February 2010
Volume 51, Issue 2
Free
Retina  |   February 2010
Noncoding Variant in the Complement Factor H Gene and Risk of Exudative Age-Related Macular Degeneration in a Chinese Population
Author Affiliations & Notes
  • Lei Cui
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Haiying Zhou
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Jie Yu
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Erdan Sun
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Yinbo Zhang
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Wei Jia
    the Sekwa Eye Hospital, Beijing, China; and
  • Yiqun Jiao
    the Sekwa Eye Hospital, Beijing, China; and
  • Torkel Snellingen
    the Sekwa Eye Hospital, Beijing, China; and
  • Xipu Liu
    the Sekwa Eye Hospital, Beijing, China; and
  • Apiradee Lim
    the Department of Mathematic and Computer Science, Faculty of Science and Technology, Prince of Songkhla University, Pattani Campus, Thailand.
  • Ningli Wang
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Ningpu Liu
    From the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China;
  • Corresponding author: Ningpu Liu, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, No. 1 Dong Jiao Min Xiang, Dongcheng District, Beijing 100730, China; nliu001@gmail.com
Investigative Ophthalmology & Visual Science February 2010, Vol.51, 1116-1120. doi:10.1167/iovs.09-4265
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      Lei Cui, Haiying Zhou, Jie Yu, Erdan Sun, Yinbo Zhang, Wei Jia, Yiqun Jiao, Torkel Snellingen, Xipu Liu, Apiradee Lim, Ningli Wang, Ningpu Liu; 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(2):1116-1120. doi: 10.1167/iovs.09-4265.

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Abstract

Purpose.: To investigate whether the previously reported noncoding variant of the complement factor H (CFH) gene and two coding variants of the complement component 3 (C3) gene are associated with exudative age-related macular degeneration (AMD) in Chinese patients.

Methods.: One hundred fifty Chinese patients with exudative AMD and 161 control individuals without AMD were recruited for the study. Genomic DNA was extracted from blood leukocytes. The noncoding variant of the CFH gene (rs1410996) and two coding variants of the C3 gene (rs2230199 and rs1047286) were genotyped by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion and direct sequencing.

Results.: Significant association was detected for exudative AMD with the CFH noncoding variant rs1410996. Frequencies of the risk C allele at rs1410996 were 72.0% in AMD cases versus 55.6% in controls (P < 0.001). The odds ratio for risk of AMD was 1.71 (95% confidence interval [CI], 0.82–3.54) for heterozygous TC genotype and 3.85 (95% CI, 1.84–8.05) for homozygous CC genotype compared with the wild TT genotype. In contrast, the C3 variants rs2230199 and rs1047286 were not associated with exudative AMD in the studied subjects. Frequencies of the risk G allele at rs2230199 and of the risk T allele at rs1047286 were 0.3% to 1.0% in both cases and controls.

Conclusions.: The data suggest that the noncoding variant rs1410996 of the CFH gene moderately increased the risk of exudative AMD in a Chinese population. The C3 variants were rare and not associated with exudative AMD in this Chinese cohort.

