Asn Allele Research Articles

C-natriuretic peptide – as an indicator of persistent increase in blood pressure in men with hypertension

Annotation. According to multiple studies hypertension (AH) is a multifactorial disease. It is recognized that one of the key mechanisms of persistent increase in blood pressure (BP) is the imbalance between vasoconstriction and vasodilation and endothelial dysfunction (ED) is one of the leading links in the pathogenesis of AH. The consequence of ED is a persistent vasoconstrictor reaction which results in myocardial remodeling in the form of left ventricular hypertrophy (LVH) and the subsequent development of congestive heart failure (CHF). One of the most important representatives of the group of vasoconstrictor peptides is endothelin-1 (ET-1). It has been previously shown that the polymorphism of the gene encoding it (Lys198Asn) is associated with fluctuations in ET-1 plasma concentration. In this regard, the corresponding changes in plasma levels of one of the most powerful vasodilators – C-natriuretic peptide (CNP) – remain poorly understood. CNP is a direct antagonist of ET-1 which increases in the blood in AH and can be used as a screening method to identify patients with high BP. The aim of the study – improving the detection of men with AH who has persistent long-term elevations in BP by using the plasma level of CNP and taking into account the carrier of polymorphic variants of the ET-1 gene. The study involved 191 men aged 40-60 years: 79 men were from control group, 62 patients with AH and LVH and 50 patients with AH complicated by CHF II-III classes for NYHA. Enzyme-linked immunosorbent assay was used to determine the plasma concentration of CNP. Genotyping of the ET-1 gene was performed using the polymerase chain reaction. Mathematical processing was performed on a personal computer using the standard statistical package STATISTICA 6.0. It is established that plasma CNP levels in men with AH and LVH (5.21±0.11) pmol/ml and in patients with AH and CHF (5.22±0.13) pmol/ml are significantly higher than in control patients (2.35±0.06) pmol/ml (p<0.0001) however did not differ in patients with AH from different groups. The obtained results allowed to calculate the limit level of CNP which is ≥3.37 pmol/ml and can be used for screening detection of males with persistently elevated BP in the survey of large populations. It was found that in patients with AH as in the control group the Lys/Lys genotype and the Lys allele of the ET-1 gene predominate. There was no significant difference in the frequency of ET-1 gene between groups (p>0.05). It should be noted that in patients with AH carrying all polymorphic variants of the ET-1 gene the level of CNP in blood was also significantly higher than in the control group, however in carriers of the Asn allele plasma level of CNP is higher than in individuals with the Lys/Lys genotype in all study groups. So it was investigated that the average plasma concentration of CNP in patients with AH is higher than in the control group which made it possible to establish a limit level of peptide for screening of individuals with persistent long-term elevation of BP. In men of the control group and in patients with AH the carrier of the Asn allele of the ET-1 gene is associated with a higher level of CNP but in all study groups the Lys/Lys genotype and the Lys allele of the ET-1 gene were dominant.

Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non–Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery

ObjectiveThe aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non–small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery. Materials and MethodsA total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (−37 C/A) polymorphisms with response and survival. ResultsThe median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03). ConclusionThe XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients.

Ratio of Endothelin-1 and C-Type Natriuretic Peptide Concentrations in Men with Hypertensive Disease of Different Severity. The Regulatory Role of Polymorphism of the Endothelin-1 Gene

