Familial aggregation in lone atrial fibrillation

Atrial fibrillation (AF) is the most common clinical arrhythmia and a major risk factor for stroke. To investigate the role of genetic factors in a typical clinical population, we determined the extent of familial aggregation in patients with lone AF. To estimate the relative risk to family members, the prevalence of AF for each class of relative was compared to the prevalence in the comparable age and sex group from the general population. Family members had an increased relative risk of AF compared to the general population (risk ratio; 95% confidence intervals): sons (8.1; 2.0–32), daughters (9.5; 1.3–67), brothers (70; 47–102), sisters (34; 14–80), mothers (4.0; 2.5–6.5) and fathers (2.0; 1.2–3.6). Relatives of probands with lone AF are at a substantially increased risk of developing this arrhythmia suggesting a Mendelian genetic contribution to the etiology of this common trait.     

Survivin promoter ?31G/C (rs9904341) polymorphism and cancer susceptibility: a meta-analysis

This study aimed to perform a meta-analysis to assess the association of survivin −31 G/C promoter polymorphism and cancer risk. Thirteen case–control studies identified through PubMed and published between 2007 and 2011 with a total of 3329 cancer cases and 3979 controls were included in this meta-analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the pooled analysis showed that survivin −31C allele was associated with 1.27 fold increased risk of cancer compared with the −31G allele (95% CI = 1.091–1.479; random model). Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that survivin −31G/C polymorphism was not associated with risk of gastric cancer [OR = 2.879; 95% CI = 0.553–15.004) for CC vs.GG] and esophageal cancer [OR = 1.352; 95% CI = 0.494–3.699) for CC vs.GG]. Stratification on the basis of ethnicity showed that the risk due to −31C allele was significant only in Asian population [OR = 1.894; 95% CI = 1.206–2.974 for CC vs.GG]. The present meta-analysis suggests an important role of survivin −31 G/C polymorphism with cancer risk especially in Asian population. However, further studies with larger sample size are required to draw more comprehensive conclusions and provide more precise evidence in individual cancers.     

RNASEL −1385G/A polymorphism and cancer risk: a meta-analysis based on 21 case–control studies

Polymorphisms in the endoribonuclease L (RNASEL) gene have been hypothesized to increase the incidence of cancer. The common sequence variation in RNASEL, −1385G/A (rs486907) has been involved in several types of cancer risk. However, results of the related published studies remained conflicting rather than conclusive. To clarify the role of RNASEL −1385G/A genotype in global cancer, we performed a meta-analysis of all the available published studies involving 8,732 cancer patients and 8,748 control subjects. The overall results indicated that there was no major influence of the variant on cancer risk. However, stratified analysis by ethnicity showed that the RNASEL −1385G/A polymorphism has an increased cancer risk in African descendents in the homozygote comparison (OR = 2.59, 95% CI = 1.27–5.27), although no association was found in the analysis stratified by cancer type (OR = 1.12, 95% CI = 0.94–1.35). This meta-analysis suggested that the RNASEL −1385G/A polymorphism is associated with cancer risk in African descendents. To draw more comprehensive conclusions, further prospective studies with larger numbers of participants worldwide are still required to examine associations between RNASEL −1385G/A polymorphism and cancer risk.     

Genetic polymorphisms in transforming growth factor beta-1 (TGFB1) and childhood asthma and atopy

Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4–17 years and their parents in Mexico City. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped five TGFB1 SNPs, including two known functional SNPs [C-509T (rs1800469), T869C (rs1982073)] and three others (rs7258445, rs1800472, rs8179181), using TaqMan and Masscode assays. We analyzed the data using log-linear and polytomous logistic methods. Three associated SNPs, including the two known functional SNPs, were statistically significantly related to asthma risk. Individuals carrying the T allele of C-509T had an increased risk of asthma [relative risk (RR) = 1.42, 95% confidence interval (CI) = 1.08–1.87 for one copy; RR (95%CI) = 1.95 (1.36–2.78) for two copies]. For T869C, the RRs (95%CI) were 1.47 (1.09–1.98) for one and 2.00 (1.38–2.90) for two copies of the C allele. Similar results were found for rs7258445. The haplotype containing all three risk alleles conferred an increased risk of asthma (RR = 1.48, 95% CI = 1.11–1.95 for one copy; RR = 1.77, 95% CI = 1.22–2.57 for two copies). These three SNPs were also related to the degree of atopy. This largest study to date of genetic variation in TGFB1 and asthma and atopy adds to increasing evidence for a role in these disorders.     

Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer

In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene–gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case–control pairs of Indian women and explored possible gene–gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5′-UTR tandem repeat, TYMS 3′-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06–1.81) and MTHFR C677T (OR: 1.74 (1.11–2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55–0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5′-UTR loci (P _trend < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77–12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.     

Interferon gamma +874 T/A polymorphism contributes to cancer susceptibility: a meta-analysis based on 17 case–control studies

Interferon gamma (IFN-γ) plays a pivotal role in antiproliferative, antitumor and antiviral activities. The +874 polymorphism in IFN gene region reportedly affects cancer risk. However, pertinent studies offer conflicting results. To derive a more precise estimation, we performed a meta-analysis based on 1,929 cases and 2,830 controls from 17 published case–control studies, assessing the strength of the association using odds ratios with 95% confidence intervals. Our meta-analysis showed the evidence that IFN-γ +874 T/A was not associated with increased cancer risk in ethnicity and source of controls. However, stratified analysis by cancer type indicated a significantly increased risk of cervical cancer (AT vs. TT: OR = 1.10, 95% CI = 1.02–1.19, P = 0.961 for heterogeneity). Further prospective researches with a larger single study are required to evaluate any association with other types of cancer or in other populations.     

Systemic markers of the redox balance and apolipoprotein E polymorphism in atherosclerosis

Prospective studies have demonstrated that an imbalance between oxidative damage and antioxidative protection can play a role in the development and progression of atherosclerosis. Also, genotypes with the apolipoprotein E ζ4 allele have been associated with an increase risk for this pathology. Based on this knowledge, the aim of this study was to evaluate indicators of the redox balance, trace elements, and apolipoprotein E allelic profile in subjects from the Lisbon population with clinically stable atherosclerosis, at risk for atherosclerotic events, and in healthy subjects for comparison. The activities of superoxide dismutase in erythrocytes and glutathione peroxidase in whole blood, plasma total thiols, and serum ceruloplasmin were kept unchanged among the three groups. Serum α-tocopherol was increased in atherosclerotic patients. Total malondialdehyde in serum and protein carbonyls in plasma, which are indicators of lipid and protein oxidative damage, respectively, reached their highest values in risk subjects. The concentrations of potassium and calcium, in plasma and in blood cells, were slightly elevated in patients and might reflect an electrolytic imbalance. Regarding the apolipoprotein E polymorphism, atherosclerotic patients had an increased incidence of the high-risk genotypes for atherogenesis (ζ3/ζ4 and ζ4/ζ4). A multivariate model applied to the general population using most of the parameters clearly separated the three groups at study (i.e., the healthy group from the steady-state group of risk disease and from the atherosclerotic one). As shown by us, the usefulness of biochemical and complementary genetic markers is warranted for a better knowledge on atherosclerosis molecular basis.     

