Francesco Gianfagna

Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population

BackgroundThe distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.MethodsOne hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis.ResultsGastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27–3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03–5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45–9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22–1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27–5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45–1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52–5.93) and an AP of 52%.ConclusionGSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individuals susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.

Platelet-leukocyte interactions in thrombosis

Activated platelets may adhere to leukocytes and form circulating mixed aggregates. The latter are considered a reliable marker of a prothrombotic state and are associated with several cardiovascular conditions. The molecular mechanisms responsible of this cellular interaction include a central role of platelet P-selectin and of P-selectin glycoprotein ligand-1 (PSGL-1), its counter receptor on leukocytes in a signaling cascade, resulting in the activation of the beta-2 integrin Mac-1 and in the firm adhesion between the two cell types. The interaction of P-selectin with PSGL-1 also induces upregulation of leukocyte tissue factor, biosynthesis of several cytokines and other inflammatory reactions, thereby contributing to the thrombotic progression. In this review the main determinants of mixed aggregate formation, the heritability component, the major pathological conditions associated with higher levels of mixed aggregates in the circulation will be discussed. Besides current anti-platelet or antithrombotic drugs, natural compounds, such as the polyphenols present in vegetable foods and red wine, have been tested for their inhibitory effect on mixed aggregate formation. The promising results shown by studies in vitro and in experimental animal models, remain to be carefully investigated in humans. Platelet-leukocyte aggregates provide a novel link between inflammation and thrombosis, two central processes in atherogenesis. A better understanding of the role of platelet-leukocyte interactions in athero-thrombosis will be instrumental for the progress of prevention and treatment of ischaemic cardiovascular disease.

Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer

Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76-1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37-1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95-1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83-1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92-2.06 for head and neck and OR = 1.28, 95% CI: 0.97-1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63-1.16 for head and neck, and OR = 0.94, 95% CI: 0.79-1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk.

A systematic review evaluating the methodological aspects of meta-analyses of genetic association studies in cancer research

Meta-analyses and Individual Patient Data (IPD) meta-analyses of genetic association studies are a powerful tool to summarize the scientific evidences, however their application present considerable potential and several pitfalls. We reviewed systematically all published meta-analyses and IPD meta-analyses of genetic association studies in the field of cancer research, searching for relevant studies on the Medline, Embase, and HuGE Reviews Archive databases until January 2009. The association between selected predictors of methodological quality and the year of publication was also evaluated. 144 meta-analyses involving 299 gene-disease associations, and 25 IPD meta-analyses on 83 gene-disease were included. Overall quality of the reports showed a substantial improvement over time, as authors have become more inclusive of primary papers published in all languages since 2005 (P-valuexa0=xa00.087), as well as statistical heterogeneity and publication bias were evaluated more systematically. Only 35.4% of the meta-analyses, however, adopted a comprehensive bibliographic search strategy to identify the primary reports, 63.9% did not specify the language of the included studies, 39.8% did not test for Hardy–Weinberg Equilibrium (HWE), while 62.2 and 75.9% of the meta-analyses and IPD meta-analyses, respectively, did not declare the scientific rationale for the genetic model chosen. Additionally, the HWE assessment showed a substantial decreasing trend over time (P-valuexa0=xa00.031) while publication bias was more often evaluated when statistical heterogeneity was actually present (P-valuexa0=xa00.007). Although we showed a general methodological improvement over time, guidelines on conducting and reporting meta-analyses of genetic association studies are needed to enhance their methodological quality.

Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: An updated meta-analysis

BACKGROUNDnSeveral randomized clinical trials evaluated whether preoperative supplementation of omega-3 (n-3) polyunsaturated fatty acids protects against postoperative atrial fibrillation after cardiac surgery, a condition associated with increased cardiac and cerebral mortality. However, their efficacy remains still controversial. An updated meta-analysis was performed to clarify if preoperative n-3 polyunsaturated fatty acid supplementation prevents postoperative atrial fibrillation in patients undergoing cardiac surgery.nnnMETHODSnArticles were retrieved until November 2012 by screening electronic databases (PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials) and cross references. Two of us independently reviewed articles and agreed to select 8 randomized clinical trials. For each study, the incidence of atrial fibrillation in both the intervention and placebo groups was extracted to calculate odd ratio and 95% confidence intervals (CIs). Weighted study-specific estimates were combined using fixed (Mantel-Haenszel method) and random-effects (DerSimonian-Laird method) models.nnnRESULTSnThis meta-analysis includes 2687 patients (1337 in the intervention group) who underwent cardiac surgery. Pooled analysis using fixed-effects models showed a significant reduction (average, 16%; 95% CI, 1%-29%) in postoperative atrial fibrillation by preoperative n-3 polyunsaturated fatty acids. There was a low heterogeneity among studies (Pxa0=xa0.07 and I(2)xa0=xa046%). By using a random-effects model, the reduction averaged 25% (odds ratio, 0.75; 95% CI, 0.57-1.00; Pxa0=xa0.05). When isolated coronary artery bypass graft surgery was only considered (7 studies), a significant protection averaging 34% was observed in a fixed model (odds ratio, 0.66; 95% CI, 0.50-0.87; Pxa0=xa0.003; I(2)xa0=xa026%, Pxa0=xa0.23).nnnCONCLUSIONSnA preoperative supplementation of n-3 polyunsaturated fatty acids significantly prevents the occurrence of postoperative atrial fibrillation in patients undergoing cardiac surgery, in particular coronary artery bypass surgery.

Type 2 diabetes and polymorphisms on chromosome 9p21: A meta-analysis

BACKGROUND AND AIMSnGenome-wide association studies found some variants on chromosome 9p21 associated with type 2 diabetes (T2D). We performed a meta-analysis to estimate strength, accuracy and feature of the association of polymorphisms in 9p21 with T2D.nnnMETHODS AND RESULTSnArticles were retrieved screening electronic databases and cross references. Twenty-two publications were identified, for a total of 38,455 T2D patients and 60,516 controls. Twenty-one studies investigated the role of the SNP rs10811661; in some studies three additional SNPs (rs564398, rs10757278, rs1333040) were genotyped. Population attributable risk (PAR) was computed as: risk allele frequency∗(OR-1)/OR, using the per-allele odds ratio (OR). The risk allele (T) of rs10811661 was associated with T2D in most of the studies. In meta-analysis the overall per-allele OR was 1.24 (95% CI: 1.21-1.27; P < 10(-15)), with no difference according to ethnicity (P = 0.45), and low heterogeneity (P = 0.040) across studies partly explained by sample size. Modeling of inheritance suggested an additive effect of the T allele. PAR of T2D related to this polymorphism was 15% for Caucasians and 13% for Asians. The overall odds ratio for the T allele of the SNP rs564398 was 1.08 (95% CI: 1.05-1.12; PAR = 6%). The other SNPs showed negligible associations.nnnCONCLUSIONSnThis meta-analysis provides accurate and comprehensive estimates of the association of some genetic variants at chromosome 9p21 and T2D. A relatively small but significant role of the T allele of the rs10811661 SNP in increasing by 21-27% the risk of T2D in an additive way was apparent.

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)

Background: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. Methods: In N=79u2009793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1–97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. Results: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12–1.23 in women versus 1.31; 95% CI 1.25–1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81–0.90 versus 0.92; 95% CI, 0.88–0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. Conclusions: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.

Risk for Autism Spectrum Disorders According to Period of Prenatal Antidepressant Exposure: A Systematic Review and Meta-analysis.

