| 1. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 2. |
- Kaptoge, S., et al.
(author)
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C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:14, s. 1310-1320
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Journal article (peer-reviewed)abstract
- Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P < 0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (< 10%), " intermediate" (10% to < 20%), and "high" (>= 20%) (P < 0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of >= 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)
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| 3. |
- Wormser, David, et al.
(author)
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Adult height and the risk of cause-specific death and vascular morbidity in 1 million people : individual participant meta-analysis
- 2012
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:5, s. 1419-1433
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Journal article (peer-reviewed)abstract
- BackgroundThe extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.MethodsWe calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.ResultsFor people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.ConclusionAdult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
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| 4. |
- Schunkert, Heribert, et al.
(author)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Journal article (peer-reviewed)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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| 5. |
- Elks, Cathy E, et al.
(author)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Journal article (peer-reviewed)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 6. |
- Lange, Leslie A, et al.
(author)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Journal article (peer-reviewed)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 7. |
- Stolk, Lisette, et al.
(author)
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
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Journal article (peer-reviewed)abstract
- To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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| 8. |
- Pennells, Lisa, et al.
(author)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Journal article (peer-reviewed)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 9. |
- Smith-Warner, Stephanie A., et al.
(author)
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Alcohol and breast cancer in women : A pooled analysis of cohort studies
- 1998
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 279:7, s. 535-540
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. DATA SOURCES: We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. DATA EXTRACTION: Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. DATA SYNTHESIS: For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. CONCLUSIONS: Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.
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| 10. |
- Wild, Philipp S., et al.
(author)
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A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
- 2011
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In: Circulation: Cardiovascular Genetics. - : American Heart Association/Lippincott, Williams & Wilkins. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
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Journal article (peer-reviewed)abstract
- Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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| 11. |
- de Gonzalez, Amy Berrington, et al.
(author)
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Body-Mass Index and Mortality among 1.46 Million White Adults.
- 2010
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In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 363:23, s. 2211-2219
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Journal article (peer-reviewed)abstract
- Background: A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. Methods: We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). Results: The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. Conclusions: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9. N Engl J Med 2010;363:2211-9.
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| 12. |
- Dehghan, Abbas, et al.
(author)
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Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies : The CHARGE Consortium
- 2016
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Journal article (peer-reviewed)abstract
- Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
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| 13. |
- Genkinger, Jeanine M., et al.
(author)
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A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk
- 2011
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In: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 129:7, s. 1708-1717
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Journal article (peer-reviewed)abstract
- Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2), pancreatic cancer risk was 47% higher (95% CI:23-75%) among obese (BMI >= 30 kg/m(2)) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI >= 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2)). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2)) and not obese at baseline (BMI < 30 kg/m(2)), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI >= 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.
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| 14. |
- Schouten, Leo J., et al.
(author)
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Height, body mass index, and ovarian cancer : A pooled analysis of 12 cohort studies
- 2008
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In: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 17:4, s. 902-912
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Journal article (peer-reviewed)abstract
- Background: Although many studies have investigated the association between anthropometry and ovarian cancer risk, results have been inconsistent. Methods: The associations of height, body mass index (BMI), and ovarian cancer risk were examined in a pooled analysis of primary data from 12 prospective cohort studies from North America and Europe. The study population consisted of 531,583 women among whom 2,036 epithelial ovarian cancer cases were identified. To summarize associations, study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Results: Women with height >= 1.70 m had a pooled multivariate RR of 1.38 [95% confidence interval (95% CI), 1.16-1-65] compared with those with height <1.60 m. For the same comparison, multivariate RRs were 1.79 (95% CI, 1.07-3.00) for premenopausal and 1.25 (95% CI, 1.04-1.49) for postmenopausal ovarian cancer (P(interaction) = 0.14). The multivariate RR for women with a BMI >= 30 kg/m(2) was 1.03 (95% CI, 0.86-1.22) compared with women with a BMI from 18.5 to 23 kg/m(2). For the same comparison, multivariate RRs were 1.72 (95% CI, 1.02-2.89) for premenopausal and 1.07 (95% CI, 0.87-1.33) for postmenopausal women (P(interaction) = 0.07). There was no statistically significant heterogeneity between studies with respect to height or BMI. BMI in early adulthood was not associated with ovarian cancer risk. Conclusion: Height was associated with an increased ovarian cancer risk, especially in premenopausal women. BMI was not associated with ovarian cancer risk in postmenopausal women but was positively associated with risk in premenopausal women.
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| 15. |
- Sennblad, Bengt, et al.
