Angiotensin-converting enzyme insertion/deletion polymorphism and risk of myocardial infarction in an updated meta-analysis based on 34 993 participants

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and risk of myocardial infarction (MI) has been extensively studied. However, the results were in controversy. This study aimed to explore the association between ACE I/D polymorphism and risk of MI by using a meta-analysis. We retrieved the following databases to indentify eligible studies: Medline, Embase, ISI, VIP, CBM and Wan Fang database. The latest update was 10th May, 2012. Odds ratio and 95% confidence interval (95% CI) were used to present the strength of the association. A total of 40 case–control studies with 34 993 participants were included. Overall, D allele of ACE I/D polymorphism was significantly associated with an increased risk of MI in genetic comparison models (OR (95% CI): 1.41 (1.22–1.64) for DD vs. II; 1.11 (1.01–1.21) for ID vs. II; 1.23 (1.10–1.37) for D carriers vs. II; 1.28 (1.15–1.43) for DD vs. I carriers and 1.06 (1.02–1.10) for D carriers vs. I carriers). Subgroup analyses, according to ethnicities and countries of participants also indicated that D allele was significantly associated with an increased risk of MI in Asians (especially for Chinese) and Caucasians (especially for English, French, Germans and Italians) (OR (95% CI) of DD vs. ID + II: 2.11 (1.65–2.70) for Asians and 1.15 (1.05–1.27) for Caucasians). In conclusion, this meta-analysis indicated that D allele of ACE I/D polymorphism was a possible risk factor for MI incidence for both Asians and Caucasians.     

Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes

Genetic variants of IL-18 and IL-12B may be important in immunoregulatory abnormalities, observed in the patients with Type 1 diabetes mellitus (T1DM), that contribute to individual differences in response to a treatment. Therefore, we examined the significance of IL-18-137G/C, IL-18-607C/A, and IL-12B A/C polymorphisms in Croatians (187 patients, 236 controls), not only as factors that contribute to susceptibility to T1DM, but also as determinants of the clinical presentation of disease.     

Polymorphisms of the TLR4 gene and risk of gastric cancer

Objective

Toll-like receptor 4 (TLR4) is an important lipo-polysaccharide (LPS) receptor in gastric epithelial cell signaling transduction and plays critical roles in the development and progression of gastric cancer (GC). We investigated the effects of TLR4 gene polymorphisms and gene–environmental interactions on the risk of GC in Northeastern China.

Methods

We genotyped two single-nucleotide polymorphisms (SNPs) in TLR4 (rs10116253 and rs1927911) in 217 GC patients and 294 cancer-free controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Odds ratio (OR) and 95% confidence intervals (CIs) were estimated by unconditional logistic-regression models.

Results

Individuals carrying CC genotype of rs10116253 and TT genotype of rs1927911 had a significantly decreased risk of GC (adjusted OR = 0.33, 95% CI 0.18–0.60, P < 0.001 and adjusted OR = 0.37, 95% CI 0.21–0.67, P = 0.001 respectively), compared with TT genotype of rs10116253 and CC genotype of rs1927911. In addition, the SNP effects were additive to the effects of some known environmental factors without any interaction between them in the susceptibility to GC.

Conclusion

Our data suggested that TLR4 gene polymorphisms may be associated with a decreased risk of GC in Chinese population. And these SNPs and their combined effects with environmental factors may be associated with the risk of GC.     

Impact of cytokine and cytokine receptor gene polymorphisms on cellular immunity after smallpox vaccination

We explored associations between SNPs in cytokine/cytokine receptor genes and cellular immunity in subjects following primary smallpox vaccination. We also analyzed the genotype–phenotype associations discovered in the Caucasian subjects among a cohort of African-Americans. In Caucasians we found 277 associations (p < 0.05) between gene SNPs and inter-individual variations in IFN-α, IL-12p40, IL-1β, IL-2, and TNF-α secretion levels. A collection of SNPs in the IL1RN, IL2RB, IL4R, IL6, IL10RB, IL12A, and IL12RB2 genes had consistent associations among both Caucasians and African-Americans. A regulatory SNP (rs452204) in the IL1RN gene was significantly associated with higher levels of IL-2 secretion in an allele dose-dependent manner in both race groups (p = 0.05 for Caucasians and p = 0.002 for African-Americans). IL12RB2 polymorphism rs3790567 was associated with a dose-related decrease in IL-1β secretion (p = 0.009 for Caucasians and p = 0.01 for African-Americans). Our results demonstrate that variations in smallpox vaccine-induced cytokine responses are modulated by genetic polymorphisms in cytokine and cytokine receptor genes.     

Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case–control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA + AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR = 1.20, 95%CI: 1.03–1.40, P = 0.021; MI: RR = 1.32, 95%CI: 1.11–1.57, P = 0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR = 0.92, 95%CI: 0.73–1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84–1.03, P = 0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.     

Association between -251A>T polymorphism in the interleukin-8 gene and oral cancer risk: A meta-analysis

Background

Emerging evidence showed that the most common functional polymorphism (-251A>T, rs4073) in the promoter region of the interleukin-8 (IL-8) gene is involved in the regulation of the activities of interleukin-8, thus increasing an individual's susceptibility to oral cancer; but individually published results are inconclusive. The aim of this meta-analysis was to investigate the associations between IL-8 -251A>T polymorphism and oral cancer risk.

Methods

The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to October 1st, 2012 that addressed IL-8 -251A>T polymorphism and oral cancer risk. Statistical analyses were performed using STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

Six case–control studies were included with a total of 1324 oral cancer cases and 1879 healthy controls. When all available studies were pooled into the meta-analysis, the results showed that the AA and AT genotypes of IL-8 -251A>T polymorphism were associated with increased risk of oral cancer (OR = 1.23, 95% CI: 1.03–1.46, P = 0.025; OR = 1.25, 95% CI: 1.07–1.47, P = 0.006; respectively). In the subgroup analysis by ethnicity, significant associations were observed between the AA and AT genotypes of IL-8 -251A>T polymorphism and increased risk of oral cancer among Caucasian populations (OR = 1.40, 95% CI: 1.14–1.72, P = 0.001; OR = 1.29, 95% CI: 1.06–1.57, P = 0.011; respectively). However, no statistically significant associations were found between IL-8 -251A>T polymorphism and oral cancer risk among Asian populations.

Conclusions

Results from the current meta-analysis indicate that the AA and AT genotypes of IL-8 -251A>T polymorphism might increase the risk of oral cancer, especially among Caucasian populations.     

Single nucleotide polymorphism of CD40 in the 5′-untranslated region is associated with ischemic stroke

Objectives

Ischemic stroke is influenced by both environmental and genetic factors. The CD40/CD40L system is related to proinflammatory and prothrombogenic responses, which are involved in the pathophysiology of ischemic stroke. The aim of this study was to evaluate association between the CD40 -1C/T single nucleotide polymorphism (SNP) and ischemic stroke in a Chinese population.

Methods

We conducted a case–control study including 286 ischemic stroke patients and 336 controls. CD40 -1C/T SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods, and evaluated its relevance to ischemic stroke susceptibility.

Results

Significantly increased ischemic stroke risk was found to be associated with the T allele of CD40 -1C/T (OR = 1.273, 95% CI = 1.016–1.594). The frequencies of CT and TT/CT genotypes of CD40 -1C/T in ischemic stroke patients were significantly higher than those of controls, respectively (for CT: OR = 2.350, 95% CI = 1.601–3.449; for TT/CT: OR = 2.148, 95% CI = 1.479–3.119). And, similar results were obtained after adjusting non-matched variables. We found that the frequency of carried T genotypes (TT and TT/CT) was significantly increased in patients with history of stroke compared with patients without (for TT: OR = 6.538, 95%CI = 1.655–25.833; for TT/CT: OR = 3.469, 95%CI = 1.031–11.670), respectively.

Conclusions

The findings suggested that the CD40 -1C/T polymorphism might contribute to the susceptibility to ischemic stroke in the Chinese population, and might be associated with history of previous stroke.     

Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case–control studies

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 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 ration [OR] = 1.07, 95% confidence interval [CI] = 1.00–1.13; recessive model: OR = 1.15, 95% CI = 1.08–1.23; additive model: OR = 1.17, 95% CI = 1.08–1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin 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 XRCC3 polymorphism in cancer development.