Several previous studies have assessed the contribution of polymorphisms in genes encoding the complement factors C2/C3/CFB/CFH with the risk of age-related macular degeneration (AMD), however the results have been inconsistent. We conducted a meta-analysis to systematically review the potential association between complement factor polymorphisms and AMD.
Methods:
Studies that investigated associations between C2 (rs547154 and rs9332739), C3 (rs1047286), CFB (rs4151667 and rs641153), and CFH (rs551397 and rs2274700) polymorphisms and AMD were identified by searching PubMed, EMBASE, Web of Science, and Cochrane Library databases for articles published prior to January 1, 2018. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the association between these polymorphisms and AMD using Stata 12.0 software. Q and I2 statistics were used to evaluate between-study heterogeneity. Publication bias analyses were conducted using Begg's test. We also conducted an ethnic subgroup analysis.
Results:
A total of 53 studies that included data for 53,774 patients and 56,973 healthy controls were evaluated. The pooled ORs for rs551397, rs2274700, rs4151667, rs641153, rs1047286, rs9332739, and rs547154 in the heterozygote model were 0.53 (95% CI: 0.45-0.61), 0.53 (95% CI: 0.40-0.70), 0.54 (95% CI: 0.46-0.63), 0.48 (95% CI: 0.4-0.57), 1.42 (95% CI: 1.22-1.66), 0.5 (95% CI: 0.45-0.56), and 0.52 (95% CI: 0.43-0.62), respectively.
Conclusion:
Our findings from this analysis confirmed the protective role of C2/CFB/CFH polymorphisms in the development of AMD, but showed that the single nucleotide polymorphism in C3 was a high-risk factor for AMD. The racial analysis results suggested that the effect of variant alleles was stronger in Caucasians than Asians.
Get full access to this article
View all access options for this article.
References
1.
BabanejadM, MoeinH, AkbariMR, et al. (2016) Investigating the CFH gene polymorphisms as a risk factor for age-related macular degeneration in an Iranian population. Ophthalmic Genet, 37:144-149.
2.
BeggCB, MazumdarM (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics, 50:1088-1101.
3.
Bergeron-SawitzkeJ, GoldB, OlshA, et al. (2009) Multilocus analysis of age-related macular degeneration. Eur J Hum Genet, 17:1190-1199.
4.
ButlerJM, HallN, NarendranN, et al. (2017) Identification of candidate protective variants for common diseases and evaluation of their protective potential. BMC Genomics, 18:575.
5.
CaireJ, RecaldeS, Velazquez-VilloriaA, et al. (2014) Growth of geographic atrophy on fundus autofluorescence and polymorphisms of CFH, CFB, C3, FHR1-3, and ARMS2 in age-related macular degeneration. JAMA Ophthalmol, 132:528-534.
6.
CantsilierisS, SchacheM, AshdownML, et al. (2009) Recent patents relating to diagnostic advances in age related macular degeneration (AMD). Recent Pat DNA Gene Seq, 3:102-113.
7.
ChenJH, YangY, ZhengY, et al. (2013) No association of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort. Mol Vis, 19:944-954.
8.
ChenY, ZengJ, ZhaoC, et al. (2011) Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol, 129:344-351.
9.
ChuJ, ZhouCC, LuN, et al. (2008) Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population. Chin Med J (Engl), 121:2525-2533.
10.
CiprianiV, LeungHT, PlagnolV, et al. (2012) Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3. Hum Mol Genet, 21:4138-4150.
11.
ContrerasAV, ZentenoJC, Fernandez-LopezJC, et al. (2014) CFH haplotypes and ARMS2, C2, C3, and CFB alleles show association with susceptibility to age-related macular degeneration in Mexicans. Mol Vis, 20:105-116.
12.
CraddockN, O'DonovanMC, OwenMJ (2008) Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry, 13:649-653.
13.
CuiL, ZhouH, YuJ, et al. (2010) Noncoding variant in the complement factor H gene and risk of exudative age-related macular degeneration in a Chinese population. Invest Ophthalmol Vis Sci, 51:1116-1120.
14.
de AlmeidaLNF, CarolinoRM, SperandioDC, et al. (2009) The role of molecular genetic factors in age-related macular degeneration. Arq Bras Oftalmol, 72:567-572.
15.
de CordobaSR, de JorgeEG (2008) Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol, 151:1-13.
16.
de JongPT (2006) Age-related macular degeneration. N Engl J Med, 355:1474-1485.
17.
DesprietDD, van DuijnCM, OostraBA, et al. (2009) Complement component C3 and risk of age-related macular degeneration. Ophthalmology, 116:474.e472-480.e472.
18.
DuvvariMR, PaunCC, BuitendijkGH, et al. (2014) Analysis of rare variants in the C3 gene in patients with age-related macular degeneration. PLoS One, 9:e94165.
19.
