Associations between XPD Asp312Asn polymorphism and risk of head and neck cancer: a meta-analysis based on 7,122 subjects

Background

To investigate the association between XPD Asp312Asn polymorphism and head and neck cancer risk through this meta-analysis.

Methods

We performed a meta-analysis of 9 published case-control studies including 2,670 patients with head and neck cancer and 4,452 controls. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between XPD Asp312Asn polymorphism and head and neck cancer risk.

Results

Overall, no significant association between XPD Asp312Asn polymorphism and head and neck cancer risk was found in this meta-analysis (Asn/Asn vs. Asp/Asp: OR = 0.95, 95%CI = 0.80–1.13, P = 0.550, P _{heterogeneity} = 0.126; Asp/Asn vs. Asp/Asp: OR = 1.11, 95%CI = 0.99–1.24, P = 0.065, P _{heterogeneity} = 0.663; Asn/Asn+Asp/Asn vs. Asp/Asp: OR = 1.07, 95%CI = 0.97–1.19, P = 0.189, P _{heterogeneity} = 0.627; Asn/Asn vs. Asp/Asp+Asp/Asn: OR = 0.87, 95%CI = 0.68–1.10, P = 0.243, P _{heterogeneity} = 0.089). In the subgroup analysis by HWE, ethnicity, and study design, there was still no significant association detected in all genetic models.

Conclusions

This meta-analysis demonstrates that XPD Asp312Asn polymorphism may not be a risk factor for developing head and neck cancer.     

XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer

Polymorphisms in the XPD and the XPC gene have been associated with a lower DNA repair capacity. We determined the risk of colorectal cancer in association with the four polymorphisms XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn, and interactions between the polymorphisms and the environmental factors: smoking intensity, intake of alcohol, red meat, processed meat, fish and poultry, fruits and vegetables and dietary fibres, in relation to development of colorectal cancer in a study population of 405 colorectal cancer cases and a comparison group of 810 persons, nested within the Danish prospective cohort, Diet, Cancer and Health, of 57053 cohort members. No association was found between the XPC Lys939Gln, XPA A23G, XPD Lys751Gln, and XPD Asp312Asn polymorphisms and risk of colorectal cancer. The association of the XPD Lys751Gln polymorphism was statistically significantly different between genders, with a lower risk of colorectal cancer among women carrying the variant allele. We observed a statistically significant interaction between the XPC Lys939Gln polymorphism and consumption of red meat, with a 3.7-fold increase in colorectal cancer risk per 100g red meat intake per day among carriers of the homozygous variant, but virtually no effect of red meat intake among carriers of the wild type allele. In the light of the multiple comparisons being made, this result may be a chance finding. The results showed no interaction between the XPD Lys751Gln, XPA A23G, and XPD Asp312Asn polymorphisms and the environmental factors for the development of colorectal cancer. Overall, the results of the present study indicate that the four polymorphisms are not of major importance in colorectal cancer carcinogenesis.     

Association between SHBG Asp327Asn (rs6259) polymorphism and breast cancer risk: a meta-analysis of 10,454 cases and 13,111 controls

Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. Epidemiological studies have evaluated the association between SHBG Asp327Asn polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 10 studies were identified for the meta-analysis, including 10,454 cases and 13,111 controls for SHBG Asp327Asn polymorphism. When all studies were pooled into the meta-analysis, there was no evidence for significant association between SHBG Asp327Asn polymorphism and breast cancer risk (for Asn/Asn vs. Asp/Asp: OR = 1.20, 95 % CI = 0.94-1.55; for Asp/Asn vs. Asp/Asp: OR = 0.94, 95 % CI = 0.87-1.01; for dominant model: OR = 0.95, 95 % CI = 0.90-1.02; for recessive model: OR = 1.22, 95 % CI = 0.95-1.57). In the subgroup analyses by ethnicity, menopausal status, and source of controls, no significant associations were found in all genetic models. Interestingly, further analyses stratified by menopausal status in different ethnicities revealed that this polymorphism might provide protective effects against breast cancer risk in postmenopausal Asian women (for dominant model: OR = 0.83, 95 % CI = 0.70-0.97). Sensitivity analyses were performed by sequential removal of individual studies and cumulative statistics have showed combined ORs were not materially altered by any individual study under all comparisons. In summary, this meta-analysis suggests that SHBG Asp327Asn polymorphism is not associated with breast cancer risk overall, while it might be an important genetic susceptibility factor in postmenopausal Asian women for developing breast cancer. Larger and well-designed studies are warranted to confirm our findings in the future.     

Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence

Endogenous sex hormones have been observed to have a role in systemic lupus erythematosus (SLE) predisposition. Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex hormones to target tissues. Therefore, we examined the distribution of the SHBG functional polymorphism Asp327Asn (rs6259) in SLE patients (n = 150) and controls (n = 150) in a Polish population. We found a contribution of the SHBG327Asn variant to the development of SLE. Women with the Asp/Asn and Asn/Asn genotypes displayed a 2.630-fold increased risk of SLE (95% CI = 1.561–4.433, P = 0.0003). SHBG has a much higher affinity for testosterone than estradiol, and the SHBG327Asn variant displays a reduction of estradiol clearance. Therefore we suggest that the opposing effects of estrogens and testosterone on the immune system and imbalance in the levels of these hormones in SLE patients can be enhanced by the SHBG327Asn protein variant.     

Impact of DNA repair genes polymorphism (XPD and XRCC1) on the risk of breast cancer in Egyptian female patients

The genes involved in DNA repair system play a crucial role in the protection against mutations. It has been hypothesized that functional deficiencies in highly conserved DNA repair processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer (BC). The aim of the present study was to evaluate the association of genetic polymorphisms in 2 DNA repair genes, XPD (Asp312Asn) and XRCC1 (A399G), with BC susceptibility. We further investigated the potential combined effect of these DNA repair variants on BC risk. Both XPD (xeroderma pigmentosum group D) and XRCC1 (X-ray repair cross-complementing group 1) polymorphisms were characterized in 100 BC Egyptian females and 100 healthy women who had no history of any malignancy by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method and PCR with confronting two-pair primers (PCR-CTPP), using DNA from peripheral blood in a case control study. Our results revealed that the frequencies of AA genotype of XPD codon 312 polymorphism were significantly higher in the BC patients than in the normal individuals (P ≤ 0.003), and did not observe any association between the XRCC1 Arg399Gln polymorphism and risk of developing BC. Also, no association between both XPD Asp312Asn and XRCC1 A399G polymorphisms and the clinical characteristics of disease. Finally, the combination of AA(XPD) + AG(XRCC1) were significantly associated with BC risk. Our results suggested that, XPD gene is an important candidate gene for susceptibility to BC. Also, gene–gene interaction between XPD(AA) + XRCC1(AG) polymorphism may be associated with increased risk of BC in Egyptian women.     

The association between the Lys751Gln polymorphism in the XPD gene and the risk of bladder cancer

The Lys751Gln polymorphism in the XPD gene have been suggested as a risk factor for bladder cancer, however the results were inconclusive. The aim of the current study is to assess the association by meta-analysis. A total of 15 case–control studies concerning the association between the XPD Lys751Gln polymorphism and bladder cancer risk were included in the meta-analysis. The results suggested that the Lys751Gln polymorphism was not associated with an increased risk of bladder cancer in the dominant model (OR = 1.03, 95 % CI 0.95–1.11, P = 0.53 for Lys/Gln+Gln/Gln vs. Lys/Lys) in overall analysis. In the subgroup analysis by ethnicity, no significant association was found in Caucasians or Asians. Other comparatives suggested a slight significant association between the polymorphism with the risk of bladder cancer in the recessive comparative (OR = 1.14, 95 % CI 1.02–1.29, P = 0.03). The current meta-analysis indicated that the Lys751Gln polymorphism in the XPD gene might be a risk factor for bladder cancer. In the future, more large-scale case–control studies are needed to validate our results.     

Genetic polymorphisms of xeroderma pigmentosum group D gene Asp312Asn and Lys751Gln and susceptibility to prostate cancer: A systematic review and meta-analysis

Many studies have reported the role of xeroderma pigmentosum group D (XPD) with prostate cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk. A total of 8 studies including 2620 cases and 3225 controls described Asp312Asn genotypes, among which 10 articles involving 3230 cases and 3582 controls described Lys751Gln genotypes and were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, a significant association between prostate cancer risk and XPD Asp312Asn polymorphism was found. For Asp312Asn polymorphism, in the stratified analysis by ethnicity and source of controls, prostate cancer risk was observed in co-dominant, dominant and recessive models, while no evidence of any associations of XPD Lys751Gln polymorphism with prostate cancer was found in the overall or subgroup analyses. Our meta-analysis supports that the XPD Asp312Asn polymorphism contributed to the risk of prostate cancer from currently available evidence. However, a study with a larger sample size is needed to further evaluate gene–environment interaction on XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk.     

