Free
Genetics  |   June 2012
Association of Genetic Polymorphisms and Age-Related Macular Degeneration in Chinese Population
Author Affiliations & Notes
  • Jun Tian
    Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China;
  • Wenzhen Yu
    Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, People's Republic of China;
  • Xueying Qin
    Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China;
  • Kai Fang
    Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China;
  • Qing Chen
    Department of Hygiene Toxicology, Preventive Medical College, Third Military Medical University, Chongqing, People's Republic of China; and
  • Jing Hou
    Department of Ophthalmology, Peking University People's Hospital, Beijing, People's Republic of China;
    Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, People's Republic of China;
  • Juan Li
    Beijing Centers of Disease Control and Prevention, Beijing, People's Republic of China.
  • Dafang Chen
    Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China;
  • Yonghua Hu
    Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China;
  • Xiaoxin Li
    Department of Ophthalmology, Peking University People's Hospital, Beijing, People's Republic of China;
    Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, People's Republic of China;
  • * Each of the following is a corresponding author: Yonghua Hu, Department of Epidemiology and Biostatistics, Peking University Health Science Center, 38 Xueyuan Rd., Haidian District, Beijing 100191, P.R.China; yhhu@bjmu.edu.cn.  
  • Xiaoxin Li, Department of Ophthalmology, Peking University People's Hospital, 11 Xizhimen South St., Xicheng District, Beijing 100044, P.R.China; dr_lixiaoxin@163.com
Investigative Ophthalmology & Visual Science June 2012, Vol.53, 4262-4269. doi:https://doi.org/10.1167/iovs.11-8542
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Jun Tian, Wenzhen Yu, Xueying Qin, Kai Fang, Qing Chen, Jing Hou, Juan Li, Dafang Chen, Yonghua Hu, Xiaoxin Li; Association of Genetic Polymorphisms and Age-Related Macular Degeneration in Chinese Population. Invest. Ophthalmol. Vis. Sci. 2012;53(7):4262-4269. doi: https://doi.org/10.1167/iovs.11-8542.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose.: We explored associations between age-related macular degeneration (AMD) and genetic variants of 10 genes in a nationwide Chinese population.

Methods.: In this multicenter case-control study, 535 AMD patients and 469 controls were recruited from 16 centers that spread from the north to the south of China. All participants underwent comprehensive eye examinations, and 40 single nucleotide polymorphisms (SNPs) of 10 genes were selected. DNA samples were genotyped with the MassArray system. The effect of the genotypes and haplotypes on AMD was assessed with logistic regression analysis, adjusted for age, sex, long-term residence, and family origin.

Results.: In our study, 11 SNPs in complement H (CFH), 2 in age-related maculopathy susceptibility 2 (ARMS2), and 2 in high-temperature requirement factor A1 (HTRA1) were associated significantly with AMD. They were rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs10733086, rs10737680, rs2274700, rs1410996, and rs380390 in CFH; rs10490924 and rs2736912 in ARMS2; and rs11200638 and rs3793917 in HTRA1. Three haplotypes in CFH, predisposed the patients significantly to AMD (P < 0.001, P = 0.001, and P < 0.001, respectively). With the sample size of our study, no relationship was found for AMD and the SNPs tested in complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC); and metallopeptidase inhibitor 3 (TIMP3) genes.

Conclusions.: Gene variants in CFH, ARMS2, and HTRA1 contribute to AMD in the Chinese population.

Introduction
Age-related macular degeneration (AMD) affects elder adults and there is no effective treatment against it. In the developed world, AMD accounts for approximately half of all vision impairment or blind registrations. 1 In Asia, the pooled prevalence is 6.8% for early AMD and 0.56% for advanced AMD in populations between 40 and 79 years old. 2 For Chinese, some regional studies indicated that the prevalence of early AMD ranges from 4.7%–9.2% and that of the advanced AMD from 0.2–1.9% in elderly people. 3,4  
Despite the fact that AMD greatly impairs quality of life, its etiology remains unclear. The prevailing view on AMD etiology is that the genetic factor might have an important role. 5,6 So far, studies about the genetic background of AMD have reported tremendous progress in identifying the polymorphisms in three genes to be highly associated with AMD in different ethnic groups: complement H (CFH), age-related maculopathy susceptibility 2 (ARMS2, also known as LOC387715), and high-temperature requirement factor A1 (HTRA1). 713  
Several studies indicated that the genetic variants of other genes conferred disease risk in Caucasian populations, namely complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC), and metallopeptidase inhibitor 3 (TIMP3). 1422 However, a few studies in China and Japan reported that there were no significant contributions from C3 (rs2230199, rs1047286), SERPING1 (rs2511989, rs1005510), and VEGF (rs3025039) to AMD, 7,2326 whereas a study in Taiwan reported that VEGF (rs3025039) polymorphism was associated with wet AMD. 27 So far, to our knowledge no more convincing data have been reported about the relationship between AMD and these genetic variants in the Chinese population. Therefore, we conducted the current study to investigate the association between multiple genetic polymorphisms and AMD in a nationwide Chinese population. 
Materials and Methods
AMD Patients and Control Subjects
The current study was part of the hospital-based multicenter project of Clinical Features and Interventions of AMD supported by the Ministry of Science and Technology of China (Grant No. 2006BAI02B05). People's Hospital, and the Department of Epidemiology and Biostatistics of Peking University led the study. To represent the Chinese population comprehensively, 16 local hospitals located sporadically in the northern and southern parts of China were selected as the research centers. All researchers in these local hospitals received training about the diagnosis of AMD, inclusion and exclusion criteria of the participants, and specimen collection, which was conducted by the ophthalmologists of People's Hospital, and experts of the Department of Epidemiology and Biostatistics. PASS software (Version 08.0.3; NCSS, LLC, Kaysville, UT) was used to calculated the sample size (α = 0.05, β = 0.20). According to the frequencies of the risk allele of single nucleotide polymorphisms (SNPs) that have been reported, 485 patients and 485 controls were needed. The hospitals with a large AMD patient capacity were planned to recruit 40 patients and 40 controls, and the hospitals with a small capacity were planned to recruit 20 patients and 20 controls. After strictly re-checking by the reading center of Peking University People's Hospital, 535 patients and 469 controls were eligible. The project was approved by the Ethics Committee of Peking University People's Hospital, and the procedures were consistent with the Declaration of Helsinki. All AMD patients and controls provided written informed consent. 
Participants were enrolled from the ophthalmologic department of the 16 hospitals between 2008 and 2010. All of them received ophthalmologic examinations, including slit-lamp biomicroscopy and funduscopy. If they were revealed as having AMD by funduscopy, the patients would be examined further with fluorescence fundus angiography (FFA) (Topcon TRC-50EX; Topcon, Tokyo, Japan), indocyanine green angiography (ICGA) (Heidelberg Spectralis HRA; Heidelberg Engineering, Heidelberg, Germany), or optical coherence tomography (OCT) (Zeiss-Humphrey, Dublin, CA). When confirmed by any of the three tests, the AMD patients would be included if they were 50 years or older and had no signs of other retinal diseases. Patients were excluded if they had polypoidal choroidal vasculopathy (PCV), myopia of 6.00 diopters (D) or above, macular dystrophy, central serous chorioretinopathy, any kind of vein occlusion, diabetic retinopathy, uveitis, other diseases involving malfunction of retinal photoreceptor cells, or serious chronic diseases. Visitors who went to the ophthalmologic department were taken as controls if they were 50 years or older, confirmed negative for AMD with fundus examination, had no signs of other retinal diseases, or had no serious chronic diseases. In the end, we recruited 535 unrelated Chinese patients with AMD and 469 controls (Table 1). 
Table 1. 
 
