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The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.
Ehret, GB, Ferreira, T, Chasman, DI, Jackson, AU, Schmidt, EM, Johnson, T, Thorleifsson, G, Luan, J, Donnelly, LA, Kanoni, S, et al
Nature genetics. 2016;(10):1171-1184
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Abstract
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
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A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk.
Travis, RC, Appleby, PN, Martin, RM, Holly, JMP, Albanes, D, Black, A, Bueno-de-Mesquita, HBA, Chan, JM, Chen, C, Chirlaque, MD, et al
Cancer research. 2016;(8):2288-2300
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Abstract
The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.
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Cholesterol and breast cancer risk: a systematic review and meta-analysis of prospective studies.
Touvier, M, Fassier, P, His, M, Norat, T, Chan, DS, Blacher, J, Hercberg, S, Galan, P, Druesne-Pecollo, N, Latino-Martel, P
The British journal of nutrition. 2015;(3):347-57
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Abstract
The objective of the present study was to conduct the first systematic review and meta-analysis of prospective studies investigating the associations between total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels and the risk of breast cancer. Relevant studies were identified in PubMed (up to January 2014). Inclusion criteria were original peer-reviewed publications with a prospective design. Random-effects models were used to estimate summary hazard ratios (HR) and 95% CI. Distinction was made between studies that did or did not exclude cancer cases diagnosed during the first years of follow-up, thereby eliminating potential preclinical bias. Overall, the summary HR for the association between TC and breast cancer risk was 0.97 (95% CI 0.94, 1.00; dose-response per 1 mmol/l increment, thirteen studies), and that between HDL-C and breast cancer risk was 0.86 (95% CI 0.69, 1.09; dose-response per 1 mmol/l increment, six studies), with high heterogeneity (I2= 67 and 47%, respectively). For studies that eliminated preclinical bias, an inverse association was observed between the risk of breast cancer and TC (dose-response HR 0.94 (95% CI 0.89, 0.99), seven studies, I2= 78%; highest v. lowest HR 0.82 (95% CI 0.66, 1.02), nine studies, I2= 81%) and HDL-C (dose-response HR 0.81 (95% CI 0.65, 1.02), five studies, I2= 30 %; highest v. lowest HR 0.82 (95% CI 0.69, 0.98), five studies, I2= 0%). There was no association observed between LDL-C and the risk of breast cancer (four studies). The present meta-analysis confirms the evidence of a modest but statistically significant inverse association between TC and more specifically HDL-C and the risk of breast cancer, supported by mechanistic plausibility from experimental studies. Further large prospective studies that adequately control for preclinical bias are needed to confirm the results on the role of cholesterol level and its fractions in the aetiology of breast cancer.
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Alcohol drinking and second primary cancer risk in patients with upper aerodigestive tract cancers: a systematic review and meta-analysis of observational studies.
Druesne-Pecollo, N, Keita, Y, Touvier, M, Chan, DS, Norat, T, Hercberg, S, Latino-Martel, P
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2014;(2):324-31
Abstract
BACKGROUND We conducted a systematic review and meta-analysis of existing data from observational studies to assess the strength of the association of alcohol drinking with second primary cancer risk in patients with upper aerodigestive tract (UADT; oral cavity, pharynx, larynx, and esophagus) cancer. METHODS PubMed and Embase were searched up to July 2012 and the reference lists of studies included in the analysis were examined. Random-effects models were used to estimate summary relative risks (RR) and 95% confidence interval (CI). RESULTS Nineteen studies, 8 cohort and 11 case-control studies, were included. In highest versus lowest meta-analyses, alcohol drinking was associated with significantly increased risk of UADT second primary cancers (RR, 2.97; 95% CI, 1.96-4.50). Significantly increased risks were also observed for UADT and lung combined (RR, 1.90; 95% CI, 1.16-3.11) and all sites (RR, 1.60; 95% CI, 1.22-2.10) second primary cancers. For an increase in the alcohol intake of 10 grams per day, dose-response meta-analysis resulted in a significantly increased RR of 1.09 (95% CI, 1.04-1.14) for UADT second primary cancers. CONCLUSIONS Alcohol drinking in patients with UADT cancer is associated with an increased risk of second primary cancers. Studies conducted in alcohol drinking patients with UADT cancer and evaluating the effect of alcohol cessation on second primary cancer and other outcomes are needed. IMPACT Our results emphasize the importance of prevention policies aiming to reduce alcohol drinking. Health-care professionals should encourage alcohol drinking patients with UADT cancer to reduce their consumption and reinforce the surveillance of this at-risk subpopulation.
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A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.
Manning, AK, Hivert, MF, Scott, RA, Grimsby, JL, Bouatia-Naji, N, Chen, H, Rybin, D, Liu, CT, Bielak, LF, Prokopenko, I, et al
Nature genetics. 2012;(6):659-69
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Abstract
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
Dastani, Z, Hivert, MF, Timpson, N, Perry, JR, Yuan, X, Scott, RA, Henneman, P, Heid, IM, Kizer, JR, Lyytikäinen, LP, et al
PLoS genetics. 2012;(3):e1002607
Abstract
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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Excess body weight and second primary cancer risk after breast cancer: a systematic review and meta-analysis of prospective studies.