Significant association of caveolin-1 genotypes with bladder cancer susceptibility in Taiwan

Many articles have reported the caveolin-1 gene to be down-regulated thus suggesting that it might be a candidate tumor suppressor gene in many tumors. However, its involvement in bladder cancer is not clear and may be depending on pathological grade. In this case-control study, the association of Cav-1 polymorphisms with bladder cancer risk in a central Taiwanese population was investigated. Three hundred and seventy-five patients with bladder cancer and the same number of age- and gender-matched healthy controls were genotyped. There were significant differences between bladder cancer and control groups in the distributions of their genotypes (P = 1.0 x 10(-12) and 0.299) and allelic frequencies (P = 1.4 x 10(-14) and 6.2 x 10(-3)) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. As for haplotype analysis, subjects who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a decreased risk of bladder cancer compared to subjects with GG/TT, while those of any other combinations were of increased risk. There were joint effects of Cav-1 G14713A and T29107A genotypes with smoking status on individual bladder cancer susceptibility. This is the first report providing evidence that Cav-1 was involved in bladder cancer in that the A allele of the Cav-1 G14713A is risky, the A allele of the Cav-1 T29107A is protective, and AA/TT on these two polymorphisms may be the most risky haplotype for the development of bladder cancer and may be novel useful genomic markers for early detection of bladder cancer.     

Intramolecular charge transfer in the bacteriorhodopsin mutants Asp85-->Asn and Asp212-->Asn: effects of pH and anions.

The photovoltage kinetics of the bacteriorhodopsin mutants Asp212-->Asn and Asp85-->Asn after excitation at 580 nm have been investigated in the pH range from 0 to 11. With the mutant Asp85-->Asn (D85N) at pH 7 no net charge translocation is observed and the signal is the same, both in the presence of Cl- (150 mM) and in its absence (75 mM SO4(2-)). Under both conditions the color of the pigment is blue (lambda max = 615 nm). The time course of the photovoltage kinetics is similar to that of the acid-blue form of wild-type, except that an additional transient charge motion occurs with time constants of 60 microseconds and 1.3 ms, indicating the transient deprotonation and reprotonation of an unknown group to and from the extracellular side of the membrane. It is suggested that this is the group XH, which is responsible for proton release in wild-type. At pH 1, the photovoltage signal of D85N changes upon the addition of Cl- from that characteristic for the acid-blue state of wild-type to that characteristic for the acid-purple state. Therefore, the protonation of the group at position at 85 is necessary, but not sufficient for the chloride-binding. At pH 11, well above the pKa of the Schiff base, there is a mixture of "M-like" and "N-like" states. Net proton transport in the same direction as in wild-type is restored in D85N from this N-like state. With the mutant Asp212-->Asn (D212N), time-resolved photovoltage measurements show that in the absence of halide ions the signal is similar to that of the acid-blue form of wild-type and that no net charge translocation occurs in the entire pH range from 0 to 11. Upon addition of Cl- in the pH range from 3.8 to 7.2 the color of the pigment returns to purple and the photovoltage experiments indicate that net proton pumping is restored. However, this Cl(-)-induced activation of net charge-transport in D212N is only partial. Outside this pH range, no net charge transport is observed even in the presence of chloride, and the photovoltage shows the same chloride-dependent features as those accompanying the acid-blue to acid-purple transition of the wild-type.     

Functional IFNG polymorphism in intron 1 in association with an increased risk to promote sporadic breast cancer

Interferon (IFN)- is an important Th1 cytokine, which plays a role in immune surveillance and anti-tumor activity. A case-control study involving 54 sporadic breast cancer patients and 144 healthy controls was carried out to explore if the genotype variation of a proposed non-specific enhancer element with a dinucleotide (CA)_n repeat in intron 1 has a role in the susceptibility to promote sporadic breast cancer. Genotype analysis carried out by single-strand length polymorphism and confirmed by sequencing showed an increased frequency of (CA)₁₂ allele (P<0.001) and decreased frequencies of (CA)₁₅ (P<0.01) and (CA)_>15 (p<0.001) alleles in sporadic breast cancer patients as compared to controls. Further, in vitro reporter assays for (CA)₁₂ and (CA)₁₅ alleles suggested these to be associated with decreased and increased expressions, respectively, suggesting the (CA)₁₂/(CA)₁₂ background to act as one of the factors that could lead to low production of IFN-. The study concludes that such genetic background for a proposed non-specific enhancer element with (CA)_n repeat within intron 1 of the IFNG gene might put the individuals with this genotype at higher risk to promote the development of sporadic breast cancer due to a resultant compromised immune surveillance.Anjana Saha and Ashish Dhir contributed equally.     