Despite overall effort hypertensive disease (HD) is one of the most significant health and social problem. Essential hypertension is believed to be a multifactorial disease and polymorphism of genes that may be responsible for the regulation of blood pressure plays the key role in it. The least explored in this regard is single nucleotide polymorphism of ET-1 leading to the replacement of the amino acids of lysine (Lys) to asparagine (Asn) at position of 198th polypeptide chain (Lys198Asn).The objective of the research was to improve diagnosis of HD severity determining plasma concentration of ET-1, C-type natriuretic peptides (CNP) and the coefficient of CNP/ET-1 in patients with different genotypes of ET-1 gene.Materials and methods. The study involved 79 men without cardiovascular diseases (control group), 62 men with II stage HD and 50 men with HD complicated by chronic heart failure (CHF) II-III classes according to NYHA Classification. All patients were representative by age. Genotyping of ET-1 gene was conducted using polymerase chain reaction. ET-1 concentration in plasma was determined using ELISA method.Results. Lys/Lys genotype of ET-1 gene was found to occur in 65.82% of men in the control group, carriers of Asn allele (Lys/Asn and Asn/Asn genotypes) constituted 34.18%, Lys allele was observed in 79.75% of cases, Asn allele was detected in 20.25% of men. Among patients with II stage HD Lys/Lys genotype of ET-1 gene was observed in 56.45% of cases, the carriers of Asn allele (Lys/Asn and Asn/Asn genotypes) occurred in 43.55% of patients, Lys allele was found in 73.39% of cases, Asn allele was observed in 26.61% of patients. Among men with HD and CHF IIA genotype Lys/Lys was found in 66.00% of cases, carriers of Asn allele (Lys/Asn and Asn/Asn genotypes) was observed in 34.00% of patients, Lys allele was detected in 80.00% of cases, Asn allele was observed in 20.00% of cases. The men from the control group, patients with II stage HD and patients with HD and CHF as the carriers of Asn allele were found to have significantly higher plasma levels of ET-1 (2.53±0.12 fmol/ml, 13.90±0.22 fmol/ml and 14.07±0.18 fmol/ml, respectively) and CNP (2.98±0.08 pmol/ml, 5.90±0.11 pmol/ml and 5.93±0.18 pmol/ml, respectively) in comparison with homozygous carriers of Lys genotype (ET-1constituted 1.41±0.05 fmol/ml, 11.58±0.23 fmol/ml and 0.08±12.89 fmol/ml, respectively, CNP constituted 2.02±0.29 pmol/ml, 4.68±0.12 pmol/ml and 4.88±0.09 pmol/ml, respectively). According to the analysis of the obtained data, coefficient of CNP/ET-1 (0.40±0.003 c.u. and 0.38±0.006 c.u., respectively) and Asn allele (0.42±0.004 c.u. and 0.42±0.007 c.u., respectively) was significantly lower in patients with II stage HD and patients with HD and CHF as the carriers of Lys/Lys genotype in comparison with the control group (1.4±0.04 c.u. and 1.22±0.05 c.u., respectively). Carriers of Asn allele in the control group had significantly lower coefficient of CNP/ET-1 than genotype Lys/Lys carriers. However, the difference in the coefficient of CNP/ET-1 was not observed in patients with HD.Conclusions. Lys/Lys genotype and Lys allele of ET-1 gene were found to dominate among control group and patients with HD of different severity. Plasma concentration of ET-1, CNP were significantly higher and coefficient of CNP/ET-1 was lower in men with II stage HD and HD complicated by CHF than in men without cardiovascular diseases in case of all ET-1 gene genotypes. The carriers of Asn allele of ET-1 gene had significantly higher plasma levels of ET-1 and CNP in each study group.

Hereditary features of plasma concentrations of endothelin-1 in men with hypertension and chronic heart failure

Objective. To improve diagnosis of the severity of essential hypertension in men by determining the plasma levels of ET-1 in patients with different ET-1 gene variants.Materials and methods. We examined 191 men aged 40–60 years old, who live in Podillia region in Ukraine. Among them 79 men from control group, 62 men with uncomplicated essential hypertension (EH) with left ventricular hypertrophy (LVH) and 50 men with EH and chronic heart failure (CHF) II-III functional classes by NYHA. We used clinical, biochemical, instrumental and mathematical methods of investigation, polymerase chain reaction and enzyme immunoassay.Results. In both healthy men and patients with EH Lys/Lys genotype and the Lys allele of the ET-1 gene dominates. It was found that any inherited variant of the ET-1 gene was not associated with the risk of developing EH and CHF on its background. In patients with EH the peptide level was significantly higher than in the control group and the highest concentration of ET-1 was in patients with EH and CHF. In men from the control group, patients with uncomplicated EH with LVH and EH with CHF – carriers of genotype Lys/Lys – plasma concentration of ET-1 was significantly lower than in owners of the Asn allele. In carriers of Lys/Lys genotype the highest level of the peptide in plasma is determined in patients with EH complicated by CHF. In owners of the Asn allele concentration of ET-1 in men with EH was significantly higher than in control subjects, but the difference between patients with EH was not found. In men with uncomplicated EH with LVH, who are carriers of Lys/Lys genotype the 2d degree of arterial hypertension (AH) is significantly more common, and in carriers of the Asn allele the 3d degree of AH. In patients with EH and CHF carriage of the Asn allele is associated with 3d degree of AH.Conclusions. Lys/Lys genotype and the Lys allele of the ET-1 gene dominate among control group and patients with EH. The carriers of the Asn allele of the ET-1 gene have significantly higher plasma levels of the aforementioned peptide among the control group and in the patients with EH. The Asn allele is associated with 3d degree of AH. The ET-1 boundary levels were estimated, that can be used for screening of large contingents of people for early diagnosis of EH and CHF.

Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients

PurposeSeveral small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methodsThe analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. ResultsFor all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. ConclusionThis study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.

Effects of a High Protein/Low Carbohydrate Versus a Standard Hypocaloric Diet on Weight and Cardiovascular Risk Factors, Role of a Lys656asn Polymorphism of Leptin Receptor Gene

Background: The SNP of the leptin receptor (Lys656Asn) has been related with metabolic parameters. The aim of our design was to evaluate the influence of Lys656Asn variant of Leptin receptor gene on weight loss and metabolic parameters secondary to a high protein/low carbohydrate vs. a standard hypocaloric diets. Design: A total of 280 obese subjects were randomly allocated to one of two diets during 9 months (Diet HP (high protein-low carbohydrate hypocaloric diet) and Diet S (standard protein hypocaloric diet)). Results: After both diets and in both genotypes, body mass index (BMI), fat mass, weight, systolic blood pressure and waist circumference decreased, without differences between both diets. With the diet type HP and in both genotypes, triglycerides decreased. In subjects with Lys656Lys genotype, glucose, insulin levels, HOMA-R, total cholesterol and LDL- total cholesterol decreased after HP diet. No statistical changes were detected in Asn allele carriers. After diet S and in patients with Lys656Lys genotypes, only total cholesterol, triglycerides and LDL- total cholesterol decreased, without changes in Asn allele carriers. Conclusion: Obese subjects with Asn656 allele have a different metabolic response than Lys656Lys genotype subjects, secondary to the same weight loss with two different hypocaloric diets.

DNA repair genes XPD and XRCC1 polymorphisms and risk of end-stage renal disease in Egyptian population

DNA repair gene polymorphisms may affect DNA repair capacity and modulate susceptibility to end-stage renal disease (ESRD). We aimed to determine the association of polymorphisms in xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1) with ESRD development. Polymorphisms in XPD codons 312 and 751 and XRCC1 codon 399 were genotyped in 98 patients undergoing hemodialysis and 102 healthy controls using polymerase chain reaction and restriction fragment length polymorphism. Patients having XRCC1-399 Arg/Gln genotype or XRCC1-399 Gln/Gln genotype had a significantly higher risk of ESRD than those with XRCC1-399 Arg/Arg [odds ratio (OR): 2.48; 95% confidence intervals (CI): 1.36–4.52; p = 0.004 and OR: 4.05; 95% CI: 1.19–13.73; p = 0.03, respectively]. We also found a significantly higher frequency of the XRCC1 399Gln allele in patients with ESRD than in controls (OR: 2.22; 95% CI: 1.16–4.25; p = 0.02). Combination of the Arg/Gln or Gln/Gln genotypes of XRCC1 Arg399Gln polymorphism with Asp/Asn or Asn/Asn genotypes of XPDAsp312Asn or with the Lys/Gln or Gln/Gln genotypes of XPD Lys751Gln was significantly associated with the development of ESRD. Haplotypes association showed that association of Gln allele of XRCC1 Arg399Gln polymorphism with the Asn allele of XPDAsp312Asn polymorphism (p = 0.004) or Gln allele of XRCC1 Arg399Gln polymorphism with the Gln allele of XPD Lys751Gln polymorphism (p = 0.003) was highly significantly associated with the development of ESRD. This study revealed that XRCC1 Arg399Gln polymorphism may confer increased risk for the development of ESRD. Furthermore, larger studies should be conducted to confirm these results.