Number of Patients and Controls of the 16 Hospitals
Table 1. 
 
Number of Patients and Controls of the 16 Hospitals
Hospital City Province/Municipality Patients Controls
The Second Affiliated Hospital of Harbin Med Univ. Harbin Heilongjiang 40 34
The First Affiliated Hospital of Harbin Med Univ. Harbin Heilongjiang 42 38
The First Hospital of China Med Univ. Shenyang Liaoning 40 32
Peking University First Hospital Beijing Beijing 19 21
Peking University People's Hospital Beijing Beijing 26 17
Peking Union Medical College Hospital Beijing Beijing 37 9
The General Hospital of The People's Liberation Army Beijing Beijing 19 18
Shandong Eye Institute Qingdao Shandong 35 21
Xijing Hospital Xi'an Shaanxi 39 40
Jiangsu Province Hospital Nanjing Jiangsu 19 20
Renmin Hospital of Wuhan Univ. Wuhan Hubei 31 39
Shanghai First People's Hospital Shanghai Shanghai 41 39
West China Medical School-West China Hospital Chengdu Sichuan 40 26
The Affiliated Eye Hospital of Wenzhou Medical College Wenzhou Zhejiang 37 37
The Second Xiangya Hospital of Central South Univ. Changsha Hunan 32 39
Zhongshan Ophthalmic Center Guangzhou Guangdong 38 39
Total
 16 12 12 535 469
Classification of Age-Related Macular Degeneration
Fundus photographs taken at local hospitals were reviewed by the experts of People's Hospital. Stages of AMD were assigned based on the classification of the Age-Related Eye Disease Study (AREDS). 28 Early AMD was considered drusen with or without pigmentary abnormalities and in the absence of signs of advanced AMD. Advanced AMD was considered atrophic or neovascular AMD. Atrophic AMD was identified when geographic atrophy forms by depigmentation of the RPE and exposure of underlying choroidal vessels, and when neovascular AMD is absent. Neovascular AMD was identified when a patient had choroidal neovascularization (CNV), sensory retinal detachment, RPE serous/hemorrhagic detachment, subretinal/sub-RPE fibrosis, or disciform scars. 
Genotyping
To analyze genetic polymorphisms of AMD, we selected 40 SNPs in 10 genes for their association with AMD (Table 2). Genomic DNA was extracted from the peripheral blood with a DNA extraction kit (DP319-01; Tiangen Biotech, Beijing, China). The PCR was performed on a thermal cycler (ABI GeneAmp 9700 384 Dual; ABI, Foster City, CA). Genotypes were analyzed with Typer 4.0 software (MassARRAY Compact System; Sequenom, San Diego, CA). All SNPs in this report had a genotyping success rate of >97%. 
Table 2. 
 
The SNPs Selected of the 10 Genes
Table 2. 
 
The SNPs Selected of the 10 Genes
Gene SNPs
CFH rs3753394, rs7524776, rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs6695321, rs10733086, rs10737680, rs2274700, rs3753396, rs1410996, rs380390
ARMS2 rs10490924, rs2736912
HTRA1 rs3793917, rs11200638
C3 rs11569562, rs7257062, rs408290, rs8112351, rs2230205, rs1047286, rs2230199, rs2250656
SERPING1 rs1005510, rs2511989
VEGF rs833069, rs3025039
CETP rs173539, rs17231506, rs9939224, rs1532625, rs2303789, rs289744
nearby LPL rs12678919
nearby LIPC rs10468017
nearby TIMP3 rs9621532
Statistical Analysis
We compared the genotypes of the AMD patients to those of the controls using the χ 2 test. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the effect of genotype on the risk of AMD were estimated by the logistic regression analysis. Hardy-Weinberg equilibrium for each SNP polymorphism was tested by the χ 2 test. All the above analyses were performed with SPSS software (version 15.0 for Windows; SPSS Inc., Chicago, IL). Permutation was used to correct for multiple testing. The linkage disequilibrium (LD), haplotypes (confidence intervals algorithm proposed by Gabriel et al. 29 ) and the corrected probabilities estimated by the permutation test were examined with Haploview software (provided in the public domain, http://www.broadinstitute.org/haploview/haploview, version 4.1, April, 2008). The adjusted ORs of the haplotypes were calculated by logistic regression analysis via PLINK software (provided in the public domain, http://pngu.mgh.harvard.edu/∼purcell/plink, version 1.07, August 2009, accessed March 2011). P < 0.05 was considered statistically significant. 
Results
Of the 535 AMD patients 64 (12.0%) had early and 471 (88.0%) had advanced AMD. Among the patients with advanced AMD 464 (98.5%) had neovascular and 7 (1.5%) had atrophic AMD. There were more males in the patient group than in controls (P < 0.001) and the patients were significantly elder than controls (P < 0.001). There was no significant difference of the nationality between patients and controls (P = 0.307). The percentage of patients among the participants in the north was higher than that of the south (P = 0.025). There were more patients with family origin in the north than in the south (P = 0.043, Table 3). Because a significant difference was found in sex, age, long-term residence, and family origin in patients and controls, the following estimation of ORs were adjusted by logistic regression analysis. 
Table 3. 
 
Demographic Characteristics of AMD Patients and Controls
Table 3. 
 
Demographic Characteristics of AMD Patients and Controls
Controls Patients
All AMD Early AMD Advanced AMD
n n P* n P* n P*
Sex <0.001 0.119 <0.001
 Male 217 324 23 301
 Female 252 211 41 170
Age <0.001 0.139 <0.001
 50∼ 155 106 14 92
 60∼ 157 168 28 140
 70∼ 157 261 22 239
Nationality 0.307 0.403 0.205
 Han 450 516 63 453
 Minorities 5 10 0 10
Long-term residence 0.025 0.001 0.125
 North of China 225 297 45 252
 South of China 238 236 18 218
Family origin 0.043 0.001 0.202
 North of China 227 295 46 249
 South of China 236 237 18 219
All 40 SNPs but rs173539 showed no significant deviation from Hardy-Weinberg equilibrium in the control group (P > 0.05). The genotype frequencies for patients and controls are shown in Table 4. The risk allele frequencies of 11 SNPs tested in CFH, and 4 SNPs tested in ARMS2 and HTRA1 were significantly different between AMD patients and controls. The positive SNPs showed the same association with advanced and neovascular AMD. Other tested SNPs of C3, SERPING1, VEGF, CETP, LPL, LIPC, and TIMP3 did not reach the level of significance between AMD patients and controls. 
Table 4. 
 
