Association of glutamate carboxypeptidase II (GCPII) haplotypes with breast and prostate cancer risk

In view of the pivotal role of glutamate carboxypeptidase II (GCPII) in carcinogenesis, its expression as prostate specific membrane antigen (PSMA) and folate hydrolase (FOLH1) may be influenced by its haplotypes, contributing to the etiology of prostate and breast cancer. To test this hypothesis, breast and prostate cancer cases and controls were subjected to whole gene screening of GCPII and correlated with plasma folate levels and PSMA expression. The impact of variants on a 3-dimensional structure of GCPII was explored by in silico studies. Six novel variations i.e. V108A, P160S, Y176H, D191V, G206R and G245S; and two known variations i.e. R190W and H475Y were identified in GCPII. All-wild haplotype and a haplotype harbouring D191V showed association with breast cancer risk while haplotypes harbouring V108A and P160S reduced the risk. Haplotypes with V108A and G245S variants showed increased risk for prostate cancer due to high PSMA expression while P160S conferred protection against prostate cancer. In silico studies suggests that P160S and R190W variants result in relaxed substrate binding facilitating either rapid catalysis or exchange of substrates and products in the active site which was substantiated by high plasma folate levels associated with these variants. On the contrary, D191V was associated with very low plasma folate levels despite having a high PSMA expression. This is the first comprehensive study examining variations in GCPII in relation to breast and prostate cancer risk. Changes in the plasma folate levels and changes in PSMA expression are associated with breast and prostate cancer risk respectively.     

Epigenetic modulation of RFC1, MHC2TA and HLA-DR in systemic lupus erythematosus: Association with serological markers and six functional polymorphisms of one-carbon metabolic pathway

The current study was conducted to elucidate the effect of genetic variations in one-carbon metabolism on the epigenetic regulation of major histocompatibility complex II transactivator (MHC2TA), reduced folate carrier 1 (RFC1/SLC19A1) and human leukocyte antigen (HLA)-DR in systemic lupus erythematosus (SLE). PCR-RFLP/AFLP, bisulfite-sequencing and real-time PCR approaches were used for genetic, epigenetic and expression analysis respectively. SLE cases exhibited elevated plasma homocysteine levels compared to healthy controls (24.93 ± 1.3 vs. 11.67 ± 0.48 μmol/l), while plasma folate levels showed no association (7.10 ± 2.49 vs. 7.64 ± 2.09 ng/ml). The RFC1 80G>A polymorphism showed 1.32-fold risk (95% CI: 1.02–1.72) for SLE, while glutamate carboxypeptidase II (GCPII) 1561C>T showed reduced risk (OR: 0.47, 95% CI: 0.24–0.90). The expression of RFC1 (0.37 ± 0.09 vs. 0.60 ± 0.17) and HLA-DR (0.68 ± 0.17 vs. 0.98 ± 0.02) was down regulated in the SLE cases. The hypermethylation of RFC1 as observed in the current study may contribute for its down regulation. Plasma folate and thymidylate synthase (TYMS) 5′-UTR 28 bp tandem repeat showed an inverse association with methylation of RFC1 and MHC2TA. SLE cases with hypocomplementemia showed hypermethylation of RFC1, hypomethylation/up regulation of MHC2TA and down regulation of HLA-DR. The hypermethylation of MHC2TA and down regulation of RFC1, MHC2TA and HLA-DR were observed in anti-cardiolipin antibody positive SLE cases. The up regulation of RFC1 and HLA-DR was observed in anti-dsDNA antibody positive SLE cases. The hypomethylation/upregulation of RFC1 and MHC2TA was observed in anti-RNP antibody positive cases. To conclude, one-carbon genetic variants influence epigenetic of MHC2TA and RFC1, thus contributing to phenotypic heterogeneity of SLE.     