The polymorphism of DNA repair genes XPD, XRCC1, OGG1, and ERCC6, life expectancy, and the inclination to smoke

The polymorphism of excision repair genes XPD Asp312Asn, XRCC1 Arg399Gln, OGG1 Ser326Cys, and ERCC6 Met1097Val was analyzed by PCR-RFLP in 370 representatives of the Belarusian population of average, old, and elderly ages. Correlation analysis showed that the frequencies of wild-type homozygous combinations significantly increase with age in the group of subjects over 70 years old in the case of the interaction of two genes, XPD 312 and XRCC1399, or three genes, XPD312, XRCC1399, and ERCC6 1097. In a subgroup of the long-lived, this relationship is manifested in case of a pairwise interaction of gene XPD 312 with XRCC1 399 or ERCC6 1097, as well as an interaction of three genes, XPD 312, XRCC1 399, and ERCC6 1097. The data suggest that the optimum activity of repair processes may favor longevity. It is shown that the frequency of the Asp/Asp genotype is reduced, and the frequency of the Asn allele of the XPD 312 gene is increased in the subgroup of smokers as compared with nonsmokers, which apparently indicates an association of this gene polymorphism with an inclination to smoke. The problem requires further study.

Complex association between ERCC2 gene polymorphisms, gender, smoking and the susceptibility to bladder cancer: a meta-analysis

Genetic polymorphisms in DNA repair genes may be involved in increasing the risk of bladder cancer. Association studies on the excision repair cross-complementation group 2 (ERCC2) gene polymorphisms and bladder cancer risk have reported conflicting results. The aim of this meta-analysis of eligible cancer case-control studies is to investigate the role of ERCC2 SNPs (Arg156Arg, Asp312Asn, and Lys751Gln), gender and smoking in determining susceptibility to bladder cancer. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar databases to indentify eligible studies published before December 1, 2013. We performed a meta-analysis of 23 case-control studies with a total of 7,062 bladder cancer patients and 8,832 controls. The overall analysis suggested that ERCC2 Arg156Arg, Asp312Asn, and Lys751Gln are associated with increased bladder cancer risk. For ERCC2 Arg156Arg, the mutant allele was associated with a 1.36-fold (95 % CI=1.15-1.61) increased risk of bladder cancer. For ERCC2 Asp312Asn, individuals with the Asn allele were associated with a 1.29-fold (95 % CI=1.13-1.48) increased risk of bladder cancer. For ERCC2 Lys751Gln, individuals who carried the variant heterozygote Lys/Gln or homozygote Gln/Gln had a significantly increased bladder cancer risk, compared with the wild genotype Lys/Lys (OR=1.10, 95 % CI=1.03-1.18). Furthermore, gender and smoking may modify the association between these SNPs and bladder cancer risk. This study provides the strongest evidence to date for the role of common variants of the ERCC2 gene in bladder carcinogenesis. Further studies comprehensively characterizing other DNA repair pathways and accounting for exposure to relevant environmental factors should offer further insight into the role of DNA repair in bladder cancer.

Pharmacogenetics of DNA repair gene polymorphisms in non-small-cell lung carcinoma patients on platinum-based chemotherapy

Individual differences in chemosensitivity and clinical outcome of non-small-cell lung carcinoma (NSCLC) patients can be influenced by host-inherited factors. We investigated the impact of XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, XPD Arg156Arg, XPD Asp312Asn, XPD Asp711Asp, and XPD Lys751Gln gene polymorphisms on treatment efficacy in 375 NSCLC patients on platinum-based chemotherapy. We also examined progression-free survival and overall survival. The gene polymorphisms were analyzed by duplex PCR. The patients with XRCC1 399A/A had a significantly better response to chemotherapy. Individuals with XPD 711 Asp and XPD 312 Asn alleles responded poorly to chemotherapy when compared with the wide-type genotype. The adjusted hazard ratio (HR) in the Cox regression model was calculated. The XRCC1 399A/A polymorphism was associated with better progression free survival and overall survival of NSCLC patients (HR=0.61 and 0.55). On the other hand, the XPD 711 Asp allele was associated with poorer progression free survival and overall survival compared to the C/C genotype, with HRs of 1.89 and 1.90. The XPD 312 Asn allele was found to be associated with non-significantly reduced survival of NSCLC patients (HR = 1.73). In conclusion, we found the polymorphisms of XRCC1 and XPD to be related to the efficacy of platinum-based chemotherapy in NSCLC patients. This information should aid in therapeutic decisions for individualized therapy in NSCLC cases.