Gene Variants Observed in AMD Patients and Controls
Table 4. 
 
Gene Variants Observed in AMD Patients and Controls
Gene dbSNP ID Risk Allele Genotype Frequency
Controls* All AMD* P corr Early AMD* P Advanced AMD* P corr Neovascular AMD* P corr
CFH rs3753394 T 131/230/102 181/244/104 0.343 20/29/14 1.000 161/215/90 0.287 158/212/89 0.286
rs7524776 C 1/46/416 3/50/480 1.000 0/7/57 1.000 3/43/423 1.000 3/42/417 1.000
rs551397 G 157/224/75 248/213/55 <0.001 26/27/9 0.917 222/186/46 <0.001 218/183/46 <0.001
rs800292 C 158/221/76 249/205/56 <0.001 26/26/9 0.901 223/179/47 <0.001 219/176/47 <0.001
rs1329424 A 1/51/412 9/93/427 0.001 1/5/57 1.000 8/88/370 <0.001 8/86/365 <0.001
rs1061170 C 1/49/395 9/89/391 0.001 1/6/55 1.000 8/83/336 <0.001 8/81/331 <0.001
rs10801555 A 1/51/408 9/91/425 0.002 1/6/57 1.000 8/85/368 <0.001 8/83/363 <0.001
rs12124794 A 188/216/56 264/213/49 0.031 26/27/10 0.999 238/186/39 0.008 233/184/39 0.012
rs6695321 A 8/113/343 13/138/377 0.911 1/11/51 0.872 12/127/326 0.690 11/126/321 0.675
rs10733086 A 1/65/397 10/113/410 0.001 1/7/56 1.000 9/106/354 <0.001 8/105/349 <0.001
rs10737680 A 153/223/92 234/230/67 <0.001 23/27/13 1.000 211/203/54 <0.001 206/201/54 <0.001
rs2274700 C 137/216/88 231/216/63 <0.001 24/26/12 0.955 207/190/51 <0.001 202/188/51 <0.001
rs3753396 G 105/239/120 156/253/123 0.205 19/28/17 0.990 137/225/106 0.205 134/222/105 0.218
rs1410996 C 148/224/92 235/228/67 <0.001 23/27/13 0.999 212/201/54 <0.001 207/199/54 <0.001
rs380390 C 1/45/401 9/97/408 <0.001 1/6/55 0.998 8/91/353 <0.001 8/89/348 <0.001
ARMS2 rs10490924 T 97/223/147 251/197/82 <0.001 18/29/16 0.282 233/168/66 <0.001 228/166/66 <0.001
rs2736912 C 358/91/11 460/68/3 0.001 51/13/0 0.7580 409/55/3 <0.001 402/55/3 <0.001
HTRA1 rs3793917 C 92/221/141 256/190/79 <0.001 20/27/16 0.111 236/163/63 <0.001 231/161/63 <0.001
rs11200638 A 104/224/140 255/193/84 <0.001 19/28/16 0.309 236/165/68 <0.001 231/163/68 <0.001
C3 rs11569562 C 134/228/101 144/284/102 1.000 20/29/14 1.000 124/255/88 1.000 123/250/87 1.000
rs7257062 T 250/177/37 289/210/32 0.997 34/23/6 1.000 255/187/26 0.989 251/184/26 0.992
rs408290 C 323/127/15 390/127/12 0.675 52/10/1 0.285 338/117/11 0.906 333/115/11 0.905
rs8112351 C 383/74/4 449/76/4 0.998 58/5/0 0.402 391/71/4 1.000 385/70/4 1.000
rs2230205 A 107/221/137 130/246/156 1.000 16/31/17 0.999 114/215/139 1.000 113/210/138 1.000
rs1047286 T 0/1/455 0/2/525 1.000 0/0/63 1.000 0/2/462 1.000 0/2/455 0.999
rs2230199 G 0/2/463 0/4/528 0.995 0/0/63 1.000 0/4/465 0.982 0/4/458 0.969
rs2250656 A 273/164/21 329/171/23 0.951 41/19/4 1.000 288/152/19 0.936 283/150/19 0.948
SERPING1 rs1005510 G 28/181/256 37/201/293 0.968 5/21/38 0.951 32/180/255 0.921 32/178/250 0.876
rs2511989 A 7/86/371 13/96/422 0.837 3/9/51 0.866 10/87/371 0.856 10/86/365 0.848
VEGF rs833069 A 155/227/84 190/253/89 0.629 27/28/8 0.209 163/225/81 0.863 161/222/79 0.835
rs3025039 C 302/143/18 341/179/13 0.998 40/22/2 0.958 301/157/11 0.990 299/153/10 0.931
CETP rs173539‡ T 14/4/397 19/6/465 0.984 2/0/59 0.982 17/6/406 0.959 17/6/400 0.943
rs17231506 T 18/116/331 15/150/364 0.992 1/21/41 0.992 14/129/323 0.999 14/126/319 0.999
rs9939224 T 5/84/374 9/94/427 1.000 1/8/53 0.982 8/86/374 0.996 8/86/367 0.989
rs1532625 A 45/172/248 43/226/262 0.980 3/29/31 1.000 40/197/231 0.968 39/193/229 0.982
rs2303789 T 320/131/14 388/130/14 0.707 46/16/2 0.999 342/114/12 0.700 338/112/11 0.613
rs289744 A 211/193/37 260/210/49 1.000 32/27/5 0.999 228/183/44 1.000 225/179/44 1.000
LPL rs12678919 A 386/76/5 438/86/5 0.939 51/11/1 0.746 387/75/4 0.876 380/75/4 0.936
LIPC rs10468017 C 316/136/10 374/145/11 0.492 45/17/1 0.693 329/128/10 0.563 325/125/10 0.525
TIMP3 rs9621532 A 439/26/0 510/22/0 0.306 60/4/0 1.000 450/18/0 0.214 443/18/0 0.278
The adjusted ORs, 95% CIs, and P values of the positive SNPs are shown in Table 5. The homozygosity of risk alleles for five SNPs in CFH (rs551397, rs800292, rs10737680, rs2274700, rs1410996) and one SNP in ARMS2 (rs2736912) conferred a 2.11-fold (95% CI, 1.41–3.26), 2.13-fold (95% CI, 1.41–3.23), 2.01-fold (95% CI, 1.37–2.97), 2.26-fold (95% CI, 1.52–3.38), 2.08-fold (95% CI, 1.41–3.07), and 4.83-fold (95% CI, 1.31–17.83) increased likelihood of AMD. Five SNPs in CFH (rs1329424, rs1061170, rs10801555, rs10733086, rs380390), one in ARMS2 (rs10490924) as well as the two in HTRA1 (rs11200638, rs3793917) showed significant association with AMD for heterozygosity and homozygosity of risk alleles. The homozygosity of risk alleles for rs12124794 in CFH conferred a 1.63-fold (95% CI, 1.02–2.61) risk of advanced AMD. 
Table 5. 
 