Age-related macular degeneration (AMD) is the primary cause of irreversible visual impairment in the elderly population. 13 It is a complex disease, with both genetic and environmental factors influencing susceptibility. 47 Recent association studies have successfully identified a coding variation Y402H in the complement factor H (CFH) gene on chromosome 1, region q32, to be strongly associated with AMD in numerous Caucasian populations. 820 The Y402H variant, however, does not show significant association with AMD in Japanese, 2124 Korean, 25 and Chinese 26,27 populations, suggesting ethnic variations in genetic susceptibility to AMD. It is therefore imperative to replicate association studies in diverse ethnic populations for a better understanding of the genetic contributions to the pathogenesis of AMD. 
More recently, several research groups have discovered CFH polymorphisms other than Y402H that are associated with AMD. 2830 In particular, an intronic noncoding variant in the CFH gene (rs1410996) has been reported to be associated with a higher risk of AMD in Caucasian and Japanese populations. 2830 The role of complement in AMD pathogenesis is further supported by the discovery that variations in the complement component 3 (C3) gene, rs2230199 (R102G) and rs1047286 (P314L), are also linked to AMD in Caucasians. 3134 The purpose of this study was to investigate whether the previously reported noncoding variant of CFH and coding variants of C3 are associated with exudative AMD in native Chinese patients. 
Methods
Subjects and Clinical Evaluation
The study subjects were recruited among outpatients visiting the Beijing Tongren Hospital, Capital Medical University, China. All study subjects were native Chinese. The study protocol was approved by the Ethics Committee of the Beijing Tongren Hospital. Informed consent was obtained from all participants, and the procedures used conformed to the tenets of the Declaration of Helsinki for research involving human subjects. All participants received a standard ophthalmic examination, including visual acuity measurement, slit lamp biomicroscopy, and dilated fundus examination performed by a retinal specialist. All patients with AMD were examined with fluorescein and/or indocyanine green fundus angiography. The diagnosis of exudative AMD was based on the ophthalmic and fluorescein angiographic findings. Inclusion and exclusion criteria for patients and controls were described previously. 26  
DNA Extraction and PCR
Genomic DNA was extracted from peripheral blood leukocytes with a genomic DNA extraction and purification kit (TIANamp Swab DNA Kit, Tiangen Biotech, Beijing, China) used according to the manufacturer's protocol. Genotyping was performed with a method of PCR followed by allele-specific restriction enzyme digestion and/or direct sequencing. The primer sequences used in this study are presented in Table 1. The PCR reaction was performed in a DNA thermocycler (Eppendorf, Hamburg, Germany) in a 25-μL mixture, as previously described. 26 Samples were denatured at 94°C for 5 minutes followed by 35 cycles under the following conditions: denaturing at 94°C for 30 seconds, annealing at 56°C (for rs2230199 and rs1047286) or 50.0°C (for rs1410996) for 30 seconds, and extension at 72°C for 45 seconds. The final extension step was lengthened to 5 minutes. Aliquots of amplified uncut products were resolved by electrophoresis in 2% (wt/vol) agarose gels with 0.5 μg/mL ethidium bromide and visualized under ultraviolet light. PCR products were then used for either allele-specific restriction enzyme digestion or direct sequencing. 
Table 1.
 
Primers Used for PCR Amplification and Sequencing
Table 1.
 
Primers Used for PCR Amplification and Sequencing
Genes SNP Primer Sequence (5′→3′)
CFH rs1410996 (noncoding) F: TTG GAC ATT AGG ACT CTT AG
R: GTA CTC CTT TTT AGG CAC T
C3 rs2230199 (R102G) F: CCC TCG CAC CTC CTT CAC
R: CCT CTG GCT GGC ACC TCA AT
C3 rs1047286 (P314L) F: CCT CAA GCG CAT TCC GGT
R: AGC CTC CCT CCT TAG ACT
Restriction Digestion and Direct Sequencing
The amplified products for rs2230199 and rs1410996 were analyzed by restriction enzyme digestion according to the manufacturer's protocol (New England Biolabs, Ipswich, MA). The restriction digestion was performed at either 37°C for 3.5 hours (HhaI for rs2230199) or 65°C for 5 hours (Tsp45I for rs1410996). Samples were electrophoresed on a 2% (wt/vol) agarose gel with 0.5 μg/mL ethidium bromide. Images were made of the gel (Molecular Imager Gel Doc XR System; Bio-Rad, Hercules, CA). Genotypes were determined based on the restriction patterns that were further confirmed by sequencing of the PCR products with an automatic DNA analyzer (model 3730XL; Applied Biosystems, Inc. [ABI], Foster City, CA) in a selected subset of subjects. For rs1047286, the genotypes were determined by direct sequencing of the PCR products. 
Statistical Analysis
Compliance with Hardy-Weinberg (H-W) equilibrium for distribution of genotypes was examined by using Haploview, version 4.0. 35 Numerical data were examined by Student's t-test. Genotypes and allele frequencies between cases and controls were compared by χ2 test. Odds ratio (OR) and 95% confidence intervals (CI) were calculated according to Woolf's equation. 36 P < 0.05 was considered statistically significant. 
Results
The study subjects included 150 patients with exudative AMD and 161 healthy control subjects (Table 2). No subjects were blood relatives. The ages of the study cases ranged from 50 to 89 years with a mean of 66.6 (SD 8.4). The ages of the controls ranged from 50 to 81 years with a mean of 65.7 (SD 7.8). There was no significant difference in age between the cases and controls (P = 0.364). The AMD group was 58.7% male and the control group 52.2% (P = 0.250; Table 2). 
Table 2.
 
