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Objective: To investigate the association between common transforming growth factor beta (TGF-β) single nucleotide polymorphisms (SNP) and significant complications of coronary heart disease (CHD). Method: We performed a meta-analysis of published case-control studies assessing the association of TGF-β SNPs with a range of CHD complications. A random effects model was used to calculate odds ratios and confidence intervals. Analyses were conducted for additive, dominant and recessive modes of inheritance. Results: Six studies involving 5535 cases and 2970 controls examining the association of common SNPs in TGF-β1 with CHD were identified. Applying a dominant model of inheritance, three TGF-β1 SNPs were significantly associated with CHD complications: The T alleles of rs1800469 (OR = 1.125, 95% CI 1.016-1.247, p = 0.031) and rs1800470 (OR = 1.146, 95% CI 1.026-1.279, p = 0.021); and the C allele of rs1800471 (OR = 1.207, 95% CI 1.037-1.406, p = 0.021). Conclusion: This meta-analysis suggests that common genetic polymorphisms in TGF-β1 are associated with complications of CHD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The role of transforming growth factor (TGF)-beta in abdominal aortic aneurysm (AAA) is controversial. The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) within TGFBR1 and TGFBR2 with AAA and infrarenal aortic diameter by combining data from previously published studies. Methods: We performed a meta-analysis using individual subject data from three independent case-control groups from Western Australia (n =1675), New Zealand (n =1209), and the Netherlands (n =1636) with 610, 601, and 693 cases of AAA (maximum infrarenal aortic diameter ≥30mm), respectively. Data were available for two TGFBR1 (rs10819634, rs1571590) and six TGFBR2 (rs304839, rs1346907, rs1036095, rs9831477, rs9843143, rs764522) SNPs. Results: There was marked heterogeneity between studies. The G alleles of the TGFBR2 rs764522 and rs1036095 SNPs were associated with AAA under a recessive model (OR=1.69, 95% CI 1.28–2.25, P <0.001 and OR=1.59, 95% CI 1.23–2.07, P <0.001) when a fixed effects model was used. Both associations remained significant after adjustment for multiple testing. Conclusion: This study suggests that two common genetic polymorphisms in TGFBR2 are associated with the risk of developing AAA although this association was mainly driven by findings in the Netherlands group and marked between study heterogeneity was detected. [Copyright &y& Elsevier]

Abstract: Objective: Abdominal aortic aneurysm (AAA) is a late onset degenerative condition with an inherited component thought to be due to multiple risk alleles. A locus on chromosomes 19q13 has been previously associated with AAA. The gene encoding kallikrein 1 (KLK1) is located on chromosome 19q13 and the single nucleotide polymorphism (SNP) rs5516 has been previously shown to lead to structural changes in the KLK1 transcription regulatory region. The aim of this study was to investigate whether rs5516 was associated with AAA and aortic diameter. Methods: We performed a case–control study on two independent subject groups from Western Australia (n =1304) and Queensland (n =325) of which 609 and 225 had an AAA, respectively. In addition, we analysed RNA extracted from abdominal aortic biopsies from 12 patients undergoing AAA surgery and 6 organ donors. Results: After adjusting for other risk factors the G allele of the rs5516 polymorphism was associated with large but not small AAA using a dominant model in the Western Australian men and a recessive model in Queensland subjects. In subjects with large AAA the G allele was associated with aortic diameter. The short splice variant of KLK1 was upregulated within AAA compared to control biopsies. Conclusion: This study suggests that a genetic polymorphism in KLK1 may contribute to the risk of developing later stage AAA. [Copyright &y& Elsevier]

Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5α reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C>T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P=0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Abdominal aortic aneurysm (AAA) has been recognized as a multi-factorial disease with both genetic and environmental risk factors. A locus residing within non-coding DNA on chromosome 9p21.3 has recently been associated with AAA. To further investigate the significance of this site for AAA, we performed an association study on a large group of 3371 men aged 65–83 years of whom 513 had an AAA. Methods: All men were assessed for other risk factors in a uniform way and an ultrasound of the abdominal aorta was performed. Results: Our findings validated the strong association of the chromosome 9p21.3 SNPs rs10757278 and rs1333049 with AAA and demonstrated the upregulation of LINE-1 elements at the site of AAA. Conclusion: This study confirms a reproducible association between risk alleles on chromosome 9p21.3 and AAA. We also provide preliminary evidence for an association of LINE-1 elements with AAA which will require further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Apolipoprotein E (ApoE) genotype has been associated with systemic inflammation and athero-thrombosis however the association with abdominal aortic aneurysm (AAA) has not been previously examined. We assessed the association between ApoE genotype with AAA presence and growth, and serum C-reactive protein (CRP). Methods: Serum concentrations of CRP (in 1358 men) and 6 single nucleotide polymorphisms (SNPs) for ApoE (in 1711 men) were examined in subjects from the Health In Men Study. 640 men with small AAAs were followed by ultrasound surveillance for a mean of 4.1 years. Results: There was no association between ApoE genotype and AAA presence. Men heterozygote for the ApoE p.Arg176Cys polymorphism had slower AAA growth, odds ratio for AAA progression≥median 0.41, 95% confidence intervals 0.21–0.80, p =0.01. Men heterozygote for the ApoE g.50093756A>G polymorphism had slightly more rapid AAA growth, odds ratio for AAA progression≥median 1.48, 95% confidence intervals 1.02–2.14, p =0.04. None of the ApoE SNPs were associated with AAA growth however taking into account multiple testing. Two SNPs in ApoE were associated with serum CRP under a co-dominant model, ApoE p.Cys130Arg (SNP ID rs429358), p =0.00003 and ApoE g.50114786A>G (SNP ID rs4420638), p =0.00013. Adjusting for other risk factors plus serum creatinine the ɛ4 allele was associated with lower serum CRP under a dominant model, coefficient 0.089, p =0.002. Conclusion: We found no consistent association between ApoE genotype and AAA. We confirmed an association between ApoE genotype and serum CRP. [Copyright &y& Elsevier]

Objective We have previously demonstrated high concentrations of the glycoprotein osteoprotegerin (OPG) in biopsies of abdominal aortic aneurysm (AAA), and demonstrated that ligation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) downregulates OPG in vitro and within a mouse model. The aims of this study were to assess the associations between circulating concentrations of OPG, polymorphisms of the gene encoding PPARγ (PPARG), AAA presence and growth. Design, patients and measurements Two genetic polymorphisms in PPARG were assessed in 4227 men, 699 of whom had an AAA. For 631 men, who had AAAs, maximum aortic diameter was monitored by yearly ultrasound for a median of 5 years. Plasma OPG was measured in 838 men, 318 of whom had an AAA. Results Plasma concentrations of OPG were independently associated with AAA (adjusted odds ratio 1.38, 95% CI 1.10–1.72). The PPARG c.1347C > T polymorphism was associated with plasma concentrations of OPG (beta 0.12, P < 0.01). The PPARG c.34G > C polymorphism was weakly associated with AAA (adjusted odds ratio 1.28, 95% CI 1.01–1.61). PPARG c.1347C > T was associated with increased AAA growth (recessive model, P = 0.03). Conclusions Circulating concentrations of osteoprotegerin are associated with abdominal aortic aneurysm and with one peroxisome proliferator-activated receptor gamma gene polymorphism. Peroxisome proliferator-activated receptor gamma gene polymorphisms are weakly associated with abdominal aortic aneurysm presence and growth. Confirmation of these findings is required in other cohorts. [ABSTRACT FROM AUTHOR]