Association of GSTM1T1 genes with COPD and prostate cancer in north Indian population

The glutathione S-transferase (GST) family of enzymes is known to play a pivotal role in phase II of biotransformation of xenobiotics, environmental carcinogens and pharmacological drugs. The objective of the present study was to investigate the role of GSTM1 and GSTT1 null genotypes as risk factors for chronic obstructive pulmonary disease (COPD) and prostate cancer. The subjects appraised were 200 COPD cases, 150 prostate cancer cases, 150 benign prostatic hyperplasia (BPH) cases, 200 age matched controls for COPD and 172 age matched controls for prostate cancer. GSTM1 and GSTT1 null genotype was found to confer 2.5 (OR 2.45; 95% CI 1.56–3.82; P value = 0.00008) and 2.4-fold (OR 2.39; 95% CI 1.36–4.20; P value = 0.002) significant higher risk for prostate cancer. Smoking imparted a 2.2-fold significant risk of prostate cancer cases (OR 2.23; 95% CI 1.36–3.65 P value = 0.001) and twofold risk in BPH (OR 2.09; 95% CI 1.26–3.46; P value = 0.005). In case of COPD only null genotype of GSTT1 has shown 2.1-fold (OR 2.11; 95% CI 1.22–3.62; P value = 0.007) significant increased risk.     

Genetics of rheumatoid arthritis: what have we learned?

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5–1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70–74 of the DRβ1 chain are associated with the disease. The HLA molecules carrying these “shared epitope” sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA.     

Analysis of cytokine gene polymorphisms in recipient’s matched with living donors on acute rejection after renal transplantation

Despite advances in immunosuppressive therapy in last few years, allograft rejection still remains the concern for kidney graft failure. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. They are not allospecific so both recipient as well as donor cells may be subjected to cytokine changes. We sought to ascertain whether IL-1B −511, IL-1B +3954, TNF-A −308, TGF-B Codon 10 and 25, IL-2 −330, IL-6 −174, IL-10 −1082, IL-10 −819 (SNPs), IL-1RN, IL-4 (VNTR) and TGF-B C-del (deletion) genes in two hundred subjects including recipients and their live matched donors influence renal allograft outcome. Screening was performed using PCR-RFLP and amplification refractory mutation system (ARMS-PCR). The risk for rejection appeared significant amongst recipients for pro-inflammatory cytokines IL-1B + 3954 (P = 0.045) and TNF-A −308 (0.031). No association of cytokine gene variants with rejection was observed in donors group. Further evaluating combinational effect of TNF-A (−308), IL-4 and IL-10 (−819) genes with the risk of allograft rejection showed no additive influence. Haplotype analysis between IL-1 gene cluster, TGF-B Codon 10 and 25 and IL-10 −1082 and −819 revealed that haplotypes of IL-1 gene 240-T–C, 410-T–C and 410-T–T showed very high risk among the recipients (>16, >5 and >12 folds risk respectively) when compared to donors. Interestingly, all these three haplotypes contained the variant allele T* of IL-B −511. In conclusion, our results suggest that high producing genotypes of pro-inflammatory cytokine genes in recipients have risk for allograft rejection. Lack of association in donors may be suggestive of having no conspicuous role in allograft outcome. Further analysis of diversity in haplotype variations in large populations could conceivably provide the basis for defined approaches to limit the rejections.     

Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a highly suspected candidate gene for RA susceptibility. However, association studies on the polymorphism of CTLA-4 exon-1 +49A/G in RA have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported association. In order to look for ethnic effect, we performed subgroup meta-analysis in populations of European descent and Asian descent. Meta-regression analysis was also performed to explore the possible heterogeneity between the two subgroups. Ten studies (11 comparisons) with the CTLA-4 exon-1 +49A/G genotyping on 2,315 patients with RA and 2,536 controls were selected for our meta-analysis. Overall, the fixed-effects odds ratio (OR) for the G versus A allele was 1.11 (P=0.02, 95% confidence interval (CI) 1.02–1.21), with no between-study heterogeneity. Subgroup and meta-regression analysis according to the ethnicity (European or Asian) demonstrated different scenarios concerning the CTLA-4 exon-1 +49A/G polymorphism’s role in RA susceptibility for the two different subgroups. No effect of G on susceptibility was seen in European descent (five comparisons; OR=1.04, P=0.30, 95% CI 0.95–1.19; no significant between-study heterogeneity). However, there is a significant association in Asian descent under both fixed [OR=1.21, 95% CI (1.06–1.39), P=0.005] and random-effect models [OR=1.19, 95% CI (1.01–1.42), P=0.04]. Meta-regression analysis also supports the heterogeneity between the two subgroups (P=0.082). We also explored the role of this polymorphism on RA risk under other various interested genetic contrasts. These results further support that this polymorphism could not be a risk factor for Europeans. Interestingly, we find that in Asians the G allele has a greater tendency to cause RA in a recessive genetic model. However, sensitivity analysis showed that the combined result of Asian populations was unstable. In conclusion, our meta-analysis results suggest that CTLA-4 exon-1 +49G allele would not be a risk factor for RA in Europeans but might play a role in RA susceptibility for Asians.Shizhong Han and Yao Li have contributed equally to this paper.     