Age and Sex of Patients with Exudative AMD and Control Subjects
Table 2.
 
Age and Sex of Patients with Exudative AMD and Control Subjects
Sample Controls (n = 161) AMD Cases All Subjects (n = 311)
Unilateral (n = 117) Bilateral (n = 33) Total (n = 150)
Age, y (mean ± SD) 65.7 ± 7.8 66.0 ± 8.5 68.7 ± 7.7 66.6 ± 8.4 66.1 ± 8.1
Sex
    Male 84 (52.2) 69 (59.0) 19 (57.6) 88 (58.7) 172
    Female 77 (47.8) 48 (41.0) 14 (42.4) 62 (41.3) 139
Genotypes for rs2230199 and rs1410996 were determined by restriction enzyme digestion in all participants, which was further confirmed by direct sequencing in 40 randomly selected subjects. The data from the sequencing method were consistent with data from the restriction enzyme digestion method used in all study subjects. Direct sequencing was applied to detect genotypes for rs1047286 in all samples. The allele and genotype distribution, association, and OR for SNPs rs2230199, rs1410996, and rs1047286 are given in Table 3. Genotype distributions for all three SNPs were in H-W equilibrium in the AMD cases and control subjects (P ≥ 0.724). 
Table 3.
 
Genotype and Allele Frequencies in Cases of Exudative AMD and Controls
Table 3.
 
Genotype and Allele Frequencies in Cases of Exudative AMD and Controls
Genotypes AMD Cases (n = 150) Controls (n = 161) χ2 P OR (95% CI)
CFH rs1410996:T>C (noncoding)
    Genotype
        TT 13 (8.7) 31 (19.3) 1.00
        TC 58 (38.7) 81 (50.3) 1.71 (0.82–3.54)
        CC 79 (52.7) 49 (30.4) 17.834 <0.001 3.85 (1.84–8.05)
H-W P = 0.724 H-W P = 0.968
    Allele
        T 84 (28.0) 143 (44.4) 1.00
        C 216 (72.0) 179 (55.6) 29.849 <0.001 2.48 (1.79–3.45)
C3 rs2230199:C>G (R102G)
    Genotype
        CC 147 (98.0) 160 (99.4) 1.00
        CG 3 (2.0) 1 (0.6) 0.330 0.565 3.27 (0.34–31.74)
        GG 0 (0) 0 (0)
H-W P = 1.0 H-W P = 1.0
    Allele
        C 297 (99.0) 321 (99.7) 1.00
        G 3 (1.0) 1 (0.3) 0.328 0.567 3.24 (0.34–31.34)
C3 rs1047286:C>T (P314L)
    Genotype
        CC 148 (98.7) 160 (99.4) 1.00
        CT 2 (1.3) 1 (0.6) 0.004 0.951 2.16 (0.19–24.09)
        TT 0 (0) 0 (0)
H-W P = 1.0 H-W P = 1.0
    Allele
        C 298 (99.3) 321 (99.7) 1.00
        T 2 (0.7) 1 (0.3) 0.004 0.951 2.15 (0.19–23.88)
Significant association with exudative AMD was detected for SNP rs1410996 in the CFH gene (Table 3). The risk C allele frequencies were 72.0% in AMD cases and 55.6% in controls (P < 0.001). Differences in genotype distributions of this CFH noncoding polymorphism between AMD cases and controls were statistically significant (P < 0.001). Compared with the wild-type TT genotype, the OR for the risk of AMD was 1.71 (95% CI, 0.82–3.54) for the heterozygous TC genotype and 3.85 (95% CI, 1.84–8.05) for the homozygous CC genotype. 
Among the 150 patients, 117 (78%) had unilateral and 33 (22%) had bilateral AMD (Table 4). No significant difference was observed between these two groups in age (P = 0.099) and sex (P = 0.885). Frequencies of the risk C allele at rs1410996 were 70.1% in the unilateral and 78.8% in the bilateral AMD groups (P = 0.164). Frequencies of homozygous CC genotype at rs1410996 were 48.7% in the unilateral and 66.7% in the bilateral AMD groups, but genotype distribution between bilateral and unilateral AMD was not significantly different (P = 0.145). When compared with the control subjects, the OR for patients with the homozygous CC genotype was 3.61 (95% CI, 1.61–8.10) in the unilateral and 4.64 (95% CI, 1.28–16.81) in the bilateral AMD groups. 
Table 4.
 