Acetylation regulates the stability of glutamate carboxypeptidase II protein in human astrocytes

Glutamate carboxypeptidase II (GCPII) is known to be implicated in brain diseases such as schizophrenia and bipolar disorder, and dramatically increases in prostate cancer. Here, we investigated the regulation of GCPII expression in astrocytes and examined whether GCPII is epigenetically regulated through histone modification. In this study, valproic acid (VPA), a drug used for bipolar disorder and epilepsy and a known histone deacetylase (HDAC) inhibitor was used. We found that acute exposure of VPA for 4–6 h increased the GCPII protein level in human astrocyte U87MG cells but did not have a similar effect after 12–24 h exposure. Real-time polymerase chain reaction analysis revealed that VPA did not affect the GCPII mRNA expression. In contrast, decrease in GCPII protein level by cycloheximide treatment was blocked by VPA, indicating that VPA increases GCPII protein stability. Treatment with MG132, a proteasome inhibitor, suggested that the VPA-induced increase of GCPII protein level is dependent on the ubiquitin/proteasome pathway. In addition, immunoprecipitation analysis revealed that VPA increased the acetylation of GCPII protein at the lysine residues and facilitated a decrease of the poly-ubiquitinated GCPII level. Similarly, M344, a specific HDAC 1/6 inhibitor, also increased the GCPII protein level. In contrast, treatment with C646, a histone acetyltransferase inhibitor of p300/CBP, significantly reduced the level of GCPII protein. Taken together, this study demonstrated that the increase in GCPII induced by VPA is not due to the classical epigenetic mechanism, but via enhanced acetylation of lysine residues in GCPII.     

Role of CYP1A2*1F polymorphism in cancer risk: Evidence from a meta-analysis of 46 case–control studies

Background

Emerging evidence showed that the common polymorphism (CYP1A2*1F, rs762551 C → A) in the promoter region of the CYP1A2 gene might be associated with susceptibility to cancer in humans. But individually published results were inconclusive. The aim of this meta-analysis is to investigate the association between CYP1A2*1F polymorphism and cancer risk.

Methods

The Pubmed, Embase, Web of Science and Chinese BioMedical databases were searched for all articles published up to September 1st, 2012. Statistical analyses were performed using the STATA 12.0 software.

Results

Forty-six case–control studies were included with a total of 22,993 cancer cases and 28,420 healthy controls. Meta-analysis results showed that the A allele of CYP1A2*1F polymorphism was associated with a decreased cancer risk (odds ratio [OR] = 0.92, 95% confidence interval [CI]: 0.87–0.98, P = 0.013). In the subgroup analysis by cancer types, the A allele of CYP1A2*1F polymorphism may increase the risk of breast cancer (OR = 1.05, 95% CI: 1.01–1.10, P = 0.024), and is also associated with a decreased risk of ovarian cancer (OR = 0.70, 95% CI: 0.54–0.89, P = 0.004). However, similar results were not found in lung, colorectal, bladder, endometrial, pancreatic and gastric cancers. Further subgroup analysis by ethnicity also showed a significant association between the A allele of CYP1A2*1F polymorphism and a decreased cancer risk among Caucasian populations (OR = 0.91, 95% CI: 0.84–0.98, P = 0.014); but no significant associations were observed among Asian populations.

Conclusions

Results from the current meta-analysis indicate that the A allele of CYP1A2*1F polymorphism may be associated with breast and ovarian cancer risk, especially among Caucasian populations.     

Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in cancer: A meta-analysis

Toll-like receptor 4 (TLR4) is critical in the recognition of Gram-negative bacteria serving as a key immune system effector. Recently, a number of case-control studies were conducted to investigate the association between TLR4 gene polymorphism and cancer risk, especially Asp299Gly and Thr399Ile polymorphisms. However, published data were still conflicting. In this paper, we summarized 9463 cancer cases and 10,825 controls from 22 studies and attempted to assess the susceptibility of TLR4 gene polymorphism to cancers by a synthetical meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the relationship. Our results suggested that Asp299Gly represented a risk factor on cancers in digestive system (G allele versus A allele, OR = 1.64, 95% CI: 1.02–2.64; GA + GG versus AA, OR = 1.64, 95% CI: 1.00–2.71) but tend to have a protective effect on prostate cancer (GG versus AA, OR = 0.37, 95% CI: 0.14–0.98; GG versus GA + AA, OR = 0.37, 95% CI: 0.14–0.98). Thr399Ile polymorphism was significantly associated with an elevated cancer risk in overall analysis (T allele versus C allele, OR = 1.72, 95% CI: 1.27–2.33; TC versus CC, OR = 1.63, 95% CI: 1.18–2.26; TT + TC versus CC, OR = 1.70, 95% CI: 1.24–2.34) and especially in gastrointestinal subgroup (T allele versus C allele, OR = 2.01, 95% CI: 1.40–2.89; TC versus CC, OR = 1.86, 95% CI: 1.26–2.74; TT + TC versus CC, OR = 1.97, 95% CI: 1.35–2.88). Further prospective researches with larger numbers of worldwide participants are warranted to draw comprehensive and true conclusions.     

Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease

Progranulin is the precursor of granulins, and its down-regulation leads to neurodegeneration. Recent studies have indicated an association of progranulin polymorphism rs5848 with Alzheimer's disease (AD) risk, but the results remain controversial. To verify the association between rs5848 and AD risk, we retrieved the published literature from PubMed and other databases, and performed a meta-analysis by pooling all five studies containing 2502 AD cases and 2162 controls. The results showed that rs5848 is associated with increased risk of AD in homozygous (TT vs. CC: OR, 1.36; 95% CI, 1.11–1.66; P = 0.003) and recessive models (TT vs. CC + CT: OR, 1.31; 95% CI, 1.08–1.58; P = 0.006). This association was remained in Caucasian (2227 cases and 1902 controls). Our data indicate that TT allele of rs5848 is associated with increased risk of AD, suggesting that genetic variant of progranulin gene may play an important role in AD development.     

The XRCC1 Arg280His polymorphism contributes to cancer susceptibility: an update by meta-analysis of 53 individual studies

The X-ray repair cross-complementing group 1 (XRCC1) protein plays a central role in DNA repair pathways. Epidemiological studies have revealed the association between XRCC1 Arg280His polymorphism and cancer risk, but the results were inconsistent. We conducted this meta-analysis to assess the effect of XRCC1 Arg280His polymorphism on cancer susceptibility with accumulated data. Up to January 2012, 53 case‐control studies with 21,349 cases and 23,649 controls were available for our study. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for XRCC1 Arg280His polymorphism and cancer were estimated using fixed‐ or random-effects models when appropriate. Our meta-analysis identified that elevated cancer risk was statistically associated with the minor variant His allele and Arg–His/His–His genotypes both in the overall population (allele comparison, His versus Arg: OR = 1.16; 95% CI: 1.08–1.25; dominant comparison, Arg–His/His–His versus Arg–Arg: OR = 1.17; 95% CI: 1.08–1.27) and in terms of subgroup analyses by ethnicity for both Caucasians and non‐Caucasians. However, no significant result was observed in the stratified analysis by cancer type. Moreover, significantly increased cancer risk was observed in smokers. These findings indicated that XRCC1 Arg280His polymorphism may play a role in cancer development.     

The relationship between five widely-evaluated variants in CDKN2A/B and CDKAL1 genes and the risk of type 2 diabetes: A meta-analysis

The genes encoding two cyclin-dependent kinases-inhibitor-2A/B (CDKN2A/B) and 5 regulatory subunit-associated protein-like 1 (CDKAL1) have been investigated extensively in associations with type 2 diabetes; the results, however, are often irreproducible. We therefore sought to evaluate these associations by performing a meta-analysis on five widely-evaluated variants from the two genes. There were 38 studies (patients/controls: 51,940/52,234) for rs10811661, 16 studies (20,029/24,419) for rs564398 in CDKN2A/B gene, and 27 studies (28,383/47,635) for rs7756992, 26 studies (28,816/31,713) for rs7754840, 21 studies (29,260/38,400) for rs10946398 in CDKAL1 gene. Overall risk estimates for type 2 diabetes conferred by rs10811661-T, rs564398-A, rs7754840-C, rs7756992-G, and rs10946398-C alleles were 1.17 (95% CI: 1.10–1.23; P < 0.0005; I² = 83.9%), 1.1 (95% CI: 1.0–1.21; P = 0.051; I² = 88.3%), 1.24 (95% CI: 1.18–1.3; P < 0.0005; I² = 74.3%), 1.2 (95% CI: 1.11–1.3; P < 0.0005; I² = 92.0%), and 1.19 (95% CI: 1.1–1.29; P < 0.0005; I² = 90.8%), respectively. There was evident publication bias for rs564398 and rs7754840. Subgroup analyses by ethnicity showed remarkable divergences in risk estimate for rs564398 between Asians (odds ratio [OR] = 1.01; 95% CI: 0.86–1.19; P = 0.868) and Caucasians (OR = 1.19; 95% CI: 1.03–1.35; P = 0.012) (P < 0.05). For all variants examined, the results of studies in retrospective design or with population-based controls were comparative with that of overall studies. In meta-regression analyses, age was found to exert a significant influence on the association between rs10811661 and type 2 diabetes (P = 0.003), as well as between rs7754840 and gender (P = 0.034). Taken together, our findings provide evidence for a significant contribution of CDKN2A/B gene rs10811661 and CDKAL1 gene rs7756992 and rs10946398 to type 2 diabetes.     

