Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration

被引：273

作者：

Seddon, Johanna M. ^{[1
,2
,3
]}

Yu, Yi ^{[1
]}

Miller, Elizabeth C. ^{[4
]}

Reynolds, Robyn ^{[1
]}

Tan, Perciliz L. ^{[5
,6
,7
]}

Gowrisankar, Sivakumar ^{[8
]}

Goldstein, Jacqueline I. ^{[9
,10
]}

Triebwasser, Michael ^{[4
]}

Anderson, Holly E. ^{[11
]}

Zerbib, Jennyfer ^{[12
]}

Kavanagh, David ^{[11
]}

Souied, Eric ^{[12
]}

Katsanis, Nicholas ^{[5
,6
,7
]}

Daly, Mark J. ^{[9
,10
]}

Atkinson, John P. ^{[4
]}

Raychaudhuri, Soumya ^{[8
,9
,13
,14
,15
]}

机构：

[1] Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA

[2] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA

[3] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA

[4] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA

[5] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA

[6] Duke Univ, Dept Cell Biol, Durham, NC USA

[7] Duke Univ, Dept Pediat, Durham, NC 27706 USA

[8] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA

[9] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[10] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[11] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[12] Univ Paris Est Creteil, Hop Henri Mondor, Hop Intercommunal Creteil, Dept Ophthalmol, Creteil, France

[13] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[14] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[15] Univ Manchester, Fac Med & Human Sci, Manchester, Lancs, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 11期

基金：

美国国家卫生研究院;

关键词：

HEMOLYTIC-UREMIC SYNDROME; COMPLEMENT FACTOR-I; WHOLE-GENOME ASSOCIATION; DNA-SEQUENCING DATA; FACTOR-H; MISSENSE MUTATION; WIDE ASSOCIATION; COMMON VARIANTS; FACTOR B; SUSCEPTIBILITY;

D O I：

10.1038/ng.2741

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related 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 (odds ratio (OR) = 3.6; P = 2 x 10-8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p. Lys155Gln (replication P = 3.5 x 10(-5), OR = 2.8; joint P = 5.2 x 10(-9), OR = 3.8) and an allele in C9 encoding p. Pro167Ser (replication P = 2.4 x 10(-5), OR = 2.2; joint P = 6.5 x 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 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.

引用

页码：1366 / +

页数：8

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