Estimated ORs, P Values of CFH, ARMS2, and HTRA1 Gene Variants
Table 5. 
 
Estimated ORs, P Values of CFH, ARMS2, and HTRA1 Gene Variants
dbSNP ID All AMD Patients Advanced AMD Patients
ORhetero (95% CI)* P* ORhomo (95% CI)† P ORhetero (95% CI)* P* ORhomo (95% CI)† P
CFH
 rs551397 1.18 (0.78–1.78) 0.427 2.11 (1.41–3.26) <0.001 1.24 (0.80–1.91) 0.339 2.29 (1.48–3.56) <0.001
 rs800292 1.17 (0.77–1.75) 0.465 2.13 (1.41–3.23) <0.001 1.21 (0.78–1.86) 0.387 2.28 (1.48–3.53) <0.001
 rs1329424 1.73 (1.19–2.53) 0.004 8.15 (1.02–65.44) 0.048 1.86 (1.27–2.73) 0.002 8.37 (1.03–68.39) 0.047
 rs1061170 1.86 (1.27–2.74) 0.002 8.50 (1.06–68.38) 0.044 1.98 (1.34–2.95) 0.001 8.84 (1.08–72.39) 0.042
 rs10801555 1.71 (1.17–2.50) 0.005 8.15 (1.02–65.42) 0.048 1.81 (1.23–2.66) 0.003 8.38 (1.03–68.40) 0.047
 rs12124794 0.93 (0.60–1.45) 0.747 1.46 (0.94–2.28) 0.093 1.00 (0.62–1.60) 0.988 1.63 (1.02–2.61) 0.043
 rs10733086 1.66 (1.18–2.34) 0.004 9.40 (1.19–74.59) 0.034 1.76 (1.24–2.50) 0.002 9.73 (1.21–78.26) 0.032
 rs10737680 1.22 (0.84–1.78) 0.303 2.01 (1.37–2.97) <0.001 1.29 (0.86–1.93) 0.217 2.21 (1.46–3.34) <0.001
 rs2274700 1.22 (0.83–1.80) 0.309 2.26 (1.52–3.38) <0.001 1.29 (0.85–1.94) 0.234 2.45 (1.60–3.74) <0.001
 rs1410996 1.21 (0.83–1.77) 0.318 2.08 (1.41–3.07) <0.001 1.28 (0.86–1.92) 0.229 2.28 (1.51–3.44) <0.001
 rs380390 2.07 (1.40–3.05) <0.001 8.83 (1.10–70.72) 0.040 2.19 (1.48–3.26) <0.001 9.04 (1.11–73.53) 0.040
ARMS2
 rs10490924 1.51 (1.07–2.12) 0.018 4.25 (2.94–6.13) <0.001 1.62 (1.13–2.34) 0.009 4.90 (3.33–7.21) <0.001
 rs2736912 2.64 (0.69–10.06) 0.156 4.83 (1.31–17.83) 0.018 2.10 (0.54–8.12) 0.282 4.35 (1.17–16.22) 0.028
HTRA1
 rs3793917 1.56 (1.03–2.06) 0.033 4.56 (3.14–6.64) <0.001 1.58 (1.09–2.30) 0.016 5.31 (3.58–7.88) <0.001
 rs11200638 1.41 (1.01–1.99) 0.048 3.82 (2.65–5.49) <0.001 1.51 (1.05–2.18) 0.027 4.42 (3.01–6.48) <0.001
With the exception of rs3753394, all SNPs genotyped in CFH were included within three haplotype blocks (see Fig.). The frequencies, P values, and ORs for haplotypes with a frequency greater than 5% are shown in Table 6. There were three SNPs within the first block: rs7524776 (intron), rs551397 (intron), and rs800292 (exon, Val62Ile). The haplotypes TGC and TAT showed significant association with AMD (TGC OR = 1.52, P corr < 0.001 for all AMD, and OR = 1.57, P corr < 0.001 for advanced AMD; TAT OR = 0.64, P corr < 0.001 for all AMD, and OR = 0.62, P corr < 0.001 for advanced AMD). After permutation, these two haplotypes remained significant. Block 2 contained seven SNPs: rs1329424 (intron), rs1061170 (exon, Tyr402His), rs10801555 (intron), rs12124794 (intron), rs6695321 (intron), rs10733086 (intron), and rs10737680 (intron). Only the haplotype ACAAAAA predisposed significantly to AMD after permutation (OR = 1.92, P corr = 0.001 for all AMD, and OR = 2.05, P corr < 0.001 for advanced AMD). Block 3 contained four SNPs: rs2274700 (exon, Ala473Ala), rs3753396 (exon, Gln672Gln), rs1410996 (intron), and rs380390 (intron). The haplotypes TATG and CACC were associated significantly with AMD (TATG OR = 0.63, P corr < 0.001 for all AMD, and OR = 0.60, P corr < 0.001 for advanced AMD; CACC OR = 2.27, P corr < 0.001 for all AMD, and OR = 2.39, P corr < 0.001 for advanced AMD). 
Figure. 
 
LD between the polymorphism in the complement factor H gene. The D between any two single nucleotide polymorphisms is listed in the cross cells.
Figure. 
 
LD between the polymorphism in the complement factor H gene. The D between any two single nucleotide polymorphisms is listed in the cross cells.
Table 6.  
 
Haplotype Analysis of the CFH Gene
Table 6.  
 