Association of the Asp298Asn polymorphism in the mc4r gene with back fat thickness in pigs of the large white breed

The association of the Asp298Asn polymorphism in the mc4r gene with the development of traites such as spinal fat thickness in pigs of the Large White breed from AF “Orzhitska” population was investigated. A tendency towards the development of thinner spinal fat was found in animals with the AG genotype. No significant difference was detected in the spinal fat thickness between animal groups with different genotypes of the mc4r gene caused by Asp298Asn polymorphism. The heterogeneous origin of the studied animals can be a possible cause of the absence of any statistically significant difference. A conclusion was reached that it was not expedient to use Asp298Asn polymorphism of the mc4r gene in the selection of pigs of the Large White breed from AF “Orzhitska” population.     

The association between KL polymorphism and prostate cancer risk in Korean patients

The Klotho (KL) gene is a classical “aging suppressor” gene. Although recent studies have shown that KL participates in the progression of several types of human cancers, the relationship between KL polymorphism and prostate cancer was unknown. The present study aimed to investigate the association between KL genetic polymorphisms and prostate cancer. Twenty-five common single nucleotide polymorphisms (SNPs) in KL gene (including KL gene polymorphism C1818T in exon 4) were assessed in 272 prostate cancer cases and 173 controls. Single-locus analyses were conducted using unconditional logistic regression. In addition, we did a haplotype analysis for the 25 KL SNPs tested. CC genotype of C1548T KL polymorphism had approximately twofold increased prostate cancer risk compared with the homozygous genotype TT and heterozygote CT (odds ratio 1.85 [95 % CI, 1.09–3.12], P = 0.02). We also found that non-T allele carriers had significantly higher prostate cancer risk associated with the prostate cancer clinical characteristics (tumor stage or Gleason score). Our findings suggested that the C1548T polymorphism of KL gene is associated with the prostate cancer and may act as a risk factor for the development of prostate cancer.     

Significant association of interleukin-4 gene intron 3 VNTR polymorphism with susceptibility to knee osteoarthritis

Objective

Interleukin-4 (IL-4) is a strong chondroprotective cytokine and polymorphisms within this gene may be a risk factor for osteoarthritis (OA). We aimed to investigate genotype and allele frequencies of IL-4 gene intron 3 variable number of tandem repeats (VNTR) polymorphism in patients with knee OA in a Turkish population.

Methods

The study included 202 patients with knee OA and 180 healthy controls. Genomic DNA was isolated and IL-4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers followed by restriction fragment length polymorphism (RFLP) analysis.

Results

Our result show that there was statistically significant difference between knee OA patients and control group with respect to IL-4 genotype distribution and allele frequencies (p = 0.000, OR: 0.20, 95% CI: 0.10–0.41, OR: 0.22, 95% CI: 0.12–0.42, respectively).

Conclusions

Our findings suggest that there is an association of IL-4 gene intron 3 VNTR polymorphism with susceptibility of a person for development of knee OA. As a result, IL-4 gene intron 3 VNTR polymorphism could be a genetic marker in OA in a Turkish study population. This is the first association study that evaluates the associations between IL-4 gene VNTR polymorphism and knee OA.     

Lack of association between Glu298Asp polymorphism and coronary artery disease in North Indians

Nitric Oxide (NO) is an important molecule carrying number of different functions in humans. Published studies suggest that it may inhibit several key steps involved in the pathogenesis of atherosclerosis. Inhibition or reduction of NO due to Glu298Asp polymorphism may accelerate atherosclerosis. The aim of this study was to determine whether Glu298Asp polymorphism is implicated in the pathogenesis of coronary artery disease (CAD) among North Indian population from the state of Uttar Pradesh, India. We selected 253 CAD patients and 174 healthy, normotensive, non-diabetic controls, which were matched for gender and ethnicity. The Glu298Asp (rs1799983) variant was detected by genotyping subjects, using a polymerase chain reaction followed by restriction fragment length polymorphism. There was no significant difference found in the genotypic and allelic frequencies between patients and controls. Our study indicated that Glu298Asp polymorphism does not play any critical role in the pathogenesis of CAD, at least in North Indian population.     