Importance Several studies have examined the links between prenatal exposure to antidepressants and autism spectrum disorders (ASDs) in children, with inconsistent results, especially regarding the impact of the trimester of exposure. Objective To perform a systematic review of the literature and a meta-analysis of published studies to assess the association between ASDs and fetal exposure to antidepressants during pregnancy for each trimester of pregnancy and preconception. Data Sources PubMed, EMBASE, and PsycINFO databases up to May 2016 were searched in June 2016 for observational studies. For the meta-analyses, data were analyzed on RevMan version 5.2 using a random-effect model. For the review, studies were included if they had been published and were cohort or case-control studies, and for the meta-analysis, studies were included if they were published studies and the data were not derived from the same cohorts. Study Selection We included all the studies that examined the association between ASDs and antenatal exposure to antidepressants. Data Extraction and Synthesis Three reviewers independently screened titles and abstracts, read full-text articles, and extracted data. The quality of the studies was also assessed. Main Outcomes and Measures Primary outcome was the association between antidepressants during pregnancy and ASDs. Secondary outcomes were the associations between antidepressants in each individual trimester or before pregnancy and ASDs. Results Our literature search identified 10 relevant studies with inconsistent results. For prenatal exposure, the meta-analysis on the 6 case-control studies (117u2009737 patients) evidenced a positive association between antidepressant exposure and ASDs (odds ratio [OR], 1.81; 95% CI, 1.49-2.20). The association was weaker when controlled for past maternal mental illness (OR, 1.52; 95% CI, 1.09-2.12). A similar pattern was found whatever the trimester of exposure considered (first trimester: OR, 2.09, 95% CI,1.66-2.64; second: OR, 2.00, 95% CI, 1.55-2.59; and third: OR, 1.90, 95% CI, 1.20-3.02. Controlled for past maternal mental illness: first trimester: OR, 1.79; 95% CI, 1.27-2.52, second: OR, 1.67, 95% CI, 1.14-2.45; and third: OR, 1.54, 95% CI, 0.82-2.90). No association was found when the 2 cohort studies were pooled (772u2009331 patients) for the whole pregnancy (hazard ratio, 1.26; 95% CI, 0.91-1.74) or for the first trimester. In addition, preconception exposure to antidepressants was significantly associated with an increased risk for ASDs (OR controlled for past maternal illness, 1.77; 95% CI, 1.49-2.09). Conclusions and Relevance There is a significant association between increased ASD risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for ASDs. Future studies should address the problem of this potential confounder.

From candidate gene to genome-wide association studies in cardiovascular disease.

Continuous updating of the genotyping technology has led to improvement of genetic study design. The recent advances in technology coupled with the advances in our understanding of the molecular mechanisms have allowed a more comprehensive examination of the role of genetics, environment and their interaction in determining the individual risk of cardiovascular disease (CVD). Initial candidate gene studies identified a limited number of polymorphisms associated with disease, explaining only a minor part of trait variance. Furthermore, results were not often concordant, with meta-analyses not reaching the statistical power to confirm an association in many cases. The advent of the genome-wide design furnished an enormous quantity of information and decreased time of genotyping, while increased complexity of analyses and costs. Their results were more concordant, even when they suggested associations between CVD and polymorphisms distant from codifying regions or in genes involved in previously unsuspected pathways. Future results from genome-wide studies coupled with results from functional studies and investigation on gene-environment interactions will allow improvement of cardiovascular risk assessment and discovery of new targets for therapy and prevention. In this review, a brief history of cardiovascular genetics is reported, from candidate gene to genome wide association studies, that led to the identification of association between CVD and SNPs in the 9p21 region, firstly thought a gene desert without importance.

A case-control study investigating the role of sulfotransferase 1A1 polymorphism in head and neck cancer.

Purpose: Sulfotransferases (SULT) 1A1 detoxifie and bioactivate a broad spectrum of substrates including xenobiotics. The SULT1A1 gene possesses a G→A polymorphism that results in an Arg to His substitution at codon 213, with the His allele having a low activity. The purpose of this study was to evaluate whether SULT1A1 Arg213His polymorphisms are risk factors for head and neck squamous cell carcinoma (SCCHN). Methods: A total of 124 consecutive primary SCCHN patients and 249 age- and sex-matched hospital controls were enrolled in this study. Genomic DNA was isolated from peripheral blood lymphocytes and genotyping was performed by PCR-RFLP. A comprehensive epidemiological interview was conducted on all participants to collect their lifestyle data. Results: The His/His frequencies in cases and controls were 6.5% (8/123) and 3.6% (9/247), respectively (P=0.049). Multivariate logistic regression analysis showed a significant association of SCCHN and His/His genotype (OR=3.60; 95% CI=1.01–12.88). This association was stronger amongst older people, alcohol and low fruit consumers. The resulted SULT1A1 His/His genotype also associated with a higher risk of neck node positive status (OR=5.82; 95% CI=1.10–30.68). Conclusions: These preliminary findings show for the first time that the SULT1A1 His213 allele is a possible risk factor for head and neck cancer development.