(author)
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Genome- wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels
- 2017
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 26:3, s. 637-649
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Journal article (peer-reviewed)abstract
- Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators. We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays. Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 x 10(-302)), F11 (rs4253417, P-value = 2.86 x 10(-193)), and a novel association in GCKR (rs780094, P-value = 3.56 x 10(-09)), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR. These results should open the door to new therapeutic targets for thrombosis prevention.
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| 16. |
- Cho, Eunyoung, et al.
(author)
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Alcohol intake and colorectal cancer : a pooled analysis of 8 cohort studies
- 2004
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In: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 140:8, s. 603-613
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Journal article (peer-reviewed)abstract
- BACKGROUND: Epidemiologic studies have generally reported positive associations between alcohol consumption and risk for colorectal cancer. However, findings related to specific alcoholic beverages or different anatomic sites in the large bowel have been inconsistent. OBJECTIVE: To examine the relationship of total alcohol intake and intake from specific beverages to the incidence of colorectal cancer and to evaluate whether other potential risk factors modify the association. DESIGN: Pooled analysis of primary data from 8 cohort studies in 5 countries. SETTING: North America and Europe. PARTICIPANTS: 489,979 women and men with no history of cancer other than nonmelanoma skin cancer at baseline. MEASUREMENTS: Alcohol intake was assessed in each study at baseline by using a validated food-frequency questionnaire. RESULTS: During a maximum of 6 to 16 years of follow-up across the studies, 4687 cases of colorectal cancer were documented. In categorical analyses, increased risk for colorectal cancer was limited to persons with an alcohol intake of 30 g/d or greater (approximately > or =2 drinks/d), a consumption level reported by 4% of women and 13% of men. Compared with nondrinkers, the pooled multivariate relative risks were 1.16 (95% CI, 0.99 to 1.36) for persons who consumed 30 to less than 45 g/d and 1.41 (CI, 1.16 to 1.72) for those who consumed 45 g/d or greater. No significant heterogeneity by study or sex was observed. The association was evident for cancer of the proximal colon, distal colon, and rectum. No clear difference in relative risks was found among specific alcoholic beverages. LIMITATIONS: The study included only one measure of alcohol consumption at baseline and could not investigate lifetime alcohol consumption, alcohol consumption at younger ages, or changes in alcohol consumption during follow-up. It also could not examine drinking patterns or duration of alcohol use. CONCLUSIONS: A single determination of alcohol intake correlated with a modest relative elevation in colorectal cancer rate, mainly at the highest levels of alcohol intake.
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| 17. |
- Lee, Jung Eun, et al.
(author)
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Intakes of coffee, tea, milk, soda and juice and renal cell cancer in a pooled analysis of 13 prospective studies.
- 2007
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 121:10, s. 2246-53
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Journal article (peer-reviewed)abstract
- Specific beverage intake may be associated with the risk of renal cell cancer through a diluting effect of carcinogens, alterations of hormone levels, or other changes in the renal tubular environment, but few prospective studies have examined these associations. We evaluated the associations between coffee, tea, milk, soda and fruit and vegetable juice intakes and renal cell cancer risk in a pooled analysis of 13 prospective studies (530,469 women and 244,483 men). Participants completed a validated food-frequency questionnaire at baseline. Using the primary data, the study-specific relative risks (RRs) were calculated and then pooled using a random effects model. A total of 1,478 incident renal cell cancer cases were identified during a follow-up of 7-20 years across studies. Coffee consumption was associated with a modestly lower risk of renal cell cancer (pooled multivariate RR for 3 or more 8 oz (237 ml) cups/day versus less than one 8 oz (237 ml) cup/day = 0.84; 95% CI = 0.67-1.05; p value, test for trend = 0.22). Tea consumption was also inversely associated with renal cell cancer risk (pooled multivariate RR for 1 or more 8 oz (237 ml) cups/day versus nondrinkers = 0.85; 95% CI = 0.71-1.02; pvalue, test for trend = 0.04). No clear associations were observed for milk, soda or juice. Our findings provide strong evidence that neither coffee nor tea consumption increases renal cell cancer risk. Instead, greater consumption of coffee and tea may be associated with a lower risk of renal cell cancer. (c) 2007 Wiley-Liss, Inc.
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| 18. |
- Smith-Warner, Stephanie A., et al.