Analysis of XPD genetic polymorphisms of esophageal squamous cell carcinoma in a population of Yili Prefecture, in Xinjiang, China

To evaluate the association with genetic polymorphisms in Xeroderma pigmentosum complementation group D (XPD) gene of esophageal squamous cell carcinoma (ESCC) risk in a population of Yili Prefecture, in Xinjiang, China. A hospital-based case–control study was designed with 571 samples including 213 ESCC patients and 358 controls with age, gender and ethnicity-matched subjects (Kazakh, Uygur and Han ethnic). Genotypes were determined by PCR restriction fragment length polymorphism (PCR-RLFP) and confirmed by sequence. Relative risk associated with a particular genotype was estimated by calculating odds ratios (OR) along with 95% confidence intervals (CI). Significant ESCC risk was observed for XPD Lys751Gln (rs13181) frequency of presence C allele (OR: 1.409, 95% CI: 1.005–1.976) in the three ethnics. XPD Asp312Asn (rs1799793) of Han ethnic was associated with a borderline decrease of ESCC (OR: 0.362, 95% CI: 0.145–0.906), however, it was associated with ESCC risk in Uygur ethnic (OR: 2.403, 95% CI: 1.087–5.310). The results demonstrated an association between the XPD Lys751Gln (rs13181) for frequency of presence C allele and risk for ESCC in the three ethnics of Yili Prefecture, in Xinjiang, China. XPD Asp312Asn (rs1799793), which was associated with a borderline decrease of Han ethnic and risk of Uygur ethnic of ESCC, may play a different role in the three ethnics of ESCC.     

C677T Methylentetrahydrofulate Reductase and Angiotensin Converting Enzyme Gene Polymorphisms in Patients with Alzheimer’s Disease in Iranian Population

In recent years numerous data suggest that vascular risk factors may be play a role in Alzheimer’s disease (AD). To determine the association of AD with methylentetrahydrofulate reductase (MTHFR) and angiotensin converting enzyme (ACE) as two main vascular risk factors, we examined MTHFR C677T and ACE insertion/deletion (I/D) gene polymorphism in 117 late-onset AD cases and 125 controls. We found no difference in ACE I/D genotype distribution between AD cases and control (P > 0.05) but there was a significant association between AD and the common MTHFR polymorphism C677T. The T allele conferred an increased risk of AD compared to carrying a C allele (P = 0.001, OR = 1.97, 95% CI: 1.3–2.09). Our result suggests a significant increase in risk of AD in cases with the MTHFR T allele, atleast in the Iranian population.     

