Polymorphisms of DNA repair genes XPD and XRCC1 and risk of cataract development
Introduction
Age related cataract is the leading cause of blindness worldwide, with an estimated 18 million individuals bilaterally blind (World Health Organization report). The etiology of age-related changes in the lens is not fully understood and is likely to be multifactorial. A growing body of research has focused on risk factors that might contribute to cataract development and preventive factors that might retard their growth (Asbell et al., 2005).
Endogenous oxidative damage to proteins, lipids, and DNA has been hypothesized to be an important etiologic factor in aging and the development of systemic diseases such as cancer, atherosclerosis, and ocular disorders including cataract, glaucoma, uveitis, and age-related macular degeneration (McCall and Frei, 1999, Ohia et al., 2005). Association between oxidative stress and DNA damage has been well-known (Johnson and Barton, 2007). In recent years, many studies focused on the association between DNA damage to the lens epithelium and the development of lens opacities (Spector, 1995, Sasaki et al., 1998, Pendergrass et al., 2005). Ultraviolet (UV) light, one of the contributing factors to cataractogenesis, has been also shown to cause DNA damage in lens epithelium (Jose and Yielding, 1977, Sidjanin et al., 1993, Kleiman et al., 1990a, Reddy et al., 1998, Risa et al., 2004). Chromosomal abnormalities as evidence for such damage have been reported in lens epithelia from patients with cataract (Worgul et al., 1991).
DNA repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by exposure to cytotoxic compounds or carcinogens (Wood et al., 2001). Recently, it has been hypothesized in many studies that polymorphisms in DNA repair genes reduce their capacity to repair DNA damage and thereby lead to increased cancer or other age-related disease susceptibility (Clarkson and Wood, 2005, Ladiges et al., 2003, Liu et al., 2007, Povey et al., 2007, Stern et al., 2006). Some studies have already indicated the role and importance of DNA repair in lens epithelial cells (Colitz et al., 2004, Jose and Yielding, 1977, Spector et al., 1989, Kleiman et al., 1990a, Sidjanin et al., 1993, Grabner and Brenner, 1982). Although the exact pathogenetic mechanism of cataract development has not yet been fully clarified, the involvement of oxidative or UV light damage to DNA and the existence of DNA repair in cataract development indicate the role of DNA repair enzymes.
Repair of oxidative DNA damage is mediated by both base excision repair (BER) and nucleotide excision repair (NER) mechanisms (Frosina, 2000). Many DNA repair genes and their polymorphisms have been reported to be related with some diseases. Amongst them, polymorphisms of xeroderma pigmentosum complementation group D (XPD), X-ray cross-complementing group 1 (XRCC1) and X-ray cross-complementing group 3 (XRCC3) have been studied extensively (Clarkson and Wood, 2005).
X-ray cross-complementing group 1 (XRCC1), a DNA repair protein involved in single-strand breaks (SSBs) and BER pathway, has been reported to be responsible for the efficient repair of DNA damage caused by active oxygen, ionization, and alkylating agents (Caldecott, 2003). It is a multidomain protein that interacts with the nicked DNA and participates with at least three different enzymes, poly-ADP-ribose polymerase (PARP), DNA ligase III, and DNA polymerase β, to repair SSBs (Caldecott, 2003). Many polymorphisms were detected in XRCC1 gene and three of them received most attention (Ladiges et al., 2003). These coding polymorphisms, resulting in amino acid substitutions, were detected at codons 194 (Arg-Trp), 280 (Arg-His) and 399 (Arg-Gln). The most common polymorphism of XRCC1 gene is at codon Arg399Gln resulting from a guanine to adenine nucleotide substitution which occurs in the PARP binding domain and may affect complex assembly or repair efficiency (Ladiges et al., 2003).
Xeroderma pigmentosum complementation group D (XPD) encodes a helicase, which participates in both NER and basal transcription as part of the transcription factor IIH (Clarkson and Wood, 2005). Mutations destroying enzymatic function of the XPD protein are manifested clinically in combinations of three severe syndromes, Cockayne syndrome, xeroderma pigmentosum and trichothiodystrophy depending on the location of the mutation (Clarkson and Wood, 2005). Because XPD is important in multiple cellular tasks and rare XPD mutations result in genetic diseases, XPD polymorphisms may operate as genetic susceptibility factors. Several single nucleotide polymorphisms (SNPs) in XPD gene exons have been identified, of them Asp312Asn and Lys751Gln polymorphisms are the most common (Shen et al., 1998). The XPD-Lys751Gln polymorphism may produce the most relevant change in XPD function and may influence DNA repair capacity (Lunn et al., 2000, Benhamou and Sarasin, 2002).
Screening for the possible relationship between polymorphisms of DNA repair genes and cataract may contribute to understanding the pathogenesis of cataract development and may be useful in the prevention of this disease. No studies have examined previously the relationship between DNA repair enzymes polymorphisms and risk of maturity onset cataract development. As the XPD codon 751 (Lys-Gln) and XRCC1 codon 399 (Arg-Trp) polymorphisms are very common in the population and have immediate functional significance, we initiated this case control study to determine the possible association with these polymorphisms and the development of maturity onset cataract.
Section snippets
Patients and controls
This case-control study included a total of 195 patients with maturity onset cataract (75 patients with cortical, 53 with nuclear, 37 with posterior subcapsular, and 30 with mixed type) and 194 disease-free controls. All subjects were of Turkish nationality belonging to the Turkish ethnic group. The patients with cataract were selected consecutively and had phacoemulsification cataract surgery at İstanbul University Cerrahpasa Medical Faculty Ophthalmology Department. All subjects were selected
Results
Table 1 shows the demographic data of the patients and controls. The groups were not statistically different with respect to age and gender (P > 0.05).
The genotypic and allelic distributions of the polymorphisms in XPD and XRCC1 genes for both cases and controls are shown in Table 2. The distributions of the XPD-Lys751Gln and XRCC1-Arg399Gln genotypes were in accordance with the Hardy–Weinberg equilibrium among the controls (P = 0.65, P = 0.068, respectively) and the cases (P = 0.50, P = 0.82,
Discussion
The recent hypothesis is that SNPs in the population may contribute significantly to genetic risk for common diseases including age related disorders. The relationship between genetic polymorphisms and maturity onset cataract development has been subject of interest. A novel allelic variant (Osaka variant) in the human galactokinase (GALK) gene has been reported to have a role in the development of cataract in elderly Japanese and Koreans (Okano et al., 2001). Also, polymorphic gluthatione S
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