Current Eye Research, 2015; 40(7): 676–682 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.957325

ORIGINAL ARTICLE

Polymorphisms of DNA Repair Genes XPD (Lys751Gln) and XRCC1 (Arg399Gln), and The Risk of Age-Related Cataract: A Meta-Analysis Xiao-Cui Liu1, Xiao-Fei Liu2, Zhi-De Hu2 and Zhao-Hui Li1 1

Department of Ophthalmology, Chinese PLA (People’s Liberation Army) General Hospital, Beijing, China, and 2 Department of Laboratory Medicine, General Hospital of Ji’nan Military Region of PLA, Ji’nan, Shandong Province, P.R. China

ABSTRACT Purpose: A meta-analysis of available studies was used to test the association between two DNA repair genes and age-related cataract. Materials and Methods: A systematic search of the Chinese National Knowledge Infrastructure, EMBASE and PubMed databases identified six studies that were analyzed. Meta-analysis was used to evaluate single nucleotide polymorphisms (SNP) of the DNA repair gene xeroderma pigmentosum complementation group D (XPD) (Lys751Gln) and the X-ray repair cross-complementing gene 1 (XRCC1) (Arg399Gln). Only articles published before June 6, 2014, were included. The quality of the studies was determined using Newcastle– Ottawa Scale tools. The summary odds ratio (OR) and corresponding confidence interval (CI) for XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms and risk of age-related cataract were estimated by random and fixed-effects models. Sensitivity analysis was employed to determine the robustness of the conclusions. Results: Six studies, with a total of 1518 patients with cataractous lenses and 1437 subjects with clear lenses, were included in the meta-analysis. XRCC1 Arg399Gln polymorphisms were associated with cataract risk (recessive model: ORfixed = 0.79, 95% CI: 0.67–0.93; dominant model: ORfixed = 0.84, 95% CI: 0.64–1.11; additive model: ORfixed = 0.82, 95% CI: 0.72–0.92). Analysis of Chinese, but not non-Chinese subgroups, confirmed this association. The OR of XPD Lys751Gln polymorphisms for cataract was not significant. The associations remained significant after sensitivity analysis. Conclusions: This meta-analysis indicates that XRCC1 Arg399Gln polymorphisms, but not XPD Lys751Gln polymorphisms, are associated with risk of age-related cataract. Keywords: Age-related cataract, DNA repair genes, meta-analysis, polymorphisms, risk of cataract

INTRODUCTION

monolayer of lens epithelial cells, which cover the anterior portion of the lens. This damage may contribute to cataractogenesis.6–8 The physiological role of DNA repair is to protect the genome against damage caused by environmental factors, and therefore is critically important for the maintenance of a clear lens.9 DNA repair depends on several enzymes that are coded for by DNA repair genes. Single nucleotide polymorphisms (SNP) of

Age-related cataract is a major cause of visual impairment and blindness in the world.1,2 Although the molecular mechanisms of cataractogenesis remain unknown, certain risk factors have been identified, including exposure to ultraviolet light and oxidative damage.3–5 These environmental factors can cause DNA damage or mutations in the DNA located in the

Received 19 March 2014; revised 9 July 2014; accepted 18 August 2014; published online 6 October 2014 Correspondence: Zhi-De Hu, E-mail: [email protected] and Zhao-Hui Li, E-mail: [email protected]

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Polymorphisms of DNA Repair Genes and Cataract these repair genes may affect the activity of the DNA repair enzymes and thus alter the capacity for DNA repair.10,11 Several studies have investigated the association between SNPs of DNA repair genes and risk of cataract. Among the SNPs, the xeroderma pigmentosum complementation group D (XPD) gene (Lys751Gln) and the X-ray repair crosscomplementing 1 (XRCC1) gene (Arg399Gln) are the most widely studied. However, the results of the available studies are inconsistent. Meta-analysis is often capable of finding relationships across studies that are obscured using other approaches,12 so we performed a meta-analysis to analyze the relationship between XPD Lys751Gln, XECC1 Arg399Gln and risk of cataract.