Oxidative Stress is Associated with Genetic Polymorphisms in One-Carbon Metabolism in Coronary Artery Disease

In view of growing body of evidence favouring the association of aberrations in one-carbon metabolism and oxidative stress in the aetiology of coronary artery disease (CAD), we investigated the risk associated with polymorphisms regulating the folate uptake and transport such as the glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier 1 (RFC1) G80A and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T. We further evaluated the impact of seven putatively functional polymorphisms of this pathway on oxidative stress markers. Genotyping was performed on 288 CAD cases and 266 healthy controls along with the dietary folate assessment. GCPII C1561T polymorphism was found to be an independent risk factor (OR 2.71, 95% CI 1.47–4.98) for CAD, whereas cSHMT C1420T conferred protection (OR 0.51, 95% CI 0.37–0.70). Oxidative stress markers like the plasma levels of malondialdehyde, protein carbonyls and 8-oxo-deoxyguanosine were significantly increased and total glutathione was significantly decreased in CAD cases. Elevated oxidative stress was observed in subjects carrying GCPII 1561T and MTRR 66A-variant alleles and low oxidative stress was observed in the subjects carrying cSHMT 1420T and TYMS 5′-UTR 2R allele. GCPII C1561T, MTHFR C677T and MTRR A66G polymorphisms were observed to influence the homocysteine levels (P < 0.05). SHMT and TYMS variants were found to decrease oxidative stress by increasing the folate pool (r = 0.38, P = 0.003) and also by increasing the antioxidant status (r = 0.28, P = 0.03). Influence of dietary folate status was not observed. Overall, this study revealed elevated oxidative stress that was associated with the aberrations in one-carbon metabolism which could possibly influence the CAD risk.     

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism and ischemic stroke in Chinese population: A meta-analysis

Previous studies have indicated that the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism is associated with risk of ischemic stroke (IS), but the results remain inconclusive even in Chinese population. A meta-analysis of 10 case-control studies was conducted on the relationship between ALOX5AP SG13S114 polymorphism and susceptibility to IS in Chinese population published domestically and abroad from September 2007 to December 2012. Data were extracted by two authors and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Meta-analysis results showed that the significant association between SG13S114 variant and IS was found under the allelic (OR = 0.87, 95% CI: 0.80–0.96, P = 0.004), dominant (OR = 0.75, 95% CI: 0.62–0.92, P = 0.005), and recessive (OR = 0.89, 95% CI: 0.82–0.97, P = 0.005) genetic models in Chinese population. In subgroup meta-analysis, SG13S114 variant and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the allelic (OR = 0.86, 95% CI: 0.80–0.92, P < 0.0001), dominant (OR = 0.72, 95% CI: 0.57–0.91, P = 0.006), and recessive (OR = 0.86, 95% CI: 0.78–0.95, P = 0.002) models. ALOX5AP SG13S114 polymorphism is associated with susceptibility to IS in Chinese population.     

Poly (AT) deletion/insertion polymorphism of the XPC gene contributes to urinary system cancer susceptibility: A meta-analysis