Haplotype Analysis of the CFH Gene
Haplotype Controls All AMD Patients Advanced AMD Patients
Freq. Freq. P/P corr* OR† Freq. P/P corr* OR†
Block1: rs7524776, rs551397, rs800292
 TGC 0.59 0.68 <0.001/<0.001 1.52 0.69 <0.001/<0.001 1.57
 TAT 0.36 0.27 <0.001/<0.001 0.64 0.26 <0.001/<0.001 0.62
 CAT 0.05 0.05 0.88/1.00 NS 0.05 0.90/1.00 NS
Block2: rs1329424, rs1061170, rs10801555, rs12124794, rs6695321, rs10733086, rs10737680
 CTGAGTA 0.49 0.53 0.09/0.57 NS 0.54 0.051/0.43 NS
 CTGTGTC 0.35 0.30 0.01/0.06 0.78 0.28 0.002/0.02 0.74
 ACAAAAA 0.06 0.11 <0.001/ 0.001 1.92 0.11 <0.001/<0.001 2.05
Block3: rs2274700, rs3753396, rs1410996, rs380390
 CGCG 0.48 0.53 0.03/0.22 1.22 0.53 0.03/0.23 1.23
 TATG 0.44 0.34 <0.001/<0.001 0.63 0.33 <0.001/<0.001 0.60
 CACC 0.06 0.11 <0.001/<0.001 2.27 0.11 <0.001/<0.001 2.39
Discussion
Our study described the genotype characteristics of AMD in a Chinese population, which revealed a significant association between AMD and CFH, ARMS2, and HTRA1 gene variants. With the current sample size, we did not find a significant association between AMD and the genetic variants of C3, SERPING1, VEGF, CETP, LPL, LIPC, and TIMP3 genes. 
CFH has been identified by various studies as a major AMD susceptible gene in the Chinese, Japanese, and Caucasian populations, 7,8,11,12,26 which is consistent with our study. The frequency of the risk allele of rs1061170, which has been identified as an important genetic variant in CFH for developing AMD in Caucasians, is lower in the Chinese population (10.9% for C allele in our study) compared to Caucasians (34.9% for C allele). 30 This may explain why some studies, especially those with small sample size, failed to find the association between this SNP and AMD in Chinese populations. 8,31 In our study, rs1061170 was associated significantly with AMD, though not as strong as in the Caucasian population. We also found out that other genetic variants in CFH, including rs551397, rs800292, rs1410996, rs2274700, rs380390, rs1329424, rs10801555, and rs10737680, were associated with AMD, and this is consistent with some previous studies. 7,8,23,26,3234 Moreover, our study found that rs12124794 and rs10733086 in CFH were associated significantly with AMD. Both of these SNPs are intron and their molecular effects still are not clear. After adjusting for rs2274700, rs12124794 did not reach the significant level (P = 0.075). Meanwhile, after adjusting for rs1061170, rs10733086 did not reach the significant level (P = 0.723). Therefore, these two SNPs might not associate with AMD independently and they might just reflect the effect of the known SNPs that are in linkage disequilibrium with them. Furthermore, we found three haplotype blocks. Each of the first two haplotypes contained one SNP that encoded for a missense amino acid change, whereas 2 SNPs in block 3 encoded for synonymous changes. The haplotypes composed by the detrimental alleles of SNPs that had significant association with AMD in the single association analysis conferred a 1.52 (TGC), 1.92 (ACAAAAA), and 2.27 (CACC)-fold increased risk of AMD, whereas the haplotypes that contained the non-detrimental alleles had evident protective effect. Our results regarding the block containing rs551397 and rs800292, and another block containing rs2274700 and rs3753396 are consistent with the previous reports. However, there was a difference in haplotypes between Caucasian and Asian populations. In Caucasians, rs1061170 was in the same block with rs551397 and rs800292, while studies in an Asian population, which were consistent with our results, found that rs1061170 did not occur in the same block with rs551397 and rs80029. 8,33  
In agreement with previous studies, we found that rs10490924 in ARMS2, and rs11200638 and rs3793917 in HTRA1 conferred strong susceptibility for AMD. The ORhomo values in our study are similar to those of studies in a Caucasian population and some Chinese populations. 13,31,35 However, some other studies in Chinese populations revealed much higher ORs. 9,10,36,37 DeWan et al reported that individuals with the risk-associated genotype were estimated to have a likelihood of wet AMD developing around 10 times (ORhomo = 11.14 for rs10490924, ORhomo = 10.00 for rs11200638) that of individuals with the wild-type genotype. 9 Yang et al found that individuals with the homo risk genotype were around 10-fold more likely to have AMD (ORhomo = 8.99 for rs10490924, ORhomo = 12.93 for rs11200638) than individuals without the risk genotype in a Han Chinese cohort. 10 This difference in the estimation of ORs might have resulted from the sample size or study design. In a word, no matter how great the OR, ARMS2 and HTRA1 conferred susceptibility for AMD. 
Our study also revealed that the tested SNPs of C3, SERPING1, VEGF, CETP, LPL, LIPC, and TIMP3 were not associated significantly with AMD in a Chinese population, although they were associated with AMD in previous genome-wide association studies (GWAS) or candidate studies in Caucasian populations. 14,17,1922,38,39 In a Chinese population, Liu et al indicated that none of the SNPs they tested in C3 showed significant association with AMD, 7 while Pei et al showed that the G allele of C3 (rs2250656) might be a significant protective factor for neovascular AMD. 40 Most studies in Chinese and Japanese populations did not provide evidence for the role of VEGF to AMD, 25,26 and this is consistent with our results. However, Lin et al reported that VEGF-rs3025039 polymorphisms were associated dependently with wet AMD in the Taiwan Chinese population. 27 This disagreement with our study possibly is due to the difference in inclusion and exclusion criteria of the two studies. In addition, our study in a Chinese population concerned the relationship about AMD, and genetic variants of CETP, LPL, LIPC, and TIMP3, though no significant association was disclosed. This disagrees with results of studies in Caucasians, 2022 which might be due to the fact that we only included a few SNPs of the above genes, possibly missing some other SNPs that could have an effect. Besides, with our sample size, the powers of the negative associations were less than 0.5, which was not adequate to state the negative association. Based on the above situations, further study with more SNPs and larger sample size may be needed. 
Strengths of our study include the large, nationwide, well-characterized Chinese patients, classification of AMD by standardized ophthalmologic examinations, and the reading center. Besides, to our knowledge, this is the first study to examine the association on the genetic variants of rs12124794, rs10733086, rs6695321, and rs7524776 in CFH; rs2736912 in ARMS2; rs408290, rs8112351, rs11569562, and rs7257062 in C3; and rs2303789, rs17231506, rs1532625, rs289744, and rs9939224 in CETP to AMD, as well as the first study to examine the association on the genetic variants of rs12678919 nearby LPL, rs10468017 nearby LIPC, and rs9621532 nearby TIMP3 to AMD in the Chinese population. 
In conclusion, we confirmed that CFH, ARMS2, and HTRA1 genetic variants were related to risk of AMD in the Chinese population. Further research is needed to explore the interaction of heredity and environment, so that the pathogenic mechanisms of AMD can be featured and intervened. 
Acknowledgments