(author)
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Methods for pooling results of epidemiologic studies - The pooling project of prospective studies of diet and cancer
- 2006
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In: American Journal of Epidemiology. - Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NCI, Nutr Epidemiol Branch, Bethesda, MD USA. Loma Linda Univ, Sch Med, Ctr Hlth Res, Loma Linda, CA 92350 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. NCI, Epidemiol Unit, Milan, Italy. Maastricht Univ, Fac Hlth Sci, Dept Epidemiol, Maastricht, Netherlands. Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Ctr Canc Prevent, Boston, MA USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. TNO Qual Life, Dept Epidemiol, Zeist, Netherlands. No Calif Canc Ctr, Fremont, CA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Amer Canc Soc, Epidemiol & Surveilliance Res, Atlanta, GA USA. Univ Toronto, Fac Med, Dept Publ Hlth Sci, Toronto, ON, Canada. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. NYU, Sch Med, Dept Environm Med, New York, NY USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. : OXFORD UNIV PRESS INC. - 0002-9262 .- 1476-6256. ; 163:11, s. 1053-1064
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Journal article (peer-reviewed)abstract
- With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined.
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| 19. |
- Lee, Jung Eun, et al.
(author)
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Alcohol intake and renal cell cancer in a pooled analysis of 12 prospective studies
- 2007
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In: Journal of the National Cancer Institute. - Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Dept Hlth & Hlth Serv, NIH, Bethesda, MD USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA USA. Univ So Calif, Norriss Comprehens Canc Ctr, Los Angeles, CA USA. Maastricht Univ, Dept Epidemiol, Nutr & Toxicol Res Inst, Maastricht, Netherlands. Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. No Calif Canc Ctr, Fremont, CA USA. Amer Canc Soc, Epidemiol & Surveillance Res, Atlanta, GA USA. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. Mayo Clin, Coll Med, Dept Urol, Jacksonville, FL USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 99:10, s. 801-810
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Journal article (peer-reviewed)abstract
- Background The association between alcohol intake and risk of renal cell cancer has been inconsistent in case-control studies. An inverse association between alcohol intake and risk of renal cell cancer has been suggested in a few prospective studies, but each of these studies included a small number of cases. Methods We performed a pooled analysis of 12 prospective studies that included 530469 women and 229575 men with maximum follow-up times of 7-20 years. All participants had completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RRs) for renal cell cancer were calculated using Cox proportional hazards models and then pooled using a random-effects model. All statistical tests were two-sided. Results A total of 1430 (711 women and 719 men) cases of incident renal cell cancer were identified. The study-standardized incidence rates of renal cell cancer were 23 per 100000 person-years among nondrinkers and 15 per 100000 person-years among those who drank 15 g/day or more of alcohol. Compared with non-drinking, alcohol consumption (>= 15 g/day, equivalent to slightly more than one alcoholic drink per day) was associated with a decreased risk of renal cell cancer (pooled multivariable RR = 0.72, 95% confidence interval = 0.60 to 0.86; P-trend <.001); statistically significant inverse trends with increasing intake were seen in both women and men. No difference by sex was observed (P-heterogeneity = .89). Associations between alcohol intake and renal cell cancer were not statistically different across alcoholic beverage type (beer versus wine versus liquor) (P = .40). Conclusion Moderate alcohol consumption was associated with a lower risk of renal cell cancer among both women and men in this pooled analysis.
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| 20. |
- Lindberg, Gunnar, et al.
(author)
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Serum sialic acid and its correlates in community samples from Akita, Japan and Minneapolis, USA
- 1997
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In: International Journal of Epidemiology. - 1464-3685. ; 26:1, s. 58-63
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The concentration of serum total sialic acid (S-TSA) is one recently investigated risk marker for cardiovascular mortality and atherosclerosis. Since the mortality from coronary heart disease is higher in the United States than in Japan, one could expect the S-TSA to be higher among Caucasian US citizens than among Japanese citizens, a hypothesis that is tested in this study. DESIGN: Cross-sectional study of population-based samples of Japanese and US Caucasian men and women. SETTING: The rural community Akita, Japan, and the suburbs of Minneapolis, Minnesota. SUBJECTS: These were 75 consecutive men and women from Akita and Minneapolis respectively aged 47-69 years in 1990. People who had smoked cigarettes during the past 5 years; who had a history of diabetes mellitus, liver disease, coronary heart disease, or stroke; or who were taking anticoagulants were excluded. OUTCOME MEASURES: Serum total sialic acid levels in male and female Japanese and US Caucasian subjects with adjustment for age, systolic blood pressure, fibrinogen, triglycerides and in women also for menopausal status. Race and sex-specific correlations with serum total sialic acid for selected cardiovascular risk markers. RESULTS: The entire sialic acid distributions were shifted to the right in Caucasian men and women compared to Japanese men and women. The mean +/- standard deviation concentrations of S-TSA were 54.1 +/- 5.3 mg/dl in Japanese men and 58.7 +/- 5.6 mg/dl in Caucasian men (P < 0.001). In women, the concentrations were 54.8 +/- 5.1 and 63.1 +/- 6.0 mg/dl respectively (P < 0.001). S-TSA level correlated significantly and positively with fibrinogen levels in Caucasian and Japanese men and women and with triglyceride levels in Caucasian and Japanese men and in Caucasian women but not in Japanese women. After adjustment for age, systolic blood pressure, fibrinogen, triglycerides and menopausal status, the sialic acid levels were 2.2 (P = 0.009) and 6.2 (P < 0.001) mg/dl higher in Caucasian compared to Japanese men and women respectively. CONCLUSIONS: Higher S-TSA levels in Caucasians living in Minneapolis compared to Japanese living in Akita, Japan is in concordance with the higher cardiovascular mortality in the US. Differences in S-TSA levels may reflect international differences in the prevalence of atherosclerosis.
