Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.
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DOI：
10.1038/ng.2741
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发表时间：
2013-11
期刊：
影响因子：
30.8
通讯作者：
Raychaudhuri, Soumya
中科院分区：
文献类型：
--
作者：
Seddon, Johanna M.;Yu, Yi;Miller, Elizabeth C.;Reynolds, Robyn;Tan, Perciliz L.;Gowrisankar, Sivakumar;Goldstein, Jacqueline I.;Triebwasser, Michael;Anderson, Holly E.;Zerbib, Jennyfer;Kavanagh, David;Souied, Eric;Katsanis, Nicholas;Daly, Mark J.;Atkinson, John P.;Raychaudhuri, Soumya
为了确定罕见变异在晚期年龄相关性黄斑变性（AMD）风险中的作用，我们对2，493例病例和对照组中AMD相关基因座和通路内的681个基因的外显子进行了测序。我们首先测试了每个基因与对照组相比病例中罕见变异的增加或减少负担。我们发现，7.8%的AMD病例与2.3%的对照组相比，是罕见错义CFI变体的携带者（OR=3.6，p=2×10−8）。与对照组相比，病例中功能障碍性变体占主导地位。然后，我们测试了个体变异与疾病的关联。我们观察到与CFI以外的罕见错义等位基因的显著关联。5,115个独立样本的基因分型证实了AMD与C3中的K155 Q等位基因（复制p=3.5×10−5，OR=2.8;联合p=5.2×10−9，OR=3.8）和C9中的P167 S等位基因（复制p=2.4×10−5，OR=2.2;联合p=6.5×10−7，OR=2.2）的关联。最后，我们表明，在C3的155 Q等位基因的结果在抵抗CFH和CFI的蛋白水解失活。这些结果暗示AMD发病机制中C3蛋白调节的丧失和过度的替代补体激活，从而告知这种疾病的作用方向和机制基础。
To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within AMD-associated loci and pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2×10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association to disease. We observed significant association with rare missense alleles outside CFI. Genotyping in 5,115 independent samples confirmed associations to AMD with a K155Q allele in C3 (replication p=3.5×10−5, OR=2.8; joint p=5.2×10−9, OR=3.8) and a P167S allele in C9 (replication p=2.4×10−5, OR=2.2; joint p=6.5×10−7, OR=2.2). Finally, we show that the 155Q allele in C3 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
3.9
作者：
Hicks, Stephanie;Wheeler, David A.;Plon, Sharon E.;Kimmel, Marek
通讯作者：
Kimmel, Marek
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
影响因子：
5.2
作者：
Fagerness, Jesen A.;Maller, Julian B.;Seddon, Johanna M.
通讯作者：
Seddon, Johanna M.