The following collaborators recruited participants: Shaomin Peng (Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University), Hao Cui (Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University), Zheli Liu (Department of Ophthalmology, The First Hospital of China Medical University), Liu Yang (Department of Ophthalmology, Peking University First Hospital), Youxin Chen (Department of Ophthalmology, Peking Union Medical College Hospital), Maonian Zhang (Department of Ophthalmology, The General Hospital of The People's Liberation Army), Xiaoguang Dong (Department of Ophthalmology, Shandong Eye Institute), Yusheng Wang (Department of Ophthalmology, Xijing Hospital), Qinghuai Liu (Department of Ophthalmology, Jiangsu Province Hospital), Yiqiao Xing (Department of Ophthalmology, Renmin Hospital of Wuhan University), Xiaodong Sun (Department of Ophthalmology, Shanghai First People's Hospital), Junjun Zhang (Department of Ophthalmology, West China Medical School-West China Hospital), Xiaoling Liu (Department of Ophthalmology, The Affiliated Eye Hospital of Wenzhou Medical College), Xiaohua Zhu (Department of Ophthalmology, The Second Xiangya Hospital of Central South University), and Xiaoling Liang (Department of Ophthalmology, Zhongshan Ophthalmic Center). Zhang Jian edited the manuscript. 
References
Chakravarthy U Evans J Rosenfeld PJ . Age related macular degeneration. BMJ . 2010;340:c981.
Kawasaki R Yasuda M Song SJ The prevalence of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology . 2010;117:921–927. [CrossRef] [PubMed]
Chen SJ Cheng CY Peng KL Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Invest Ophthalmol Vis Sci . 2008;49:3126–3133. [CrossRef] [PubMed]
Yang K Liang YB Gao LQ Prevalence of age-related macular degeneration in a rural Chinese population: the Handan Eye Study. Ophthalmology . 2011;118:1395–1401. [PubMed]
Seddon JM Reynolds R Maller J Fagerness JA Daly MJ Rosner B . Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci . 2009;50:2044–2053. [CrossRef] [PubMed]
Maller J George S Purcell S Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet . 2006;38:1055–1059. [CrossRef] [PubMed]
Liu X Zhao P Tang S Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population. Retina . 2010;30:1177–1184. [CrossRef] [PubMed]
Ng TK Chen LJ Liu DT Multiple gene polymorphisms in the complement factor h gene are associated with exudative age-related macular degeneration in chinese. Invest Ophthalmol Vis Sci . 2008;49:3312–3317. [CrossRef] [PubMed]
Dewan A Liu M Hartman S HTRA1 promoter polymorphism in wet age-related macular degeneration. Science . 2006;314:989–992. [CrossRef] [PubMed]
Yang Z Tong Z Chen Y Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet . 2010;6:e1000836. [CrossRef] [PubMed]
Seddon JM Francis PJ George S Schultz DW Rosner B Klein ML . Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA . 2007;297:1793–1800. [CrossRef] [PubMed]
Seddon JM Gensler G Rosner B . C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration. Ophthalmology . 2010;117:1560–1566. [CrossRef] [PubMed]
Tuo J Ross RJ Reed GF The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples. Ophthalmology . 2008;115:1891–1898. [CrossRef] [PubMed]
Maller JB Fagerness JA Reynolds RC Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet . 2007;39:1200–1201. [CrossRef] [PubMed]
Spencer KL Olson LM Anderson BM C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet . 2008;17:1821–1824. [CrossRef] [PubMed]
Despriet DD van Duijn CM Oostra BA Complement component C3 and risk of age-related macular degeneration. Ophthalmology . 2009;116:474–480. [CrossRef] [PubMed]
Ennis S Jomary C Mullins R Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet . 2008;372:1828–1834. [CrossRef] [PubMed]
Lee AY Kulkarni M Fang AM Edelstein S Osborn MP Brantley MA . The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration. Br J Ophthalmol . 2010;94:915–917. [CrossRef] [PubMed]
Galan A Ferlin A Caretti L Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. Ophthalmology . 2010;117:1769–1774. [CrossRef] [PubMed]
Chen W Stambolian D Edwards AO Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A . 2010;107:7401–7406. [CrossRef] [PubMed]
Neale BM Fagerness J Reynolds R Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A . 2010;107:7395–7400. [CrossRef] [PubMed]
Reynolds R Rosner B Seddon JM . Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology . 2010;117:1989–1995. [CrossRef] [PubMed]
Cui L Zhou H Yu J Noncoding variant in the complement factor H gene and risk of exudative age-related macular degeneration in a Chinese population. Invest Ophthalmol Vis Sci . 2010;51:1116–1120. [CrossRef] [PubMed]
Lu F Zhao P Fan Y An association study of SERPING1 gene and age-related macular degeneration in a Han Chinese population. Mol Vis . 2010;16:1–6. [CrossRef] [PubMed]
Qu Y Dai H Zhou F Vascular endothelial growth factor gene polymorphisms and risk of neovascular age-related macular degeneration in a Chinese cohort. Ophthalmic Res . 2011;45:142–148. [CrossRef] [PubMed]
Mori K Horie-Inoue K Gehlbach PL Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology . 2010;117:928–938. [CrossRef] [PubMed]
Lin JM Wan L Tsai YY Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. Am J Ophthalmol . 2008;145:1045–1051. [CrossRef] [PubMed]
Davis MD Gangnon RE Lee LY The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol . 2005;123:1484–1498. [CrossRef] [PubMed]
Gabriel SB Schaffner SF Nguyen H The structure of haplotype blocks in the human genome. Science . 2002;296:2225–2229. [CrossRef] [PubMed]
Thakkinstian A Han P McEvoy M Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet . 2006;15:2784–2790. [CrossRef] [PubMed]
Xu Y Guan N Xu J Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population. Mol Vis . 2008;14:1373–1381. [PubMed]
Mori K Gehlbach PL Kabasawa S 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 . 2007;48:5315–5319. [CrossRef] [PubMed]
Hughes AE Orr N Esfandiary H Diaz-Torrez M Goodship T Chakravarthy U . A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet . 2006;38:1173–1177. [CrossRef] [PubMed]
Raychaudhuri S Ripke S Li M Associations of CFHR1CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet . 2010;42:553–555. [CrossRef] [PubMed]
Yang Z Camp NJ Sun H A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science . 2006;314:992–993. [CrossRef] [PubMed]
Lu F Hu J Zhao P HTRA1 variant increases risk to neovascular age-related macular degeneration in Chinese population. Vision Research . 2007;47:3120–3123. [CrossRef] [PubMed]
Jiang H Qu Y Dang G Analyses of single nucleotide polymorphisms and haplotype linkage of LOC387715 and the HTRA1 gene in exudative age-related macular degeneration in a Chinese cohort. Retina . 2009;29:974–979. [CrossRef] [PubMed]
Yates JR Sepp T Matharu BK Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med . 2007;357:553–561. [CrossRef] [PubMed]
Seddon JM Reynolds R Rosner B . Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration. Mol Vis . 2010;16:2412–2424. [PubMed]
Pei XT Li XX Bao YZ Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a chinese population. Curr Eye Res . 2009;34:615–622. [CrossRef] [PubMed]
Footnotes
 Supported by the Mega-projects of Science Research for the 11th Five-Year Plan from The Ministry of Science and Technology of the People's Republic of China (2006BAI02B05), and the National Basic Research Program of China (973 Program, 2011CB510200). The funding organization had no role in the design or conduct of this research.
Footnotes
  2 These authors contributed equally to the work presented here and should therefore be considered equivalent authors.
Footnotes
 Disclosure: J. Tian, None; W. Yu, None; X. Qin, None; K. Fang, None; Q. Chen, None; J. Hou, None; J. Li, None; D. Chen, None; Y. Hu, None; X. Li, None
Figure. 
 