Comparison of Genotype and Allele Frequencies of the CFH Noncoding Variant rs1410996 among Control Subjects, Patients with Unilateral AMD, and Patients with Bilateral AMD
Table 4.
 
Comparison of Genotype and Allele Frequencies of the CFH Noncoding Variant rs1410996 among Control Subjects, Patients with Unilateral AMD, and Patients with Bilateral AMD
Controls (n = 161) Unilateral (n = 117) P * OR (95% CI) Bilateral (n = 33) P * OR (95% CI)
Genotype
    TT 31 (19.3) 10 (8.5) 1.00 3 (9.1) 1.00
    TC 81 (50.3) 50 (42.7) 1.91 (0.86–4.24) 8 (24.2) 1.02 (0.25–4.10)
    CC 49 (30.4) 57 (48.7) 0.002 3.61 (1.61–8.10) 22 (66.7) <0.001 4.64 (1.28–16.81)
Allele
    T 143 (44.4) 70 (29.9) 1.00 14 (21.2) 1.00
    C 179 (55.6) 164 (70.1) 0.001 1.87 (1.31–2.67) 52 (78.8) <0.001 2.97 (1.58–5.57)
SNPs rs2230199 and rs1047286 in the C3 gene were not associated with exudative AMD (Table 3). Frequencies of the risk G allele at rs2230199 was 1.0% in the AMD cases and 0.3% in the controls (P = 0.567). Frequencies for the risk T allele at rs1047286 were 0.7% in the AMD cases and 0.3% in the controls (P = 0.951). No significant differences in the rs2230199 and rs1047286 genotypes were observed between the cases and controls. The homozygous GG genotype of rs2230199 or homozygous TT genotype of rs1047286 was not identified in this Chinese cohort. 
Discussion
Our data showed significant association of the risk of AMD with the noncoding variant rs1410996 in the CFH gene. Consistent with published findings in Caucasian 29 and Japanese 30 populations, this study in a Chinese population showed a higher risk of AMD with the C allele of rs1410996. The frequencies of the risk C allele were 72% in the cases and 55.6% in the controls, similar to those reported in Caucasians (80.8% in cases and 57.1% in controls) 29 and Japanese (66.8% in cases and 50.4% in controls) 30 populations. Compared with individuals with the wild TT genotype of rs1410996, individuals with the homozygous CC genotype had a 3.85-fold increased risk of AMD. As an important regulator of the complement system, CFH inhibits C3 convertase and downregulates the excessive activity of the alternative pathway. 37,38 Depletion or the absence of CFH due to genetic reasons could lead to uncontrolled C3 activation, which then impairs normal tissues. 39 The mechanism of the relationship between AMD and the noncoding variant of the CFH gene is unclear. One intriguing hypothesis is that the associated noncoding variant modulates the risk of AMD by regulating the expression of CFH, rather than disrupting the CFH protein function. 28  
AMD may affect one or both eyes. Approximately 40% of AMD cases are bilateral in the Caucasian population. 3,40 Bilateral AMD, by reducing functional vision, has a more severe impact on the individual's quality of life than does unilateral AMD. 41 In the Japanese and Chinese populations, however, most cases of exudative AMD occur in one eye; bilateral AMD is less common. 4244 In the present study, 22% of the patients with AMD had bilateral AMD, and the frequencies of the risk C allele at rs1410996 in the CFH gene were higher in bilateral cases than in unilateral cases. Similarly, the frequency of the homozygous CC genotype at rs1410996 was found to be higher in the patients with bilateral AMD. Although the difference in allele frequencies and genotype distributions between the bilateral and unilateral cases were not significant, our data suggest that individuals with the homozygous CC genotype of the CFH noncoding variant may carry a higher risk of bilateral exudative AMD. Further studies with a significantly larger sample size are needed to confirm this observation. The frequency of bilateral exudative AMD has also been reported to be significantly higher than that of unilateral AMD in those with the homozygous CFH Y402H variant and HTRA1 polymorphisms. 45,46  