POLYMORPHISM OF EXCISION REPAIR GENES XPD, XRCC1, hOGG1 IN THE POPULATION OF THE REPUBLIC OF BELARUS AND ITS IMPACT ON CARCINOGENESIS

Background. DNA damage and induced mutational events are known to contribute notably to carcinogenesis, so the study of excision repair gene polymorphisms and their association with cancer risk is of great interest and importance. Materials and Methods. Excision repair gene polymorphisms (XRCC1 Arg399Gln, hOGG1 Ser326Cys, XPD Asp312Asn) were analyzed using a PCR-RFLP method in the group of bladder cancer (BC) patients compared to clinically healthy individuals. Results. In the healthy population, the frequencies of the minor alleles of XPD 312, XRCC1 399, hOGG1 326 genes were 42,1 %, 35,4 % and 24,4 %, respectively, i. e., in the range of values observed in Caucasian populations. The frequencies of genotypes/alleles in the group of BC patients did not differ from those in the control group. However, the frequency of Asn allele of XPD gene was significantly higher in men with BC recurrences as compared to primary tumors. The cancer risk was decreased in carriers of combined Asp/Asp, Arg/Arg, Ser/Ser genotypes of XPD, XRCC1 and hOGG1 genes (OR95 %CI = 0,46 [0,23 - 0,91] p = 0,024 and OR95 %CI = 0,42 [0,18 - 0,98] p = 0,045 for combination of two and three genes, respectively). Conclusion. In Belarus, the frequencies of the XPD, XRCC1 and hOGG1 minor alleles are similar to those in Caucasian populations. Although single nucleotide polymorphisms investigated did not affect the risk of bladder cancer, the risk of cancer recurrence was increased in carriers of the XPD Asn allele. Combined homozygous wild type alleles of indicated excision repair genes appeared to possess a protective effect against carcinogenesis.

Predictive Value of XPD Polymorphisms on Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

BackgroundThe correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms.MethodsDatabases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed.ResultsA total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele (Asn vs. Asp: OR = 0.435, 95% CI: 0.261–0.726). Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian (AspAsn vs. AspAsp: HR = 0.781, 95% CI: 0.619–0.986) but unfavorable survival in Asian (AspAsn+AsnAsn vs. AspAsp: HR = 1.550, 95% CI: 1.038–2.315).ConclusionsThese results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted.

Lys656Asn Polymorphism of Leptin Receptor Gene Is Related With Leptin Changes After a High Monounsaturated Fat Diet in Obese Patients

BackgroundHuman obesity is characterized by high levels of leptin, and it has been suggested that obese patients may be leptin resistant. The aim of our study was to investigate the...

Genetic polymorphisms of xeroderma pigmentosum group D and prostate cancer risk: A meta-analysis

The Xeroderma pigmentosum group D (XPD, also referred to as excision repair cross complementing gene 2, ERCC2) is one of key genes involved in nucleotide excision repair and two potentially functional polymorphisms of XPD (Asp312Asn and Lys751Gln) have been widely investigated in various cancers including prostate cancer. However, the results were conflicting rather than conclusive. Thus, we conducted a meta-analysis to evaluate the associations between these two polymorphisms of XPD and the risk of prostate cancer. An electronic search of PubMed and Embase was conducted to select relevant studies. Studies containing available genotype frequencies of XPD Asp312Asn and Lys751Gln were chosen, and the associations were assessed by pooled odds ratios with 95% confidence intervals. According to PubMed and Embase databases, we identified seven eligible studies from six articles, including 2641 cases and 3259 controls for Asp312Asn and nine eligible studies from eight articles, including 3255 cases and 3654 controls for Lys751Gln. The meta-analysis showed that no overall association was observed between XPD Asp312Asn and prostate cancer risk. However, the significantly increased risk of 312Asp allele was found among Asians and Africans, but it seemed to be protective in Caucasians when stratified by ethnicity. For XPD Lys751Gln, overall findings had implicated null effects. These findings indicated that the Asn allele of XPD Asp312Asn might be a risk-factor for developing prostate cancer among Asian and African men but protective for Caucasian population.