LD between the polymorphism in the complement factor H gene. The D between any two single nucleotide polymorphisms is listed in the cross cells.
Figure. 
 
LD between the polymorphism in the complement factor H gene. The D between any two single nucleotide polymorphisms is listed in the cross cells.
Table 1. 
 
Number of Patients and Controls of the 16 Hospitals
Table 1. 
 
Number of Patients and Controls of the 16 Hospitals
Hospital City Province/Municipality Patients Controls
The Second Affiliated Hospital of Harbin Med Univ. Harbin Heilongjiang 40 34
The First Affiliated Hospital of Harbin Med Univ. Harbin Heilongjiang 42 38
The First Hospital of China Med Univ. Shenyang Liaoning 40 32
Peking University First Hospital Beijing Beijing 19 21
Peking University People's Hospital Beijing Beijing 26 17
Peking Union Medical College Hospital Beijing Beijing 37 9
The General Hospital of The People's Liberation Army Beijing Beijing 19 18
Shandong Eye Institute Qingdao Shandong 35 21
Xijing Hospital Xi'an Shaanxi 39 40
Jiangsu Province Hospital Nanjing Jiangsu 19 20
Renmin Hospital of Wuhan Univ. Wuhan Hubei 31 39
Shanghai First People's Hospital Shanghai Shanghai 41 39
West China Medical School-West China Hospital Chengdu Sichuan 40 26
The Affiliated Eye Hospital of Wenzhou Medical College Wenzhou Zhejiang 37 37
The Second Xiangya Hospital of Central South Univ. Changsha Hunan 32 39
Zhongshan Ophthalmic Center Guangzhou Guangdong 38 39
Total
 16 12 12 535 469
Table 2. 
 
The SNPs Selected of the 10 Genes
Table 2. 
 
The SNPs Selected of the 10 Genes
Gene SNPs
CFH rs3753394, rs7524776, rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs6695321, rs10733086, rs10737680, rs2274700, rs3753396, rs1410996, rs380390
ARMS2 rs10490924, rs2736912
HTRA1 rs3793917, rs11200638
C3 rs11569562, rs7257062, rs408290, rs8112351, rs2230205, rs1047286, rs2230199, rs2250656
SERPING1 rs1005510, rs2511989
VEGF rs833069, rs3025039
CETP rs173539, rs17231506, rs9939224, rs1532625, rs2303789, rs289744
nearby LPL rs12678919
nearby LIPC rs10468017
nearby TIMP3 rs9621532
Table 3. 
 
Demographic Characteristics of AMD Patients and Controls
Table 3. 
 
Demographic Characteristics of AMD Patients and Controls
Controls Patients
All AMD Early AMD Advanced AMD
n n P* n P* n P*
Sex <0.001 0.119 <0.001
 Male 217 324 23 301
 Female 252 211 41 170
Age <0.001 0.139 <0.001
 50∼ 155 106 14 92
 60∼ 157 168 28 140
 70∼ 157 261 22 239
Nationality 0.307 0.403 0.205
 Han 450 516 63 453
 Minorities 5 10 0 10
Long-term residence 0.025 0.001 0.125
 North of China 225 297 45 252
 South of China 238 236 18 218
Family origin 0.043 0.001 0.202
 North of China 227 295 46 249
 South of China 236 237 18 219
Table 4. 
 
Gene Variants Observed in AMD Patients and Controls
Table 4. 
 
Gene Variants Observed in AMD Patients and Controls
Gene dbSNP ID Risk Allele Genotype Frequency
Controls* All AMD* P corr Early AMD* P Advanced AMD* P corr Neovascular AMD* P corr
CFH rs3753394 T 131/230/102 181/244/104 0.343 20/29/14 1.000 161/215/90 0.287 158/212/89 0.286
rs7524776 C 1/46/416 3/50/480 1.000 0/7/57 1.000 3/43/423 1.000 3/42/417 1.000
rs551397 G 157/224/75 248/213/55 <0.001 26/27/9 0.917 222/186/46 <0.001 218/183/46 <0.001
rs800292 C 158/221/76 249/205/56 <0.001 26/26/9 0.901 223/179/47 <0.001 219/176/47 <0.001
rs1329424 A 1/51/412 9/93/427 0.001 1/5/57 1.000 8/88/370 <0.001 8/86/365 <0.001
rs1061170 C 1/49/395 9/89/391 0.001 1/6/55 1.000 8/83/336 <0.001 8/81/331 <0.001
rs10801555 A 1/51/408 9/91/425 0.002 1/6/57 1.000 8/85/368 <0.001 8/83/363 <0.001
rs12124794 A 188/216/56 264/213/49 0.031 26/27/10 0.999 238/186/39 0.008 233/184/39 0.012
rs6695321 A 8/113/343 13/138/377 0.911 1/11/51 0.872 12/127/326 0.690 11/126/321 0.675
rs10733086 A 1/65/397 10/113/410 0.001 1/7/56 1.000 9/106/354 <0.001 8/105/349 <0.001
rs10737680 A 153/223/92 234/230/67 <0.001 23/27/13 1.000 211/203/54 <0.001 206/201/54 <0.001
rs2274700 C 137/216/88 231/216/63 <0.001 24/26/12 0.955 207/190/51 <0.001 202/188/51 <0.001
rs3753396 G 105/239/120 156/253/123 0.205 19/28/17 0.990 137/225/106 0.205 134/222/105 0.218
rs1410996 C 148/224/92 235/228/67 <0.001 23/27/13 0.999 212/201/54 <0.001 207/199/54 <0.001
rs380390 C 1/45/401 9/97/408 <0.001 1/6/55 0.998 8/91/353 <0.001 8/89/348 <0.001
ARMS2 rs10490924 T 97/223/147 251/197/82 <0.001 18/29/16 0.282 233/168/66 <0.001 228/166/66 <0.001
rs2736912 C 358/91/11 460/68/3 0.001 51/13/0 0.7580 409/55/3 <0.001 402/55/3 <0.001
HTRA1 rs3793917 C 92/221/141 256/190/79 <0.001 20/27/16 0.111 236/163/63 <0.001 231/161/63 <0.001
rs11200638 A 104/224/140 255/193/84 <0.001 19/28/16 0.309 236/165/68 <0.001 231/163/68 <0.001
C3 rs11569562 C 134/228/101 144/284/102 1.000 20/29/14 1.000 124/255/88 1.000 123/250/87 1.000
rs7257062 T 250/177/37 289/210/32 0.997 34/23/6 1.000 255/187/26 0.989 251/184/26 0.992
rs408290 C 323/127/15 390/127/12 0.675 52/10/1 0.285 338/117/11 0.906 333/115/11 0.905
rs8112351 C 383/74/4 449/76/4 0.998 58/5/0 0.402 391/71/4 1.000 385/70/4 1.000
rs2230205 A 107/221/137 130/246/156 1.000 16/31/17 0.999 114/215/139 1.000 113/210/138 1.000
rs1047286 T 0/1/455 0/2/525 1.000 0/0/63 1.000 0/2/462 1.000 0/2/455 0.999
rs2230199 G 0/2/463 0/4/528 0.995 0/0/63 1.000 0/4/465 0.982 0/4/458 0.969
rs2250656 A 273/164/21 329/171/23 0.951 41/19/4 1.000 288/152/19 0.936 283/150/19 0.948
SERPING1 rs1005510 G 28/181/256 37/201/293 0.968 5/21/38 0.951 32/180/255 0.921 32/178/250 0.876
rs2511989 A 7/86/371 13/96/422 0.837 3/9/51 0.866 10/87/371 0.856 10/86/365 0.848
VEGF rs833069 A 155/227/84 190/253/89 0.629 27/28/8 0.209 163/225/81 0.863 161/222/79 0.835
rs3025039 C 302/143/18 341/179/13 0.998 40/22/2 0.958 301/157/11 0.990 299/153/10 0.931
CETP rs173539‡ T 14/4/397 19/6/465 0.984 2/0/59 0.982 17/6/406 0.959 17/6/400 0.943
rs17231506 T 18/116/331 15/150/364 0.992 1/21/41 0.992 14/129/323 0.999 14/126/319 0.999
rs9939224 T 5/84/374 9/94/427 1.000 1/8/53 0.982 8/86/374 0.996 8/86/367 0.989
rs1532625 A 45/172/248 43/226/262 0.980 3/29/31 1.000 40/197/231 0.968 39/193/229 0.982
rs2303789 T 320/131/14 388/130/14 0.707 46/16/2 0.999 342/114/12 0.700 338/112/11 0.613
rs289744 A 211/193/37 260/210/49 1.000 32/27/5 0.999 228/183/44 1.000 225/179/44 1.000
LPL rs12678919 A 386/76/5 438/86/5 0.939 51/11/1 0.746 387/75/4 0.876 380/75/4 0.936
LIPC rs10468017 C 316/136/10 374/145/11 0.492 45/17/1 0.693 329/128/10 0.563 325/125/10 0.525
TIMP3 rs9621532 A 439/26/0 510/22/0 0.306 60/4/0 1.000 450/18/0 0.214 443/18/0 0.278
Table 5. 
 