EdwardsAO, FridleyBL, JamesKM, et al. (2008) Evaluation of clustering and genotype distribution for replication in genome wide association studies: the age-related eye disease study. PLoS One, 3:e3813.
20.
EggerM, Davey SmithG, SchneiderM, et al. (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ, 315:629-634.
21.
FarwickA, DaschB, WeberBH, et al. (2009) Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study. Eye (Lond), 23:2238-2244.
22.
FrancisPJ, HamonSC, OttJ, et al. (2009) Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet, 46:300-307.
23.
FriedmanDS, O'ColmainBJ, MunozB, et al. (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol, 122:564-572.
24.
GoldB, MerriamJE, ZernantJ, et al. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet, 38:458-462.
25.
GotoA, AkahoriM, OkamotoH, et al. (2009) Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor, 2:164-175.
26.
GotohN, YamadaR, HirataniH, et al. (2006) No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet, 120:139-143.
27.
HagemanGS, AndersonDH, JohnsonLV, et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A, 102:7227-7232.
28.
HamptonT (2010) Genetic research provides insights into age-related macular degeneration. JAMA, 304:1541-1543.
29.
HavvasI, MarioliDI, DeliA, et al. (2014) Complement C3, C2, and factor B gene polymorphisms and age-related macular degeneration in a Greek cohort study. Eur J Ophthalmol, 24:751-760.
30.
HeckerLA, EdwardsAO, RyuE, et al. (2010) Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Hum Mol Genet, 19:209-215.
31.
HelgasonH, SulemP, DuvvariMR, et al. (2013) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet, 45:1371-1374.
32.
HigginsJP, ThompsonSG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med, 21:1539-1558.
33.
HolzFG, StraussEC, Schmitz-ValckenbergS, et al. (2014) Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology, 121:1079-1091.
34.
HuangL, LiY, GuoS, et al. (2014) Different hereditary contribution of the CFH gene between polypoidal choroidal vasculopathy and age-related macular degeneration in Chinese Han people. Invest Ophthalmol Vis Sci, 55:2534-2538.
35.
HuangL, MengQ, ZhangC, et al. (2015) Gene-gene interaction of CFH, ARMS2, and ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population. Eye (Lond), 29:691-698.
36.
IngramG, HakobyanS, RobertsonNP, et al. (2009) Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol, 155:128-139.
37.
JakobsdottirJ, ConleyYP, WeeksDE, et al. (2008) C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One, 3:e2199.
38.
KaurI, KattaS, ReddyRK, et al. (2010) The involvement of complement factor B and complement component C2 in an Indian cohort with age-related macular degeneration. Invest Ophthalmol Vis Sci, 51:59-63.
39.
KhandhadiaS, CiprianiV, YatesJRW, et al. (2012) Age-related macular degeneration and the complement system. Immunobiology, 217:127-146.
40.
KimSJ, LeeSJ, KimNR, et al. (2012) Association of polymorphisms in C2, CFB and C3 with exudative age-related macular degeneration in a Korean population. Exp Eye Res, 96:42-47.
41.
KimYH, KimHS, MokJW, et al. (2013) Gene-gene interactions of CFH and LOC387715/ARMS2 with Korean exudative age-related macular degeneration patients. Ophthalmic Genet, 34:151-159.
42.
KleinML, SchultzDW, EdwardsA, et al. (1998) Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol, 116:1082-1088.
43.
LiM, Atmaca-SonmezP, OthmanM, et al. (2006) CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet, 38:1049-1054.
44.
LiuX, ZhaoP, TangS, et al. (2010) Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population. Retina, 30:1177-1184.
45.
LoyetKM, DeForgeLE, KatschkeKJ, et al. (2012) Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. Invest Ophthalmol Vis Sci, 53:6628-6637.
46.
LuF, ShiY, QuC, et al. (2013) A genetic variant in the SKIV2L gene is significantly associated with age-related macular degeneration in a Han Chinese population. Invest Ophthalmol Vis Sci, 54:2911-2917.
47.
MallerJ, GeorgeS, PurcellS, et al. (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet, 38:1055-1059.
48.
Martinez-BarricarteR, RecaldeS, Fernandez-RobredoP, et al. (2012) Relevance of complement factor H-related 1 (CFHR1) genotypes in age-related macular degeneration. Invest Ophthalmol Vis Sci, 53:1087-1094.
49.
McKayGJ, SilvestriG, PattersonCC, et al. (2009) Further assessment of the complement component 2 and factor B region associated with age-related macular degeneration. Invest Ophthalmol Vis Sci, 50:533-539.
50.
MerleBM, SilverRE, RosnerB, et al. (2016) Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study. Am J Clin Nutr, 103:1135-1144.
51.
MontesT, TortajadaA, MorganBP, et al. (2009) Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci U S A, 106:4366-4371.
52.
MoriK, GehlbachPL, KabasawaS, et al. (2007) Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci, 48:5315-5319.