MATERIALS AND METHODS Studies Included in the Meta-Analysis and Data Extraction Meta-analysis was performed according to the checklist of Stroup et al.9 A systematic search of the Chinese National Knowledge Infrastructure, EMBASE and Medline (using PubMed as the search engine) databases was performed to identify case–-control studies, published prior to June 6, 2014, of cataract risks, the SNPs of XPD Lys751Gln and XRCC1 Arg399Gln, and genotype and allele frequency. Two investigators performed the searches independently, and disagreements were reconciled at meetings. Animal studies, conference abstracts and letters to the editors were excluded. For duplicate studies or studies on possibly the same patients, only the study with the largest number of samples was included. None of the authors of the eligible studies were contacted for more information. The retrieval strategies are shown in ***Supplementary File 1.

Statistical Analysis Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were employed to estimate the strength of the associations between polymorphisms of DNA repair genes and risk of cataract. To analyze the data, an additive model was first introduced, and recessive or dominant models were used if the additive model was significant, as previously described.11 Subgroup analysis was performed according to the race of the subjects. Statistical heterogeneity among the studies was estimated using a Chi-square based Q test and I2 statistics. Data were considered significant when p50.10 for the Q test and I2425% for I2 statistics. In such cases, a random-effects model was used to calculate pooled ORs; otherwise, a fixed effect model was used. Sensitivity analysis was performed by omitting individual studies to evaluate the influence of the remaining pooled results. Hardy–Weinberg equilibrium (HWE) was assessed using Fisher’s exact test. All statistical analyses were performed in Review Manager (version 5.1, The Nordic Cochrane Centre, Copenhagen).

RESULTS Summary of Eligible Studies Of the 40 studies identified for possible inclusion in the analysis (Figure 1), 9 identical studies were excluded; the remaining 31 articles relevant to the analysis were screened. Of those 31 reports, 25 were excluded according to strict criteria leaving 6 records for meta-analysis. A total of 1518 patients with cataractous lenses and 1437 subjects with clear lenses, all of whom were enrolled in hospitals, were studied in the meta-analysis.12–17 Four studies

Data Extraction and Quality Assessment Pubmed (n = 10)

Both reviewers independently reviewed and tabulated data individually by reading all studies included in the meta-analysis; any disagreements were adjudicated by a third reviewer blinded to the first two reviewers. The first author’s name, countries of subjects, publication year, genotyping methods, and the frequency of each genotype, as well as the characteristics, of the control and cataract groups were used for analysis. The Cochrane recommended case–control study quality assessment tool and the Newcastle–Ottawa Scale (NOS) tools were used to evaluate the quality of the eligible studies.10 According to NOS, three aspects of the eligible studies were assessed: selection, comparability and outcome had maximum scores of 4, 2 and 3, respectively. !

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EMBASE (n = 21) CNKI (n = 9)

Records after duplicates removed

Excluded: Other diseases (n=10)

Records screened (n = 31 )

Review (n=7) In vitro or animal study (n=5) Case report (n=1) Other SNPs (n=2)

Studies included in meta-analysis (n = 6)

FIGURE 1. A flowchart of included studies.

678 X.-C. Liu et al. investigated the association between the risk of cataract and XPD Lys751Gln polymorphism12–14,16 and five investigated the risk of cataract and XRCC1 Arg399Gln polymorphism.12–15,17 Four studies were performed in China,12,14,16,17 one was performed in Turkey13 and one was performed in India.15 All studies employed classic polymerase chain reaction– restriction fragment length polymorphism for genotyping. The controls of all SNPs in the eligible studies were in agreement with HWE except the studies that investigated XRCC1 Arg399Gln polymorphism.12,13

The characteristics of all eligible studies are summarized in Table 1. The sample sizes and genotype distributions of eligible studies are listed in Table 2.

Quality Assessment, Heterogeneity, Sensitivity and Meta-Analysis Only one study reported that patients with cataract were consecutively enrolled, and the selection domain was thus labeled with four stars (Table 1).13

TABLE 1. Characteristics of eligible studies. Control First author

Year Country

Xu H16

2013

China

Luo YF12

2011

China

Unal M13

2007

Turkey

Zhang Y14

2012

China

Padma G15 2011

India

Guo M17

China

2013

Cases

Characteristics

Sources

C/N/P/M

Diagnosed by

Match for

Genotype methods

NOS

Without ocular disease and cancer Without age-related cataract or other age-related ocular diseases Normal ocular examination presented to our outpatient department with non-specific ocular complaints Unrelated volunteers in the same clinic Without the history of cataract, diabetes, hypertension, thyroid, and other ocular diseases Without ocular disease anc cancer