Estimated ORs, P Values of CFH, ARMS2, and HTRA1 Gene Variants
Table 5. 
 
Estimated ORs, P Values of CFH, ARMS2, and HTRA1 Gene Variants
dbSNP ID All AMD Patients Advanced AMD Patients
ORhetero (95% CI)* P* ORhomo (95% CI)† P ORhetero (95% CI)* P* ORhomo (95% CI)† P
CFH
 rs551397 1.18 (0.78–1.78) 0.427 2.11 (1.41–3.26) <0.001 1.24 (0.80–1.91) 0.339 2.29 (1.48–3.56) <0.001
 rs800292 1.17 (0.77–1.75) 0.465 2.13 (1.41–3.23) <0.001 1.21 (0.78–1.86) 0.387 2.28 (1.48–3.53) <0.001
 rs1329424 1.73 (1.19–2.53) 0.004 8.15 (1.02–65.44) 0.048 1.86 (1.27–2.73) 0.002 8.37 (1.03–68.39) 0.047
 rs1061170 1.86 (1.27–2.74) 0.002 8.50 (1.06–68.38) 0.044 1.98 (1.34–2.95) 0.001 8.84 (1.08–72.39) 0.042
 rs10801555 1.71 (1.17–2.50) 0.005 8.15 (1.02–65.42) 0.048 1.81 (1.23–2.66) 0.003 8.38 (1.03–68.40) 0.047
 rs12124794 0.93 (0.60–1.45) 0.747 1.46 (0.94–2.28) 0.093 1.00 (0.62–1.60) 0.988 1.63 (1.02–2.61) 0.043
 rs10733086 1.66 (1.18–2.34) 0.004 9.40 (1.19–74.59) 0.034 1.76 (1.24–2.50) 0.002 9.73 (1.21–78.26) 0.032
 rs10737680 1.22 (0.84–1.78) 0.303 2.01 (1.37–2.97) <0.001 1.29 (0.86–1.93) 0.217 2.21 (1.46–3.34) <0.001
 rs2274700 1.22 (0.83–1.80) 0.309 2.26 (1.52–3.38) <0.001 1.29 (0.85–1.94) 0.234 2.45 (1.60–3.74) <0.001
 rs1410996 1.21 (0.83–1.77) 0.318 2.08 (1.41–3.07) <0.001 1.28 (0.86–1.92) 0.229 2.28 (1.51–3.44) <0.001
 rs380390 2.07 (1.40–3.05) <0.001 8.83 (1.10–70.72) 0.040 2.19 (1.48–3.26) <0.001 9.04 (1.11–73.53) 0.040
ARMS2
 rs10490924 1.51 (1.07–2.12) 0.018 4.25 (2.94–6.13) <0.001 1.62 (1.13–2.34) 0.009 4.90 (3.33–7.21) <0.001
 rs2736912 2.64 (0.69–10.06) 0.156 4.83 (1.31–17.83) 0.018 2.10 (0.54–8.12) 0.282 4.35 (1.17–16.22) 0.028
HTRA1
 rs3793917 1.56 (1.03–2.06) 0.033 4.56 (3.14–6.64) <0.001 1.58 (1.09–2.30) 0.016 5.31 (3.58–7.88) <0.001
 rs11200638 1.41 (1.01–1.99) 0.048 3.82 (2.65–5.49) <0.001 1.51 (1.05–2.18) 0.027 4.42 (3.01–6.48) <0.001
Table 6.  
 
Haplotype Analysis of the CFH Gene
Table 6.  
 
Haplotype Analysis of the CFH Gene
Haplotype Controls All AMD Patients Advanced AMD Patients
Freq. Freq. P/P corr* OR† Freq. P/P corr* OR†
Block1: rs7524776, rs551397, rs800292
 TGC 0.59 0.68 <0.001/<0.001 1.52 0.69 <0.001/<0.001 1.57
 TAT 0.36 0.27 <0.001/<0.001 0.64 0.26 <0.001/<0.001 0.62
 CAT 0.05 0.05 0.88/1.00 NS 0.05 0.90/1.00 NS
Block2: rs1329424, rs1061170, rs10801555, rs12124794, rs6695321, rs10733086, rs10737680
 CTGAGTA 0.49 0.53 0.09/0.57 NS 0.54 0.051/0.43 NS
 CTGTGTC 0.35 0.30 0.01/0.06 0.78 0.28 0.002/0.02 0.74
 ACAAAAA 0.06 0.11 <0.001/ 0.001 1.92 0.11 <0.001/<0.001 2.05
Block3: rs2274700, rs3753396, rs1410996, rs380390
 CGCG 0.48 0.53 0.03/0.22 1.22 0.53 0.03/0.23 1.23
 TATG 0.44 0.34 <0.001/<0.001 0.63 0.33 <0.001/<0.001 0.60
 CACC 0.06 0.11 <0.001/<0.001 2.27 0.11 <0.001/<0.001 2.39
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×