Association of ERCC2/XPD polymorphisms and interaction with tobacco smoking in lung cancer susceptibility: a systemic review and meta-analysis

The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR=1.20[1.05-1.36], P=0.006; recessive model: OR=1.20[1.06-1.35], P=0.004) and 751Gln allele(homozygous model: OR=1.31[1.17-1.46], P<0.00001; heterozygous model: OR=1.11[1.04-1.19], P=0.003; recessive model: OR=1.23[1.11-1.37], P<0.0001; dominant model: OR=1.15[1.08-1.23], P<0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR=1.46[1.09-1.95] and 1.57[1.19-2.08], P=0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions.

Lack of association between XPD Lys751Gln and Asp312Asn polymorphisms and colorectal cancer risk: a meta-analysis of case–control studies

The published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln and Asp312Asn polymorphisms and colorectal cancer remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A comprehensive literature search was conducted to identify all case-control studies of Lys751Gln and Asp312Asn polymorphisms on the susceptibility of different tumor site of colorectal cancer (colon, rectum, and colon/rectum cancer). A total of 22 eligible studies were selected for this meta-analysis, including 3,042 cases and 4,627 controls for Lys751Gln and 1,581 cases and 2,846 controls for Asp312Asn. Overall, no significantly elevated colorectal cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (for Lys751Gln polymorphism: Lys/Gln vs. Lys/Lys, OR = 1.01, 95% CI = 0.90-1.14; Gln/Gln vs. Lys/Lys, OR = 1.04, 95% CI = 0.85-1.26; dominant model, OR = 1.03, 95% CI = 0.93-1.15; recessive model, OR = 1.04, 95% CI = 0.87-1.25; and for Asp312Asn polymorphism: Asp/Asn vs. Asp/Asp, OR = 1.11, 95% CI = 0.91-1.35; Asn/Asn vs. Asp/Asp, OR = 1.13, 95% CI = 0.87-1.47; dominant model, OR = 1.09, 95% CI = 0.94-1.26; recessive model, OR = 1.11, 95% CI = 0.88-1.41). And for the additive model, individuals carrying the 751Gln or 312Asn allele were not significantly associated with increased risk to colorectal cancer (OR = 1.02, 95% CI = 0.94-1.11, OR = 1.07, 95% CI = 0.95-1.20). This meta-analysis suggests that XPD Lys751Gln and Asp312Asn polymorphisms may not be associated with colorectal cancer development.

The association between XPD Asp312Asn polymorphism and lung cancer risk: a meta-analysis including 16,949 subjects

To derive a more precise estimation of the relationship between the xeroderma pigmentosum group D (XPD) Asp312Asn polymorphism and lung cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the XPD Asp312Asn polymorphism and lung cancer risk. The pooled ORs were performed with co-dominant model (Asp/Asn vs. Asp/Asp, Asn/Asn vs. Asp/Asp), dominant model (Asp/Asn + Asn/Asn vs. Asp/Asp), and recessive model (Asn/Asn vs. Asp/Asp+Asp/Asn), respectively. A total of 18 studies including 7,552 cases and 9,397 controls were involved in this meta-analysis. Overall, significantly elevated lung cancer risk was associated with XPD Asn allele when all studies were pooled into the meta-analysis (Asn/Asn vs. Asp/Asp: OR=1.158, 95% CI=1.018-1.317; recessive model: OR=1.161, 95% CI=1.029-1.311). In the subgroup analysis by ethnicity, significantly increased risks were found for both Caucasians (Asn/Asn vs. Asp/Asp: OR=1.164, 95% CI=1.003-1.351; recessive model: OR=1.169, 95% CI=1.016-1.345) and Asians (Asn/Asn vs. Asp/Asp: OR=8.056, 95% CI=2.420-26.817; recessive model: OR=7.956, 95% CI=2.391-26.477). When stratified by study design, statistically significantly elevated risk was noted in hospital-based studies (Asn/Asn vs. Asp/Asp: OR=1.315, 95% CI=1.110-1.558; recessive model: OR=1.290, 95% CI=1.099-1.513). In conclusion, this meta-analysis suggests that the XPD Asn allele is a low-penetrant risk factor for developing lung cancer.