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| 21. |
- Lindberg, Gunnar, et al.
(author)
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The association between serum sialic acid and asymptomatic carotid atherosclerosis is not related to antibodies to herpes type viruses or Chlamydia pneumoniae. The Atherosclerosis Risk in Communities (ARIC) Study Investigators
- 1997
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In: International Journal of Epidemiology. - 1464-3685. ; 26:6, s. 1386-1391
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Journal article (peer-reviewed)abstract
- BACKGROUND: Total serum sialic acid is a recently investigated marker for cardiovascular mortality and carotid atherosclerosis. This study tested the hypothesis that past infection by Herpes simplex type 1 or type 2 viruses or Cytomegalovirus or Chlamydia pneumoniae accounts for the association between serum total sialic acid and atherosclerosis. METHODS: Population-based samples of men and women living in four US communities were used in a cross-sectional study. Cases and matched controls were defined by B-mode ultrasound measurements of carotid and popliteal arterial wall thickness. In all, there were 267 case control pairs with information about antibody titres to viruses and 256 pairs with information about antibody titres to Chlamydia pneumoniae. RESULTS: Serum total sialic acid (S-TSA) level was significantly higher in cases with carotid atherosclerosis compared to their controls. The odds ratio for carotid atherosclerosis associated with sialic acid level above 75th percentile was 1.73 (95% confidence interval [CI]: 1.02-2.95) in the sample with information about antibodies to viruses and 1.70 (95% CI: 1.00-2.93) in the sample with information about antibodies to C. pneumoniae. Adjustment for titres of antibodies to viruses and C. pneumoniae had no impact on the relation between sialic acid and carotid atherosclerosis. CONCLUSIONS: From these results, it seems unlikely that previous infection by any of these micro-organisms accounts for the relation between S-TSA level and carotid atherosclerosis.
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| 22. |
- Råstam, Lennart, et al.
(author)
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Association between serum sialic acid concentration and carotid atherosclerosis measured by B-mode ultrasound. The ARIC Investigators. Atherosclerosis Risk in Communities Study
- 1996
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 25:5, s. 953-958
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Journal article (peer-reviewed)abstract
- BACKGROUND: Previous studies have shown that the serum level of sialic acid is associated positively with mortality from coronary disease and stroke. In this study its relation with carotid atherosclerosis was evaluated. METHODS: From the Atherosclerosis Risk in Communities (ARIC) Study, 323 cases with carotid intima-media wall thickness above the 90th percentile (measured with B-mode ultrasound) were matched 1:1 with controls without atherosclerosis. Serum sialic acid, plasma LDL and HDL cholesterol, serum insulin concentrations, blood pressure, antihypertensive medication use, and smoking status were used to assess the independent contribution of the sialic acid level to carotid atherosclerosis. RESULTS: The mean (SD) serum sialic acid concentration was 75.0 (9.7) mg/dl in cases and 70.7 (8.9) mg/dl in controls (P = 0.0001). In a conditional logistic model with adjustment for age, LDL-cholesterol, HDL-cholesterol, serum insulin, smoking and hypertension, the odds ratio associated with sialic acid above the 75th percentile (> or = 78.3 mg/dl) versus below was 1.65 with a 95% confidence interval of 1.01-2.70. CONCLUSION: The sialic acid level is correlated with the presence of carotid atherosclerosis, independently of major cardiovascular disease risk factors. The biological mechanism behind this association is not resolved.
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