Druesne-Pecollo, N, Touvier, M, Barrandon, E, Chan, DS, Norat, T, Zelek, L, Hercberg, S, Latino-Martel, P
Breast cancer research and treatment. 2012;(3):647-54
Abstract
Several observational studies have investigated the role of body mass index (BMI) in second primary cancer incidence in women with breast cancer. We conducted a systematic review and meta-analysis of the evidence to assess the strength of this association. PubMed and Embase were searched for observational studies up to May 2012, and the reference lists of studies included in the analysis were examined. Random effects models were used to estimate summary relative risks (RRs) and 95 % confidence intervals (CIs). Thirteen prospective studies, five cohort and eight nested case-control studies, were included. In categorical meta-analyses of BMI, obesity was associated to significantly increased risks of contralateral breast (RR = 1.37, 95 % CI: 1.20-1.57), breast (RR = 1.40, 95 % CI: 1.24-1.58), endometrial (RR = 1.96, 95 % CI: 1.43-2.70), and colorectal (RR = 1.89, 95 % CI: 1.28-2.79) second primary cancers. For a BMI increase of 5 kg/m(2), dose-response meta-analyses resulted in significantly increased RRs of 1.12 (95 % CI: 1.06-1.20) and 1.14 (95 % CI: 1.07-1.21) for contralateral breast and breast second primary cancers, respectively. The summary RR for endometrial second primary cancers was 1.46 (95 % CI: 1.17-1.83) for a 5-unit increment. This result emphasizes the importance of prevention policies aiming to reduce overweight and obesity prevalence. Clinical trials in breast cancer patients with excess body weight evaluating the effect of normal weight restoration on second primary cancer incidence are needed.
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Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis.
Fezeu, L, Julia, C, Henegar, A, Bitu, J, Hu, FB, Grobbee, DE, Kengne, AP, Hercberg, S, Czernichow, S
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2011;(8):653-9
Abstract
The aim of this study was to assess the association between obesity and the risk of intensive care unit (ICU) admission and death among patients hospitalized for influenza A (H1N1) viral infection. A systematic review of the Medline and Cochrane databases using 'obesity', 'hospitalization', 'influenza A viral infection', various synonyms, and reference lists of retrieved articles from January 2009 to January 2010. Studies comparing the prevalence of obesity among patients with confirmed infection for influenza A virus and who were either hospitalized or admitted to ICU/died were included. A total of 3059 subjects from six cross-sectional studies, who were hospitalized for influenza A (H1N1) viral infection, were included in this meta-analysis. Severely obese H1N1 patients (body mass index ≥ 40 kg m(-2), n = 804) were as twice as likely to be admitted to ICU or die (odds ration: 2.01, 95% confidence interval: 1.29-3.14, P < 0.002) compared with H1N1 patients who were not severely obese. Having a body mass index ≥ 30 kg m(-2) was similarly associated with a more than twofold increased risk of ICU admission or death although this did not reach statistical significance (2.14, 0.92-4.99, P < 0.07). This meta-analysis supports the view that obesity is associated with higher risks of ICU admission or death in patients with influenza A (H1N1) infection. Therefore, morbid obese patients should be monitored more intensively when hospitalized.
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Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials.
Druesne-Pecollo, N, Latino-Martel, P, Norat, T, Barrandon, E, Bertrais, S, Galan, P, Hercberg, S
International journal of cancer. 2010;(1):172-84
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The effect of beta-carotene supplementation on cancer incidence has been investigated in several randomized controlled trials. The objective was to review the effect of beta-carotene supplementation on cancer incidence in randomized trials by cancer site, beta-carotene supplementation characteristics and study population. Relevant trials were retrieved by searching PubMed (up to April 2009). Authors involved in selected studies were contacted for additional information. Thirteen publications reporting results from 9 randomized controlled trials were included. Overall, no effect of beta-carotene supplementation was observed on the incidence of all cancers combined (RR, 1.01; 95% CI, 0.98-1.04), pancreatic cancer (RR, 0.99; 95% CI, 0.73-1.36), colorectal cancer (RR, 0.96; 95% CI, 0.85-1.09), prostate cancer (RR, 0.99; 95% CI, 0.91-1.07), breast cancer (RR, 0.96; 95% CI, 0.85-1.10), melanoma (RR, 0.98; 95% CI, 0.65-1.46) and non melanoma skin cancer (RR, 0.99; 95% CI, 0.93-1.05). The incidence of lung and stomach cancers were significantly increased in individuals supplemented with beta-carotene at 20-30 mg day(-1) (RR, 1.16; 95% CI, 1.06-1.27 and RR, 1.34; 95% CI, 1.06-1.70), in smokers and asbestos workers (RR, 1.20; 95% CI, 1.07-1.34 and RR, 1.54; 95% CI, 1.08-2.19) compared to the placebo group. Beta-carotene supplementation has not been shown to have any beneficial effect on cancer prevention. Conversely, it was associated with increased risk not only of lung cancer but also of gastric cancer at doses of 20-30 mg day(-1), in smokers and asbestos workers. This study adds to the evidence that nutritional prevention of cancer through beta-carotene supplementation should not be recommended.
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Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
Willer, CJ, Sanna, S, Jackson, AU, Scuteri, A, Bonnycastle, LL, Clarke, R, Heath, SC, Timpson, NJ, Najjar, SS, Stringham, HM, et al
Nature genetics. 2008;(2):161-9
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Abstract
To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.