Numerous studies have investigated the association between xeroderma pigmentosum complementation group C (XPC) poly (AT) deletion/insertion (PAT −/+) polymorphism and cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 32 publications including 10,214 cases and 11,302 controls to acquire a more robust estimation of the relationship. We searched publications from MEDLINE, EMBASE and CBM which assessed the associations between XPC PAT −/+ polymorphism and cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We found that individuals carrying the PAT +/+ genotype have significantly increased cancer risk (PAT +/+ vs. PAT −/−: OR = 1.18, 95% CI = 1.03–1.35 and recessive model: OR = 1.19, 95% CI = 1.06–1.33). Further stratification analysis showed a significantly increased risk for prostate cancer (PAT +/+ vs. PAT −/−: OR = 2.20, 95% CI = 1.39–3.48, recessive model: OR = 2.07, 95% CI = 1.33–3.23 and PAT + vs. PAT −: OR = 1.39, 95% CI = 1.12–1.71), bladder cancer (recessive model: OR = 1.33, 95% CI = 1.03–1.72), Caucasian ethnicity (recessive model: OR = 1.21, 95% CI = 1.02–1.43), population-based studies (recessive model: OR = 1.23, 95% CI = 1.05–1.43) and studies with relatively large sample size (PAT +/+ vs. PAT −/−: OR = 1.18, 95% CI = 1.04–1.35 and recessive model: OR = 1.20, 95% CI = 1.08–1.33). Despite some limitations, this meta-analysis established solid statistical evidence for the association between the XPC PAT +/+ genotype and cancer risk, especially for urinary system cancer, but this association warrants further validation in single large studies.     

Relationship between CCR2-V64I polymorphism and cancer risk: A meta-analysis

Background and objectives

The role of CCR2-V64I polymorphism in various cancers has been reported in many studies. However, results from published studies on the association between CCR2-V64I polymorphism and cancer risk are conflicting. Therefore, we performed a meta-analysis to estimate the overall cancer risk associated with the polymorphism.

Methods

Electronic searches of PubMed and EMBASE were conducted for all publications on the association between this variant and cancer. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to access the strength of this association.

Results

Sixteen studies with 2661 cancer patients and 5801 healthy controls were included. Overall, significant association was found between the CCR2-V64I polymorphism and cancer risk (OR = 1.84, 95% CI = 1.35–2.51, AA vs GA/GG, P = 0.37). In the subgroup analysis stratified by cancer types, there was a significant association between this polymorphism and bladder cancer (OR = 2.06, 95% CI = 1.02–4.15, AA vs GA/GG, P = 0.11), cervical cancer (OR = 3.34, 95% CI = 1.48–7.50, AA vs GG, P = 0.56), and oral cancer (OR = 2.04, 95% CI = 1.46–2.84, GA vs GG, P = 0.70). In the subgroup analysis stratified by ethnicities, an increased cancer risk was also found in Europeans (OR = 2.31, 95% CI = 1.45–3.68, AA vs GA/GG, P = 0.16) and Asians (OR = 1.88, 95% CI = 1.12–3.16, AA vs GA/GG, P = 0.92).

Conclusion

This meta-analysis suggested that CCR2-V64I polymorphism may contribute to an increased risk of cancer.     

Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: A community-based case–control study

Objectives

There are no data regarding the possible role of the single nucleotide polymorphism (SNP) of class I histone deacetylases (HDACs) in type 2 diabetes mellitus (DM). We designed this study to examine whether polymorphisms of HDACs can be implicated in that disease.

Methods

A community-based, case–control study was conducted, with a total of 568 subjects (284 patients and 284 controls) enrolled. Four polymorphisms of HDAC1 (rs1741981) and HDAC3 (rs11741808, rs2547547, rs2530223) were examined by the use of TaqMan technology.

Results

We found a significant association with risk of type 2 DM for three SNPs of HDAC3, including rs11741808 [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.35–0.81], rs2547547 [OR = 1.72, 95% CI: 1.13–2.64], and rs2530223 [OR = 1.39; 95% CI: 1.01–1.91]. Subgroup analysis showed that BMI ≥ 23 kg/m², high triglyceride and high blood pressure, together with the rs11741808AG genotype, were associated with a significantly decreased risk for type 2 DM, with ORs of 0.50 (95% CI: 0.27–0.91), 0.38 (95% CI: 0.20–0.71) and 0.43 (95% CI: 0.24–0.76) compared with the AA genotype, respectively. In a population with normal total cholesterol, the AG genotype yielded a significantly decreased risk of type 2 DM risk, with an OR of 0.42 (95% CI: 0.25–0.70) when compared with the persons of the AA genotype. For rs2547547, in a population with normal total cholesterol and triglyceride, the AG genotype was associated with a significantly increased risk of type 2 DM, with ORs of 1.92 (95% CI: 1.17–3.15) and 2.24 (95% CI: 1.28–3.94) when compared with the population carrying the AA genotype.