Genetic influences on the dynamics of pain and affect in fibromyalgia.

The purpose of the present investigation was to determine if variation in the catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes is associated with pain-related positive affective regulation in fibromyalgia (FM). Forty-six female patients with FM completed an electronic diary that included daily assessments of positive affect and pain. Between- and within-person analyses were conducted with multilevel modeling. Daily positive affect was the primary outcome measure. Analyses revealed a significant gene x experience interaction for COMT, such that individuals with met/met genotype experienced a greater decline in positive affect on days when pain was elevated than did either val/met or val/val individuals. This finding supports a role for catecholamines in positive affective reactivity to FM pain. A gene x experience interaction for OPRM1 also emerged, indicating that individuals with at least one asp allele maintained greater positive affect despite elevations in daily pain than those homozygous for the asn allele. This finding may be explained by the asp allele's role in reward processing. Together, the findings offer researchers ample reason to further investigate the contribution of the catecholamine and opioid systems, and their associated genomic variants, to the still poorly understood experience of FM.

The association between ERCC2 Asp312Asn polymorphism and breast cancer risk: a meta-analysis involving 22,766 subjects

To date, many publications discussed the correlation between ERCC2 Asp312Asn polymorphism and breast cancer risk. However, the results were not unanimous. In order to derive a more precise conclusion, a meta-analysis was performed in this study by searching Medline, PubMed, and ISI Web of Knowledge databases. Finally, 17 studies including 12,019 cases and 10,747 controls were collected for this meta-analysis. The strength of association between ERCC2 Asp312Asn polymorphism and breast cancer risk was assessed by calculating crude ORs with 95% CIs. Overall, no significant associations between ERCC2 Asp312Asn polymorphism and breast cancer susceptibility were found. In the stratified analysis by ethnicity, significant associations were observed for Asn/Asn versus Asp/Asp (OR = 0.55; 95% CI 0.32-0.96) and Asn/Asn versus Asn/Asp + Asp/Asp (OR = 0.53; 95% CI 0.32-0.90) in Asians. In the stratified analysis by study design, significant associations were found for Asn/Asn versus Asp/Asp (OR = 0.79; 95% CI 0.64-0.98) and Asn/Asn versus Asn/Asp + Asp/Asp (OR = 0.82; 95% CI 0.68-0.99) in population-based studies. In conclusion, this meta-analysis provides an evidence that ERCC2 312Asn allele may have a protective effect for breast cancer development in Asians.

Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density

Background Polymorphisms of the sex hormone-binding globulin (SHBG) gene are associated with differences in SHBG levels, influencing the risk for breast cancer and polycystic ovarian syndrome, but no association has been reported for osteoporosis in postmenopausal women. Objective To determine the effect of G to A substitution in the 5′UTR (rs1799941) and the Asp356Asn (rs6259) polymorphisms of the SHBG gene on bone mineral density (BMD). Methods This is a cross-sectional study in a university-based research center from May, 2002 to December, 2007. A total of two hundred and thirteen healthy postmenopausal Caucasian women ≥ 1 year from last menstrual period participated to this study. Serum estradiol by ultrasensitive radioimmnunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and urinary NTx by enzyme-linked immunoassay were measured. BMD measurements were performed by dual energy X-ray absorptiometry and genotyping by Pyrosequencing. Results There were no significant differences in SHBG levels associated with either rs1799941 or rs6259. Using a p value of < 0.00625 for significance, we found that subjects with the A allele (GA+AA) for the rs1799941, had a trend for lower free estradiol index (FEI) compared to the GG genotype ( p = 0.04). They also had significantly lower BMD at the intertrochanter ( p = 0.003) and trend for lower BMD at the total hip ( p = 0.02). There was no significant difference in FEI levels between the genotypes for the rs6259 polymorphism, but women with the Asn allele (Asp/Asn+Asn/Asn), had significantly lower BMD in the total femur ( p = 0.004) and intertrochanter (0.002) compared to those with the Asp/Asp genotype. Conclusions Our data suggest that polymorphisms of the SHBG gene are associated with significant differences in BMD at the proximal femur sites. Thus, genetic variations in the SHBG gene may influence BMD at the hip in postmenopausal women.