It has long been known that the prevalence and phenotypic spectrum of AMD vary among different ethnic groups. There is also ethnic variation in the AMD-associated CFH polymorphism Y402H. 2127 Frequencies of the risk C allele at Y402H were between 55% and 94% in AMD cases and 30% and 46% in controls in Caucasians. 912,17,47 In contrast, in both cases and controls, frequencies of the risk C allele at Y402H are approximately 3% to 11% in Chinese, 26,27,48 7% to 11% in Korean, 25 and 4% to 14% in Japanese 23,24,30 populations. These earlier findings suggesting differences in genetic susceptibility to AMD among ethnic groups are further supported by the results of the present study, in which the two coding variants of the C3 gene were found to be rare and not associated with exudative AMD. The common functional polymorphisms rs2230199 (R102G) and rs1047286 (P314L) in the C3 gene have been identified as genetic risk factors for AMD in several case–control studies in Caucasian populations. 3134 Frequencies of the risk G allele at rs2230199 were 25% to 31% in AMD cases and 19% to 21% in controls in Caucasians. 3134 Frequencies of the risk T allele at rs1047286 were 27% to 29% in AMD and 20% to 22% in controls in Caucasian populations. 31,32,34 Moreover, rs2230199 was found to be involved in the progression from the earlier stages of AMD to advanced AMD. 49 In this study, we found that the SNPs rs2230199 and rs1047286 in the C3 gene were only 0.3% to 1% in both the cases and the controls and were not associated with exudative AMD. These data confirm the ethnic differences in allele frequencies and genetic susceptibilities to AMD across populations. Studies have suggested that bioactive fragments of C3 and CFH are present in drusen, supporting the hypothesis that local inflammation and activation of the complement cascade contributes to the pathogenesis of AMD. 11,50,51 In the Chinese population, however, drusen are less frequently observed and the prevalence of the late stage of AMD is lower than in Caucasians. 52,53 Although all the predictors that influence the prevalence of AMD are still unclear, the low frequency of C3 and CFH Y402H variants, together with their weaker association with AMD, may partially explain the epidemiologic features of AMD in the Chinese. 
In summary, our data suggest that the CFH noncoding variant rs1410996 moderately increases the risk of exudative AMD. We also demonstrated substantial differences in the frequencies of the C3 coding variants rs2230199 and rs1047286 between Caucasian and Chinese populations. Furthermore, the C3 variants rs2230199 and rs1047286 were not associated with exudative AMD. Our data further support previous observations that genetic susceptibility to AMD varies among different ethnicities. The identification of genetic risk factors in various ethnic groups will undoubtedly lead to a better understanding of the pathogenesis of AMD and subsequently will identify persons at risk of the disease. 
Footnotes
 Supported by the National Basic Research Program of China (Program 973) Grant 2007CB512201 and the Beijing Medical Development Foundation Grant 2002-1019.
Footnotes
 Disclosure: L. Cui, None; H. Zhou, None; J. Yu, None; E. Sun, None; Y. Zhang, None; W. Jia, None; Y. Jiao, None; T. Snellingen, None; X. Liu, None; A. Lim, None; N. Wang, None; N. Liu, None
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Table 1.
 
Primers Used for PCR Amplification and Sequencing
Table 1.
 
