的测试用于使用负担测试评估基因中罕见和低频变异(在次要等位基因频率[MAF]≤5%或≤1%时)的总体影响。对于受影响成员基于已知的与AMD相关的常见和罕见变异的遗传风险负担较低的家庭,我们搜索了罕见变异(MAF<0.001),其风险等位基因发生在≥80%的受影响个体中,但未发生在对照组中.进行免疫组织化学以确定新基因(凝血因子II凝血酶受体样2[F2RL2])在视网膜组织中的蛋白质表达。
未授权:黄斑变性的基因型和表型。
UNASSIGNED:我们证实了补体因子H的同义变体(Ala473,rs2274700,代入内含子rs1410996,r2=1)与黄斑病变(优势比,0.64;P=4.5×10-4)。较高的AMD多基因风险评分(PRS)与中晚期AMD相关。在低PRS且无已知罕见黄斑病变变异的家庭中,我们确定了两部小说,ADAM15中的高度渗透错义罕见变体,一种整合素和金属蛋白酶,金属肽酶结构域15(p。Arg288Cys)和F2RL2(p。Leu289Arg)。免疫组织化学分析显示F2RL2蛋白在人和猪视网膜的视锥感光细胞外节和Müller胶质细胞中表达。在伴有新生血管形成的晚期AMD样品中,凝血因子II凝血酶受体样2表达在纤维化区域出现增加,提示F2RL2可能在进展为晚期黄斑疾病中发挥作用。
UNASSIGNED:ADAM15和F2RL2基因中的新错义罕见变异与黄斑病变相关。结果表明,与凝血和免疫途径相关的新基因可能参与黄斑疾病的发病。
UNASSIGNED: To select individuals and families with a low genetic burden for age-related macular degeneration (AMD), to inform the clinical diagnosis of macular disorders, and to find novel genetic variants associated with maculopathies.
UNASSIGNED: Genetic association study based on targeted and whole-exome sequencing.
UNASSIGNED: A total of 758 subjects (481 individuals with maculopathy and 277 controls), including 316 individuals in 72 families.
UNASSIGNED: We focused on 150 genes involved in the complement, coagulation, and inflammatory pathways. Single-variant tests were performed on 7755 variants shared among ≥ 5 subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low-frequency variants (at minor allele frequency [MAF] ≤ 5% or ≤ 1%) in a gene using burden tests. For families whose affected members had a low burden of genetic risk based on known common and rare variants related to AMD, we searched for rare variants (MAF < 0.001) whose risk alleles occurred in ≥ 80% of affected individuals but not in controls. Immunohistochemistry was performed to determine the protein expression of a novel gene (coagulation factor II thrombin receptor-like 2 [F2RL2]) in retinal tissues.
UNASSIGNED: Genotypes and phenotypes of macular degeneration.
UNASSIGNED: We confirmed the association of a synonymous variant in complement factor H (Ala473, rs2274700, proxy to intronic rs1410996, r 2 = 1) with maculopathy (odds ratio, 0.64; P = 4.5 × 10-4). Higher AMD polygenic risk scores (PRSs) were associated with intermediate and advanced AMD. Among families with low PRSs and no known rare variants for maculopathy, we identified 2 novel, highly penetrant missense rare variants in ADAM15, A disintegrin and metalloprotease, metallopeptidase domain 15 (p.Arg288Cys) and F2RL2 (p.Leu289Arg). Immunohistochemistry analyses revealed F2RL2 protein expression in cone photoreceptor outer segments and Müller glia cells of human and pig retinas. Coagulation factor II thrombin receptor-like 2 expression appeared increased in fibrotic areas in advanced AMD samples with neovascularization, suggesting that F2RL2 may play a role in the progression to advanced macular disease.
UNASSIGNED: New missense rare variants in the genes ADAM15 and F2RL2 were associated with maculopathies. Results suggest that novel genes related to the coagulation and immune pathways may be involved in the pathogenesis of macular diseases.