Conclusions

The results suggest that variants of HDAC3 contribute to an increased prevalence of type 2 DM in the Chinese Han population.     

Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population

Previous investigations indicated that histamine receptor H4 (HRH4) played important roles in many aspects of breast cancer pathogenesis, and that the polymorphisms of HRH4 gene may result in expression and functional changes of HRH4 proteins. However, the relationship between polymorphisms of HRH4 and breast cancer risk and malignant degree is unclear. In the present study, we conducted a case–control investigation among 185 Chinese Han breast cancer patients and 199 ethnicity-matched health controls. Four tag-SNPs (i.e. rs623590, rs16940762, rs11662595 and rs1421125) of HRH4 were genotyped and association analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. We found that the T allele of rs623590 had a decreased risk of breast cancer (adjusted OR, 0.667; 95% CI, 0.486–0.913; P = 0.012) while the A allele of rs1421125 had an increased risk (adjusted OR, 1.653; 95% CI, 1.139–2.397; P = 0.008). Further haplotype analysis showed that the CAA haplotype of rs623590–rs11662595–rs1421125 was more frequent among patients with breast cancer (adjusted OR, 1.856; 95% CI, 1.236–2.787; P = 0.003). Additionally, polymorphisms of rs623590 and rs11662595 were also correlated with clinical stages, lymph node involvement, and HER2 status. These findings indicated that the variants of rs623590, rs11662595 and rs1421125 genotypes of HRH4 gene were significantly associated with the risk and malignant degree of breast cancer in Chinese Han populations, which may provide us novel insight into the pathogenesis of breast cancer although further studies with larger participants worldwide are still needed for conclusion validation.     

The Hsa-miR-27a rs895819 (A > G) polymorphism and cancer susceptibility

Published data on the association between the rs895819 (A > G) polymorphism in the terminal loop of pre-miR-27a and cancer risk is inconclusive. Therefore, we conducted a meta-analysis to estimate the association between this polymorphism and cancer. The PubMed, Web of science, and Embase databases were searched for articles on the hsa-miR-27a rs895819 polymorphism and cancer risk published up to November 24, 2012. The genotype data obtained in the searches were pooled in our meta-analysis, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. Seven studies with a total of 3849 cases and 4781 controls were eligible for analysis. Overall, we found no significant associations between the hsa-miR-27a rs895819 (A > G) polymorphism and cancer susceptibility (homozygote model: OR = 0.88, 95% CI: 0.68–1.14; heterozygote model: OR = 0.96, 95% CI: 0.79–1.17; dominant model: OR = 0.94, 95% CI: 0.79–1.12; recessive model: OR = 0.88, 95% CI: 0.69–1.12). In the subgroup analysis by ethnicity, we found that the rs895819 AG genotype was associated with a decreased risk of cancer in white individuals (dominant model: OR = 0.85, 95% CI: 0.76–0.94; heterozygote model: OR = 0.84, 95% CI: 0.75–0.94). This meta-analysis indicated that the hsa-miR-27a rs895819 polymorphism did not correlate with overall cancer risk in the general population. However, the rs895819 AG genotype may protect against the development of cancer in white individuals. Larger, better studies of homogeneous cancer patients are needed to further assess the correlation between this polymorphism and cancer risk.     

The association of IL1α and IL1β polymorphisms with susceptibility to systemic lupus erythematosus: A meta-analysis