BackgroundOsteoprotegerin (OPG) has been associated with cardiovascular events but currently the mechanisms underlying this association are unknown. OPG is thought to play a role in controlling artery calcification and small studies have suggested that it may influence artery structure. We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men.Methods21 tagging SNPs in the region encoded by TNFRSF11B were examined in 1,071 men recruited in a population-based study of elderly men. Genotyping was carried out using the Illumina Golden Gate assay. SNPs were investigated for their association with resting systolic and diastolic blood pressure after adjusting for other variables using linear regression. The association of SNPs in the region encoded by TNFRSF11B with plasma OPG was assessed in a random subset of 467 men.ResultsOne SNP, rs11573901, was significantly associated with diastolic blood pressure, after adjusting for other risk factors and multiple testing (coefficient −4.36, P = 0.001). Men with the TC genotype had lower diastolic blood pressure than those with the common CC variation. This SNP was not associated with plasma OPG in the 467 men in which this was examined.ConclusionsThis study suggests that a SNP within the region encoded by TNFRSF11B, which is believed to code for OPG, is associated with blood pressure. The mechanism underlying this observed association is currently unclear.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.177 [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Abdominal Aortic Aneurysm (AAA) has a strong genetic predisposition. Transforming growth factor beta 1 (TGF-β1) is a causal factor in ascending aortic dilatation; however, a role in AAA pathology is unclear. The aim of the study was to determine whether genes coding TGF-β and its binding protein are associated with the presence and expansion of AAA. Methods: Four geographically distinct case control studies, totaling 1890 AAA cases and 3785 controls, were genotyped and compared to the presence, size and growth rate of AAA. 26 single nucleotide polymorphisms (SNPs) in 5 genes were genotyped in the UK cohort and the result was replicated in 3 independent cohorts. Results: No associations between genotypes or haplotypes and the presence of AAA disease were confirmed. Five SNPs in Latent TGF-β Binding Protein (LTBP4) and an allelic variant of TGFB3 were associated with a significant decrease in AAA growth (p ≤0.02), in the UK cohort. Altered growth was demonstrated in carriers of two common haplotypes of LTBP4 (+0.38mm/year, p =0.003; −0.41mm/year, p =0.02, per haplotype copy) and a single haplotype of TGFB3 (−0.53mm/year, p =0.05). This association with AAA growth could not be demonstrated in two other independent cohorts. Meta-analysis of AAA size and growth rates in larger AAA (≥45mm), in all four cohorts, demonstrated a significant association with the LTBP4 21011A>T genotype (a 2% decrease in AAA diameter, or a 0.53mm/year reduction in AAA growth rate, per T allele [p =0.03, p =0.01]). Conclusion: This study suggests that the LTBP4 gene may contribute to AAA progression. [Copyright &y& Elsevier]

Background: Accumulating evidence suggests the involvement of inflammatory processes and cytokines in particular in the pathophysiology of major depression (MDD) and resistance to antidepressant treatment. Furthermore, amygdala and anterior cingulate cortex (ACC) responsiveness to emotional stimuli has been suggested as a predictor of treatment response. This study investigated the association between genetic variants of the interleukin 1 beta (IL1B) gene and amygdala and ACC responsiveness to emotional stimuli and response to antidepressant treatment. Methods: In this analysis, 256 Caucasian patients with MDD (145 women, 111 men) were genotyped for variants rs16944, rs1143643, and rs1143634 in the IL1B gene (2q14). Response to antidepressant treatment over 6 weeks was defined as remission (≤ 7 on the Hamilton Rating Scale for Depression–21-question) and response (>50% decrease on Hamilton Rating Scale for Depression–21-question). Brain activity under visual presentation of emotional faces was assessed in a subsample of 32 depressed patients by means of functional magnetic resonance imaging at 3 T. Results: Pharmacogenetic analyses show significant associations of the GG genotypes of single nucleotide polymorphisms (SNPs) rs16944 (odds ratio = 1.74; 95% confidence interval 1.2–4.3) and rs1143643 (odds ratio = 3.1; 95% confidence interval 1.3–7.8) (compared with the AA genotype) with nonremission after 6 weeks. The imaging analyses show that the number of G-alleles in both SNPs (rs16944 and rs1143643) was associated with reduced responsiveness of the amygdala and ACC to emotional stimulation. Conclusions: The present study suggests a negative effect of the IL1B gene on pharmacological response and amygdala and ACC function involving the same genotypes of two SNPs (rs16944, rs116343), which taken together increase the risk of nonremission over 6 weeks of antidepressant treatment in MDD. [Copyright &y& Elsevier]