HB

NR

NR

None

PCR-RFLP

3/2/3

HB

NR

Slit-lamp biomicroscope

None

PCR-RFLP

3/2/3

Slit-lamp Age, gender PCR-RFLP biomicroscope

4/2/3

HB

75/53/37/30

HB

121/109/59/126

HB

HB

Slit-lamp Age, gender PCR-RFLP 3/2/3/ biomicroscope 69/69/70/0 Slit lamp Age, gender PCR-RFLP 3/2/3/ examination

NR

NR

None

PCR-RFLP 3/2/3/

HB hospital based; NOS Newcastle–Ottawa Scale; PCR–RFLP polymerase chain reaction–restriction fragment length polymorphism; C/N/P/M Cortical/Nuclear/Posterior subcapsular/Mixed; NR not reported.

TABLE 2. Major findings of eligible studies. Genotype frequencies Gene XPD Lys751Gln

XRCC1 Arg399Gln

First author

Cataract

Cataract/Control

Control

Lys/Lys

Lys/Gln

Gln/Gln

Lys/Lys

Lys/Gln

Gln/Gln

HWE

Luo YF12 Unal M13 Zhang Y14 Xu H16

180/174 195/194 415/386 260/266

158 71 270 207 Arg/Arg

22 102 134 49 Arg/Gln

0 22 11 4 Gln/Gln

148 50 264 217 Arg/Arg

25 106 113 45 Arg/Gln

1 38 9 4 Gln/Gln

Y Y Y Y

Luo YF12 Unal M13 Zhang Y14 Padma G15 Guo M17

180/174 195/194 415/386 208/151 260/266

96 65 195 90 129

71 100 186 82 114

13 30 34 36 17

115 58 194 75 161

45 115 162 56 95

14 21 30 20 10

N N Y Y Y

HWE Hardy–Weinberg equilibrium. Current Eye Research

Polymorphisms of DNA Repair Genes and Cataract The remaining studies were labeled with three stars. Generally, the major design characteristics of all eligible studies were in accordance with the NOS tool and therefore of relatively high quality. An additive model was used to test the association between XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms and the risk of cataract. No obvious association was observed between XPD Lys751Gln polymorphism and the risk of cataract (OR = 1.10, 95% CI: 0.82–1.47), and therefore, recessive or dominant models were not used for further study. For the XRCC1 gene, the association was observed between its Arg399Gln polymorphism and the risk of cataract (ORfixed = 0.82, 95% CI: 0.72–0.92) (Figure 2). Therefore, recessive or dominant models were used to further explore the association between the Arg399Gln polymorphism and risk of cataract. The

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ORs in recessive and dominant models were 0.79 (95% CI: 0.67–0.93) and 0.84 (95% CI: 0.64–1.11), respectively (Table 3). Obvious heterogeneity was observed across the four studies that investigated XPD Lys751Gln polymorphisms and cataract (I2 = 63%, p = 0.04). However, no significant heterogeneity was detected in the five studies that investigated XRCC1 Arg399Gln polymorphisms and cataract (Table 3). In a subgroup analysis, XRCC1 Arg399Gln polymorphism was associated with a risk of cataract in the Chinese subgroup using additive and recessive models, but no association was observed using the dominant model. The association was not observed in the non-Chinese subgroup using any of the genetic models (Table 2).

FIGURE 2. The relationship between XRCC1 Arg399Gln polymorphism and risk of cataract was analyzed by an additive model.

TABLE 3. Meta-analysis for XRCC1 Arg399Gln and age-related risk of cataract. Meta-analysis Comparison Recessive

Dominant

Additive

Subgroup

Model

OR

95% CI

I2 (%)

p

Total (n = 5) Chinese (n = 3) Non–Chinese (n = 2) Total (n = 5) Chinese (n = 3) Non-Chinese (n = 2) Total (n = 5) Chinese (n = 3) Non-Chinese (n = 2)

Fixed Fixed Fixed Fixed Fixed Fixed Fixed Randomed Fixed

0.79 0.73 0.95 0.84 0.97 0.70 0.82 0.75 0.89

0.67–0.93 0.60–0.89 0.70-1.28 0.64–1.11 0.67–1.40 0.46–1.06 0.72–0.92 0.59–0.97 0.72–0.10

43 38 46 0 0 0 41 59 0

0.13 0.20 0.17 0.81 0.92 0.81 0.15 0.09 0.33

CI confidence interval; OR odds ratio. !