Polymorphism in chemokine receptor genes and risk of acute myocardial infarction in North Indian population

Chemokines regulates the trafficking of leukocytes to the site of inflammation hence may be implicated in cardiac events. Currently no consistent effects have been revealed their role in acute myocardial infarction (MI). The aim of current study was to investigate the impact of human chemokine receptor genetic variants, CCR5-Δ32 insertion/deletion, CCR5-59029-A/G, CX3CR1-V249I and CX3CR1-T280 M on acute MI. 230 acute MI and 300 controls were examined. Patients carrying CCR5-Δ32 genotype were at three times higher risk of developing MI odds ratio (OR, 3.24, CI 1.127–9.356, P = 0.04). Significant association was found with risk of acute MI in recipients who possessed homozygous 59029-A allele (OR 1.47, CI 1.03–2.09, P = 0.03). While CX3CR1-I249 and M280 were found to be protective in MI patients with OR 0.46, CI 0.32–0.66, P < 0.0001 and OR 0.36, CI 0.24–0.55, P < 0.0001, respectively. It might be possible that risk of acute MI is associated with genetic variation in chemokine receptors, i.e., CCR5 and CX3CR1.     

Up-regulation of GADD45α expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths

Growth arrest and DNA damage inducible 45 alpha (GADD45α) is a central player in mediating apoptosis induced by a variety of stress stimuli and genotoxic agents. Regular usage of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac is associated with reduced risk for various cancers, including colon cancer. The role of GADD45α in NSAID-induced colon cancer cell cytotoxicity is unknown. In this study, we report that indomethacin and sulindac sulfide treatments up-regulate GADD45α mRNA expression and protein levels in colon cancer HT-29, RKO and Caco-2 cells. This up-regulation of GADD45α is accompanied by necrotic cell death and apoptosis. Anti-sense suppression of GADD45α expression inhibited indomethacin and sulindac sulfide-induced necrotic cell death and apoptosis. These findings confirm a role for GADD45α in NSAID-induced cytotoxicity, a mechanism for the anti-neoplastic effect of NSAIDs in colon tumorigenesis and cancer growth.     

Functional polymorphisms in promoter survivin gene and its association with susceptibility to bladder cancer in North Indian cohort

Survivin is a member of novel inhibitor of apoptosis protein family which expressed in human cancers. The molecular detection of bladder cancer by targeting Survivin as a novel marker may be useful in the occurrence and progression of cancer. We genotyped Survivin −31G>C, −1547A>G and −241C>T by PCR-restriction fragment length polymorphism to evaluate the risk of bladder cancer (BC) in 200 BC patients and 200 healthy controls from North Indian cohort. We observed significant increased BC risk associated with variant CC genotype of Survivin −31G>C having 2.6 fold risk. The variant genotype of Survivin −1547A>G was significantly associated with BC risk (P = 0.047). In case of Survivin −241C>T the protective genotype for BC was heterozygous (P = 0.035). Smoking significantly modulated the risk in patients with Survivin −1547A>G polymorphism. Variant as well as hetero genotype of Survivin −31G>C was associated with reduced risk of recurrence (HR = 0.22 and 0.35) in BC patients receiving BCG treatment thus showing least survival. Furthermore, the haplotype analysis revealed C–A–T haplotype to be associated with reduced BC risk. Our findings suggested that the functional polymorphism −31G>C, −1547A>G and −241C>T in the promoter of Survivin gene may play a significant role in mediating the BC risk among North Indian cohort.     

Definition of plant functional groups for informing implementation scenarios in resource-limited multi-species recovery planning

We describe an approach to multi-species recovery planning and bio-regional biodiversity assessment that uses trait-based plant functional groups as the basis for developing threat/risk assessments for rare, threatened and ‘of concern’ species. Multi-variate methods were used to extract and test emergent groups, and additional information fields related to species life history and distributional data were added to develop a species-level information assessment matrix in spreadsheet format. Relating emergent trait-based plant functional groups to habitat was found to be the most informative approach for the subsequent development of management recommendations and landscape scale threat/risk assessment to inform recovery planning. Examples on the use of the identified groups in a management context are provided. These include higher and lower resource and data availability scenarios, and the role of selected traits in adding to or ameliorating threats and risk of extinction.     

Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFα), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFα and adalimumab, a human anti-TNFα monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFα or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)γ in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFα inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARγ activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFα and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.