53.
NakataI, YamashiroK, YamadaR, et al. (2012) Significance of C2/CFB variants in age-related macular degeneration and polypoidal choroidal vasculopathy in a Japanese population. Invest Ophthalmol Vis Sci, 53:794-798.
54.
NgTK, ChenLJ, LiuDT, et al. (2008) Multiple gene polymorphisms in the complement factor h gene are associated with exudative age-related macular degeneration in Chinese. Invest Ophthalmol Vis Sci, 49:3312-3317.
55.
ParkKH, FridleyBL, RyuE, et al. (2009) Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci, 50:3386-3393.
56.
ParmeggianiF, RomanoMR, CostagliolaC, et al. (2012) Mechanism of inflammation in age-related macular degeneration. Mediators Inflamm, 2012:546786.
57.
PeiXT, LiXX, BaoYZ, et al. (2009) Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a Chinese population. Curr Eye Res, 34:615-622.
58.
Qian-QianY, YongY, JingZ, et al. (2015) Nonsynonymous single nucleotide polymorphisms in the complement component 3 gene are associated with risk of age-related macular degeneration: a meta-analysis. Gene, 561:249-255.
59.
RestrepoNA, SpencerKL, GoodloeR, et al. (2014) Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study. Invest Ophthalmol Vis Sci, 55:6839-6850.
60.
ReynoldsR, HartnettME, AtkinsonJP, et al. (2009) Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci, 50:5818-5827.
61.
RichardsonAJ, IslamFM, GuymerRH, et al. (2009) Analysis of rare variants in the complement component 2 (C2) and factor B (BF) genes refine association for age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci, 50:540-543.
62.
RodriguezE, RallapalliPM, OsborneAJ, et al. (2014) New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3. Biosci Rep, 34:635-649.
63.
Rodriguez de CordobaS, Esparza-GordilloJ, Goicoechea de JorgeE, et al. (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol, 41:355-367.
64.
Schmitz-ValckenbergS, MossnerA, FleckensteinM, et al. (2010) Therapy approaches for geographic atrophy [in German]. Ophthalmologe, 107:1016-1019.
65.
SchollHP, Charbel IssaP, WalierM, et al. (2008) Systemic complement activation in age-related macular degeneration. PLoS One, 3:e2593.
66.
SchrammEC, ClarkSJ, TriebwasserMP, et al. (2014) Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol Immunol, 61:118-125.
67.
SeddonJM, ReynoldsR, RosnerB (2009) Peripheral retinal drusen and reticular pigment: association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci, 50:586-591.
68.
SeddonJM, ReynoldsR, YuY, et al. (2014) Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration. PLoS One, 9:e87047.
69.
SeddonJM, SilverRE, RosnerB (2016) Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol, 100:1731-1737.
70.
SmailhodzicD, KlaverCC, KleveringBJ, et al. (2012) Risk alleles in CFH and ARMS2 are independently associated with systemic complement activation in age-related macular degeneration. Ophthalmology, 119:339-346.
71.
SpencerKL, HauserMA, OlsonLM, et al. (2007) Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet, 16:1986-1992.
72.
SpencerKL, OlsonLM, AndersonBM, et al. (2008) C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet, 17:1821-1824.
73.
StangA (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 25:603-605.
74.
SunC, ZhaoM, LiX (2012) CFB/C2 gene polymorphisms and risk of age-related macular degeneration: a systematic review and meta-analysis. Curr Eye Res, 37:259-271.
75.
TanakaK, NakayamaT, MoriR, et al. (2014) Associations of complement factor B and complement component 2 genotypes with subtypes of polypoidal choroidal vasculopathy. BMC Ophthalmol, 14:83.
76.
TianJ, YuW, QinX, et al. (2012) Association of genetic polymorphisms and age-related macular degeneration in Chinese population. Invest Ophthalmol Vis Sci, 53:4262-4269.
77.
WangZY, ZhaoK, ZhengJ, et al. (2014) Systematic review and meta-analysis of the association between complement factor H I62V polymorphism and risk of polypoidal choroidal vasculopathy in Asian populations. PLoS One, 9:e88324.
78.
WuL, TaoQ, ChenW, et al. (2013) Association between polymorphisms of complement pathway genes and age-related macular degeneration in a Chinese population. Invest Ophthalmol Vis Sci, 54:170-174.
79.
WuM, GuoY, MaY, et al. (2016) Association of two polymorphisms, rs1061170 and rs1410996, in complement factor H with age-related macular degeneration in an Asian population: a meta-analysis. Ophthalmic Res, 55:135-144.
80.
YatesJR, SeppT, MatharuBK, et al. (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med, 357:553-561.
81.
ZhuangW, LiH, LiuY, et al. (2014) Association of specific genetic polymorphisms with age-related macular degeneration in a northern Chinese population. Ophthalmic Genet, 35:156-161.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
