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Shi J.,Vanderbilt University | Zhang Y.,Vanderbilt University | Zheng W.,Vanderbilt University | Michailidou K.,University of Cambridge | And 146 more authors.
International Journal of Cancer

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724–129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93–0.97, conditional p = 5.8 × 10−6), rs7815245 (OR = 0.94, 95% CI = 0.91–0.96, conditional p = 1.1 × 10−6) and rs2033101 (OR = 1.05, 95% CI = 1.02–1.07, conditional p = 1.1 × 10−4) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry. © 2016 UICC Source

Stender S.,Rigshospitalet | Stender S.,Copenhagen University | Frikke-Schmidt R.,Rigshospitalet | Frikke-Schmidt R.,Copenhagen University | And 4 more authors.

Gallstone disease, a risk factor for biliary cancer, has a strong heritable component, but the underlying genes are largely unknown. To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 80+ years. Endpoints were recorded from January 1976 through May 2009. During a mean follow-up of, respectively, 31 and 4.4 years, 3124 participants developed symptomatic gallstone disease and 30 developed biliary cancer. The multifactorially adjusted hazard ratio for symptomatic gallstone disease was 1.9 (95% confidence interval, 1.7-2.1) in DH heterozygotes (prevalence, 12%), and 3.3 (2.3-4.6) in HH homozygotes (0.4%) versus noncarriers (P for trend <0.001). Mean age at onset of symptomatic gallstone disease was 56 years for noncarriers, 54 for DH heterozygotes, and 52 for HH homozygotes (P for trend <0.001). The fraction of all gallstones attributed to D19H was 11%. The multifactorially adjusted hazard ratio for biliary cancer was 4.0 (1.9-8.4) in DH heterozygotes and HH homozygotes combined versus noncarriers (P < 0.001). The fraction of all biliary cancers attributed to the D19H genotype was 27%. Finally, D19H genotype associated with stepwise increases in plasma levels of alanine aminotransferase and gamma glutamyltransferase of up to 14% and 25% in HH homozygotes, and with corresponding stepwise reductions in plasma levels of total and low-density lipoprotein cholesterol of up to 5% versus noncarriers (all comparisons, P for trend <0.001). Conclusion: In this general population cohort, ABCG8 D19H genotype was an important predictor of both symptomatic gallstone disease and biliary cancer. © 2010 American Association for the Study of Liver Diseases. Source

Varbo A.,Copenhagen University | Benn M.,Copenhagen University | Tybjaerg-Hansen A.,Copenhagen General Population Study | Tybjaerg-Hansen A.,Copenhagen University | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology

Objective-: The goal of this study was to test whether TRIB1-rs2954029 and GCKR-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population. Methods and results-: We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally. Risk of IHD and MI was examined prospectively, cross-sectionally, and in a case-control study, and a metaanalysis was performed. TRIB1 TA (50%) and AA (27%) versus TT (23%) genotypes were associated with increased levels of triglycerides (total increase, +0.16 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), apolipoprotein B (+5.7 mg/dL; P<0.001), and low-density lipoprotein cholesterol (+0.11 mmol/L; P<0.001) and with decreased levels of high-density lipoprotein cholesterol (-0.04 mmol/L; P<0.001). In metaanalyses of the 3 studies combined, TRIB1 TA and AA versus TT genotypes were associated with 13% (95% CI, 5% to 20%) and 15% (7% to 23%) increased risk of IHD, and 11% (1% to 21%) and 17% (6% to 30%) increased risk of MI, respectively. Although GCKR CT (46%) and TT (14%) versus CC (40%) genotypes had effects on triglycerides (+0.17 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), and apolipoprotein B (+4.6 mg/dL; P<0.001) similar to those of TRIB1, GCKR did not influence low-density lipoprotein cholesterol levels or risk of IHD or MI. Risks of IHD were similar after stratification for gender, age, body mass index, hypertension, diabetes mellitus, smoking, statin use, alcohol intake, and physical activity. Conclusion-: In the general population, both TRIB1-rs2954029 and GCKR-rs1260326 were associated with lipid levels, whereas TRIB1 was also associated with increased risk of IHD and MI. © 2011 American Heart Association, Inc. Source

Dahl M.,Copenhagen University | Vestbo J.,Copenhagen City Heart Study | Vestbo J.,Copenhagen University | Vestbo J.,University of Manchester | And 6 more authors.