Heterogeneity

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FIGURE 3. Sensitivity analysis for XRCC1 Arg399Gln and age-related risk of cataract.

To investigate whether one study had bias, sensitivity analysis was employed (Figure 3). For XRCC1 Arg399Gln polymorphisms, no other single study affected the pooled OR, which indicated that the results of our meta-analysis were relevant and statistically significant.

DISCUSSION This study demonstrated that XRCC1 Arg399Gln polymorphisms, but not XPD Lys751Gln polymorphisms, were associated with a risk of cataract, especially in the Chinese subgroup. The associations remained significant after sensitivity analysis. Investigating these polymorphisms could extend our knowledge related to the etiology of cataract and could also potentially provide insights to the development of therapies to prevent or delay cataract formation. The XPD gene plays a key role in nucleotide excision repair, which is crucial to the elimination of damage to the human DNA genome,18 and

polymorphisms are associated with several malignant diseases, such as esophageal,19 breast20 and lung cancer.21 The XPD gene is located in chromosome 19q13.3, is larger than 20 kb, contains 23 exons and encodes a 761-amino acid protein. The XPD Lys751Gln polymorphism, a single nucleotide substitution from A to C at the 23th exon, could lead to a change in the electronic configuration. This change is located in the important domain of interaction between the XPD protein and the p44 protein, and thus might affect the DNA repair efficiency of XPD.22 However, our meta-analysis showed that XPD Lys751Gln polymorphisms did not significantly contribute to the risk of age-related cataract. This paradox may be explained by the possibility that the DNA damage was so slight that the effect of Lys751Gln polymorphism on DNA repair efficiency, as well as the occurrence and development of cataract, was not obvious. Another explanation for the paradox is that the frequency of Lys751Gln polymorphism was affected by the subtype of cataract. Cortical cataract had a higher Lys allele.13 A review of the epidemiologic studies revealed that ultraviolet light Current Eye Research

Polymorphisms of DNA Repair Genes and Cataract exposure was a risk factor for the development of cortical cataract, while the association between nuclear and posterior subcapsular cataract was not robustly supported.23 Therefore, lacking an association between Lys751Gln polymorphism and risk of cataract may be attributed to the interference of nuclear and posterior subcapsular cataract in the patients cohort. The lack of association between XPD Lys751Gln polymorphisms and risk of cataract may also be attributed to the limited number of eligible studies. XRCC1 is another DNA repair gene that is critically involved in the DNA base excision repair pathway,24 and its Arg399Gln polymorphisms are associated with various cancers.25,26 Our meta-analysis indicated that the wild-type homozygote of the XCRR1 Arg399Gln polymorphism (Arg/Arg carriers) was associated with risk of cataract, which is partially supported by an in vitro study in which DNA repair efficiency was affected by XCRR1 Arg399Gln and the wild-type homozygote of XCRR1 Arg399Gln polymorphisms (Arg/Arg carriers), which had a lower level of DNA breaks after irritation.27 Further studies are needed to address the exact mechanisms behind XRCC1Arg399Gln polymorphism and DNA repair efficiency.26,28 Our meta-analysis had some limitations. The major limitation is that only six studies were included and four of them were conducted in China. Due to the limited number of eligible studies, the sources of heterogeneity were not explored by meta-regression, and the possibility of publication bias was not tested using a funnel plot or Egger’s test. However, the sample sizes of individual eligible studies were large, and the total sample size of the meta-analysis was adequate. In conclusion, meta-analysis indicated that XRCC1 Arg399Gln polymorphisms, but not XPD Lys751Gln polymorphisms, were associated with risk of cataract. Further, larger scale studies estimating the effects of gene–gene and gene–environment interactions may eventually provide a better and more comprehensive understanding of the roles of DNA repair gene polymorphisms and risk of cataract.

ACKNOWLEDGEMENTS We appreciate Dr. Zhi-Rui Zhou of the Department of Radiation Oncology at the Tumor Hospital of Jilin Province for his helpful discussion.

DECLARATION OF INTEREST The authors report no conflicts of interest. This work was supported by the National Natural Science Foundation of China (No. 81302541). !

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