Primers Used for PCR Amplification and Sequencing
Genes SNP Primer Sequence (5′→3′)
CFH rs1410996 (noncoding) F: TTG GAC ATT AGG ACT CTT AG
R: GTA CTC CTT TTT AGG CAC T
C3 rs2230199 (R102G) F: CCC TCG CAC CTC CTT CAC
R: CCT CTG GCT GGC ACC TCA AT
C3 rs1047286 (P314L) F: CCT CAA GCG CAT TCC GGT
R: AGC CTC CCT CCT TAG ACT
Table 2.
 
Age and Sex of Patients with Exudative AMD and Control Subjects
Table 2.
 
Age and Sex of Patients with Exudative AMD and Control Subjects
Sample Controls (n = 161) AMD Cases All Subjects (n = 311)
Unilateral (n = 117) Bilateral (n = 33) Total (n = 150)
Age, y (mean ± SD) 65.7 ± 7.8 66.0 ± 8.5 68.7 ± 7.7 66.6 ± 8.4 66.1 ± 8.1
Sex
    Male 84 (52.2) 69 (59.0) 19 (57.6) 88 (58.7) 172
    Female 77 (47.8) 48 (41.0) 14 (42.4) 62 (41.3) 139
Table 3.
 
Genotype and Allele Frequencies in Cases of Exudative AMD and Controls
Table 3.
 
Genotype and Allele Frequencies in Cases of Exudative AMD and Controls
Genotypes AMD Cases (n = 150) Controls (n = 161) χ2 P OR (95% CI)
CFH rs1410996:T>C (noncoding)
    Genotype
        TT 13 (8.7) 31 (19.3) 1.00
        TC 58 (38.7) 81 (50.3) 1.71 (0.82–3.54)
        CC 79 (52.7) 49 (30.4) 17.834 <0.001 3.85 (1.84–8.05)
H-W P = 0.724 H-W P = 0.968
    Allele
        T 84 (28.0) 143 (44.4) 1.00
        C 216 (72.0) 179 (55.6) 29.849 <0.001 2.48 (1.79–3.45)
C3 rs2230199:C>G (R102G)
    Genotype
        CC 147 (98.0) 160 (99.4) 1.00
        CG 3 (2.0) 1 (0.6) 0.330 0.565 3.27 (0.34–31.74)
        GG 0 (0) 0 (0)
H-W P = 1.0 H-W P = 1.0
    Allele
        C 297 (99.0) 321 (99.7) 1.00
        G 3 (1.0) 1 (0.3) 0.328 0.567 3.24 (0.34–31.34)
C3 rs1047286:C>T (P314L)
    Genotype
        CC 148 (98.7) 160 (99.4) 1.00
        CT 2 (1.3) 1 (0.6) 0.004 0.951 2.16 (0.19–24.09)
        TT 0 (0) 0 (0)
H-W P = 1.0 H-W P = 1.0
    Allele
        C 298 (99.3) 321 (99.7) 1.00
        T 2 (0.7) 1 (0.3) 0.004 0.951 2.15 (0.19–23.88)
Table 4.
 
Comparison of Genotype and Allele Frequencies of the CFH Noncoding Variant rs1410996 among Control Subjects, Patients with Unilateral AMD, and Patients with Bilateral AMD
Table 4.
 
Comparison of Genotype and Allele Frequencies of the CFH Noncoding Variant rs1410996 among Control Subjects, Patients with Unilateral AMD, and Patients with Bilateral AMD
Controls (n = 161) Unilateral (n = 117) P * OR (95% CI) Bilateral (n = 33) P * OR (95% CI)
Genotype
    TT 31 (19.3) 10 (8.5) 1.00 3 (9.1) 1.00
    TC 81 (50.3) 50 (42.7) 1.91 (0.86–4.24) 8 (24.2) 1.02 (0.25–4.10)
    CC 49 (30.4) 57 (48.7) 0.002 3.61 (1.61–8.10) 22 (66.7) <0.001 4.64 (1.28–16.81)
Allele
    T 143 (44.4) 70 (29.9) 1.00 14 (21.2) 1.00
    C 179 (55.6) 164 (70.1) 0.001 1.87 (1.31–2.67) 52 (78.8) <0.001 2.97 (1.58–5.57)
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