Background: It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design. Methods: The authors measured high-sensitivity CRP in plasma, genotyped for four single nucleotide polymorphisms in the CRP gene, and screened for spirometry-defined COPD and hospitalisation due to COPD in 7974 individuals from the Copenhagen City Heart Study and in 32 652 individuals from the Copenhagen General Population Study. Results: Elevated plasma CRP >3 mg/l compared with <1 mg/l was associated with risk estimates of 1.8 and 2.8 for spirometry-based COPD and of 1.6 and 1.8 for hospitalisation due to COPD in the Copenhagen City Heart Study and the Copenhagen General Population Study, respectively. Genotype combinations of the four CRP polymorphisms were associated with up to a 62% increase in plasma CRP. However, these genotype combinations did not associate with increased risk of COPD or hospitalisation due to COPD in either cohort or in the two cohorts combined. On instrumental variable analysis, a doubling of plasma CRP versus a doubling of genetically elevated CRP resulted in ORs for COPD of 1.27 (95% CI 1.25 to 1.30) versus 1.01 (0.81 to 1.26) and for COPD hospitalisation of 1.47 (1.43 to 1.51) versus 0.82(0.59 to 1.13). Conclusion: Although elevated CRP is related to both a diagnosis of COPD and subsequent hospital admission, genetically elevated plasma CRP is not associated with an increased risk of clinical COPD. This suggests that the association between CRP levels and COPD is not causal. Source

Benn M.,Copenhagen University | Tybjaerg-Hansen A.,Copenhagen General Population Study | Tybjaerg-Hansen A.,Copenhagen University | McCarthy M.I.,University of Oxford | And 4 more authors.
Journal of the American College of Cardiology

Objectives: The purpose of this study was to test whether elevated nonfasting glucose levels associate with and cause ischemic heart disease (IHD) and myocardial infarction (MI). Background: Elevated fasting plasma glucose levels associate with increased risk of IHD, but whether this is also true for nonfasting levels and whether this is a causal relationship is unknown. Methods: Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of those, IHD developed in 14,155, and MI developed in 6,257. Subjects were genotyped for variants in GCK (rs4607517), G6PC2 (rs560887), ADCY5 (rs11708067), DGKB (rs2191349), and ADRA2A (rs10885122) associated with elevated fasting glucose levels in genome-wide association studies. Results: Risk of IHD and MI increased stepwise with increasing nonfasting glucose levels. The hazard ratio for IHD in subjects with nonfasting glucose levels <11 mmol/l (<198 mg/dl) versus <5 mmol/l (<90 mg/dl) was 6.9 (95% confidence interval [CI]: 4.2 to 11.2) adjusted for age and sex, and 2.3 (95% CI: 1.3 to 4.2) adjusted multifactorially; corresponding values for MI were 9.2 (95% CI: 4.6 to 18.2) and 4.8 (95% CI: 2.1 to 11.2). Increasing number of glucose-increasing alleles was associated with increasing nonfasting glucose levels and with increased risk of IHD and MI. The estimated causal odds ratio for IHD and MI by instrumental variable analysis for a 1-mmol/l (18-mg/dl) increase in nonfasting glucose levels due to genotypes combined were 1.25 (95% CI: 1.03 to 1.52) and 1.69 (95% CI: 1.28 to 2.23), and the corresponding observed hazard ratio for IHD and MI by Cox regression was 1.18 (95% CI: 1.15 to 1.22) and 1.09 (95% CI: 1.07 to 1.11), respectively. Conclusions: Like common nonfasting glucose elevation, plasma glucose-increasing polymorphisms associate with increased risk of IHD and MI. These data are compatible with a causal association. © 2012 American College of Cardiology Foundation. Source

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