Many epidemiological studies have investigated IL1α and IL1β polymorphisms with SLE risk, but no conclusions are available because of conflicting results. This meta-analysis was performed to more precisely estimate the relationships. The databases of PubMed updated to September 1st, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as effect size were calculated by a fixed- or random-effect model. In total, six case–control studies for IL1β − 511C/T, four studies for IL1β + 3953C/T, three studies for IL1α − 889C/T and three studies for IL1α + 4845G/T were involved in this analysis. The results indicated that for IL1α − 889C/T polymorphism T allele was associated with decreased risk of SLE (OR (95% CI)) (T vs. C: 0.802 (0.679–0.949); TT + CT vs. CC: 0.615 (0.380–0.995); TT vs. CC: 0.679 (0.466–0.989)). However, when analysis for TT vs. CT + CC was conducted, the result indicated that IL1α − 889C/T polymorphism was not associated with SLE (OR (95% CI): 0.847 (0.595–1.205)). Combined analysis indicated that IL1β − 511C/T polymorphism was not overall associated with risk of SLE (OR (95% CI)) (T vs. C: 1.113 (0.954–1.298); TT vs. CT + CC: 1.146 (0.889–1.447); TT + CT vs. CC: 1.145 (0.903–1.452); TT vs. CC: 1.255 (0.928–1.698)). When subgroup analysis for Asian ethnicity was conducted, the results indicated that IL1β − 511C/T polymorphism was associated with SLE only for TT vs. CT + CC (OR (95% CI): 1.468 (1.001–2.152)), but was not associated for T vs. C (OR (95% CI): 1.214 (0.955–1.544)), TT + CT vs. CC (OR (95% CI): 1.112 (0.765–1.615)) and TT vs.CC (OR (95% CI): 1.411 (0.896–2.222)). In addition, overall analyses indicated that IL1β + 3953C/T and IL1α + 4845G/C polymorphisms were also not associated with risk of SLE (OR (95% CI)) (for IL1β + 3953C/T T vs. C: 0.996 (0.610–1.626), TT vs. CT + CC: 0.658 (0.318–1.358), TT + CT vs. CC: 1.021 (0.618–1.687), TT vs. CC: 0.640 (0.309–1.325); for IL1α + 4845G/T T vs. G: 1.067 (0.791–1.440), TT + GT vs. GG: 0.934 (0.646–1.351)).This study inferred that IL1α − 889C/T polymorphism might be moderately associated with SLE, but no sufficient evidence was available to support any associations between IL1β + 3953C/T or IL1α + 4845G/C polymorphisms and SLE. We could not draw a definite conclusion between IL1β − 511C/T polymorphism and risk of SLE owing to the limited data. Further large sample-sized studies should be required.     

Meta-analysis of genetic association of chromosome 9p21 with early-onset coronary artery disease

Purpose

A number of studies reported on associations of single nucleotide polymorphisms (SNPs) present in chromosome 9p21 with early-onset coronary artery disease (CAD). The present study was then undertaken to perform a meta-analysis of all the results published to date.

Methods

All studies of the 9p21 association with early-onset CAD that were published between 2007 and 2012 were retrieved from the PubMed database. RevMan 5.0 software was used to perform meta-analysis of the data that fulfilled the criteria for our meta-analysis. The effect size of four SNPs in the 9p21 region on early-onset CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI).

Results

A total of 7123 subjects from 7 case–control studies were genotyped. Meta-analysis demonstrated disease association for rs2383207 (OR = 0.79, 95% CI 0.71–0.88, P < 0.0001), rs2383206 (OR = 1.17, 95% CI 1.10–1.25, P < 0.00001), rs10757278 (OR = 1.28, 95% CI 1.15–1.42, P < 0.00001), and rs10757274 (OR = 1.17, 95% CI 1.08–1.33, P = 0.02).

Conclusion

Genetic variation in the chromosome 9p21 region may contribute to the etiology of early-onset CAD although their effect size is rather small.     

Association between the CYP1A1 T3801C polymorphism and risk of cancer: Evidence from 268 case–control studies

T3801C is a common polymorphism in CYP1A1, showing differences in its biological functions. Case–control studies have been performed to elucidate the role of T3801C in cancer, although the results are conflicting and heterogeneous. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and T3801C (55,963 cases and 76,631 controls from 268 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.09–1.19; recessive model: OR = 1.23, 95% CI = 1.12–1.34; CC vs. TT: OR = 1.31, 95% CI = 1.19–1.45; TC vs. TT: OR = 1.12, 95% CI = 1.07–1.18; additive model: OR = 1.14, 95% CI = 1.09–1.19) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of cervical cancer, head and neck cancer, hepatocellular cancer, leukemia, lung cancer, prostate cancer and breast cancer. In addition, significantly decreased colorectal cancer risk was also observed. In summary, this meta-analysis suggests that the participation of CYP1A1 T3801C is a genetic susceptibility for some cancer types. Moreover, our work also points out the importance of new studies for T3801C association in some cancer types, such as gallbladder cancer, Asians of acute myeloid leukemia, and thyroid cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the CYP1A1 T3801C polymorphism in cancer development.