A meta-analysis of the association of glutathione S-transferase P1 gene polymorphism with the susceptibility of breast cancer

Glutathione S-transferase P1 (GSTP1) is one of the important mutant sites for the cancer risk at present. The conclusions of the published reports on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer are still debated. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of breast cancer. The association reports were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. 35 investigations were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and breast cancer susceptibility, consisting of 40,347 subjects (18,665 patients with breast cancer and 21,682 controls). The association between GSTP1 A/G gene polymorphism and breast cancer risk was not found for overall population, Caucasians and Africans. Interestingly, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer in Asians (G allele: OR = 1.10, 95 % CI: 1.04–1.17, P = 0.001; GG genotype: OR = 1.36, 95 % CI: 1.14–1.62, P = 0.0008; AA genotype: OR = 0.92, 95 % CI: 0.85–0.98, P = 0.02). Furthermore, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer for the analysis of the controls from hospital. In conclusion, GSTP1 A/G gene polymorphism is associated with the breast cancer susceptibility in Asians. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer should be performed in further.     

Correlation between the Asp298Asn polymorphism of mc4r gene and back fat width in pigs of large white bred

Asp298Asn correlation between the mc4r gene polymorphism and development of such trait as back fat width in Large White pigs belonging to AF "Orzhitska" population was studied. The tendency of forming thinner back fat layer in animals possessing AG genotype was detected. Any reliable differences in back fat width between animal groups with various mc4r genotypes caused by the Asp298Asn polymorphism were not detected. A possible reason for the absence of statistically reliable difference may be heterogeneous origin of the studied animals. Using Asp298Asn polymorphism of mc4r gene in selecting the Large White AF "Orzhitska" pig population is unreasonable.     

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR A1298C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC vs. AA, CC vs. AA), dominant model (CC+AC vs. AA), and recessive model (CC vs. AC+AA), respectively. A total of 26 studies including 12,244 cases and 15,873 controls were involved in this meta-analysis. Overall, no significant associations were found between MTHFR A1298C polymorphism and breast cancer risk when all studies pooled into the meta-analysis (AC vs. AA: OR=0.99, 95% CI 0.94-1.05; CC vs. AA: OR 0.99, 95% CI 0.90-1.09; dominant model: OR=0.99, 95% CI 0.95-1.04; and recessive model: OR=0.98, 95% CI 0.90-1.08). In the subgroup analysis by ethnicity or study design, still no significant associations were found for all comparison models. In conclusion, this meta-analysis suggests that the MTHFR A1298C polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

Insulin-like growth factor I (Igf-1) gene polymorphism in patients with non-metastatic breast cancer

We aimed to assess the association between IGF-I gene (CA repeats) polymorphism in breast cancer patients and their clinicopathological features, as well as disease recurrence and survival. Seventy-six non-metastatic breast cancer patients were enrolled in the present study. The IGF-I (CA) repeats were studied with polymerase chain reaction by using proper primers belonging to these gene areas from DNA samples. Results show that the non 19- non 19 homozygote were more common in patients without lymph node involvement (p=0.04), with low histological grade (p=0.04), with positive hormone receptor status (p=0.01), and in patients without recurrence (p=0.06). These results suggest that the non 19-non 19 carriers have some favorable prognostic factors, and IGF-I gene polymorphism (CA repeats) may affect disease recurrence and overall survival.     

Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in Turkish patients with ischemic stroke

The low plasma nitric oxide concentrations and reduced vascular reactivity are considered major proatherogenic mechanisms in cardiovascular diseases. The present study aimed to assess the allelic frequency and the genotypic distribution of the Glu298Asp gene polymorphism at exon 7 of endothelial nitric oxide synthase (eNOS) gene in Turkish ischemic stroke patients compared to appropriate healthy controls, and to correlate the genetic findings with stroke subtypes. The study population included 146 (75 males, 71 females) patients with ischemic stroke which were categorized according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and 133 (34 males, 99 females) healthy subjects. The eNOS polymorphism was identified with a PCR followed by RFLP with the restriction enzyme BanII. Genotypes were defined as GG, GT, and TT according to the presence of the G and T alleles. In this case-control study, we did not find any significant difference in either the genotypic distribution or allelic frequency of Glu298Asp gene polymorphism between the patients and the controls. In addition, there was also no significant difference for the genotype distribution and the allelic frequency among the stroke subtypes. The results suggested the lack of the association between the Glu298Asp gene polymorphism and ischemic stroke or subtypes of ischemic stroke in the Turkish population.