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Low plasma 25-hydroxyvitamin D [25(OH)D] levels are associated with high cardiovascular risk. This may be because that low 25(OH)D levels are associated with high levels of atherogenic lipoproteins, but whether these 2 risk factors are genetically associated is unknown. We tested this hypothesis.Using a Mendelian randomization approach, potential genetic associations between plasma levels of atherogenic lipoproteins and 25(OH)D were examined in 85 868 white, Danish individuals in whom we genotyped for variants affecting plasma levels of 25(OH)D, nonfasting remnant cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Lipoprotein levels were measured in all and 25(OH)D levels in 31 435. A doubling in nonfasting remnant cholesterol levels was observationally and genetically associated with -6.0%(95% confidence interval [CI], -6.5% to -5.5%) and -8.9% (95% CI, -15% to -2.3%) lower plasma 25(OH)D levels. For low-density lipoprotein-cholesterol levels, corresponding values were -4.6% (95% CI, -5.4% to -3.7%) observationally and -11% (95% CI, -29% to +6.9%) genetically. In contrast, a halving in high-density lipoprotein-cholesterol levels was observationally associated with -1.5% (95% CI, -2.2% to -0.7%) lower but genetically associated with +20% (95% CI, +7.4% to +34%) higher plasma 25(OH)D levels. Plasma levels of lipoprotein(a) and 25(OH)D did not associate. Finally, low 25(OH)D levels did not associate genetically with levels of remnant and low-density lipoprotein-cholesterol.Genetically elevated nonfasting remnant cholesterol is associated with low 25(OH)D levels, whereas genetically reduced high-density lipoprotein-cholesterol is not associated with low 25(OH)D levels. These findings suggest that low 25(OH)D levels observationally is simply a marker for elevated atherogenic lipoproteins and question a role for vitamin D supplementation in the prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease caused by loss-of-function mutations in ABCC6 and characterized by elastic calcification leading to dermal, ocular, and ischemic vascular disease. We tested the hypothesis that heterozygosity for R1141X, the most frequent PXE-causing mutation in Caucasians, associated with risk of ischemic vascular disease, as previous studies suggested 4- to 11-fold risk of ischemic heart disease (IHD) in heterozygotes.We studied 10 276 persons from the general population, including 1985 with IHD and 989 with ischemic cerebrovascular disease (ICVD). We examined 45 603 individuals from a cross-sectional general population study, of whom 3738 had IHD and 2335 had ICVD. Finally, we compared 4851 patients with IHD and 625 patients with ICVD with, respectively, 4851 and 625 matched control subjects. We genotyped participants in all studies for ABCC6 R1141X. The frequency of R1141X was 0.6% in all populations studied. ABCC6 R1141X genotype was not associated with an increased risk of IHD, myocardial infarction, ICVD, or ischemic stroke. Furthermore, R1141X genotype did not interact with age on risk of the largest end point, IHD. Finally, R1141X genotype did not associate with variation in plasma levels of high-sensitivity C-reactive protein, fibrinogen, blood pressure, or lipid and lipoproteins in the general population.In 4 studies including 66 831 participants and 13 642 cases with ischemic vascular events, heterozygosity for ABCC6 R1141X did not associate with risk of IHD, myocardial infarction, ICVD, or ischemic stroke. [ABSTRACT FROM AUTHOR]

This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the β-blocker atenolol for 4.8 years tested whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 12 other previously well-characterized polymorphisms of hypertension susceptibility genes affected blood pressure reduction, heart rate reduction, cardiovascular events, and/or response to treatment. These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol.We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol.ACE and the 12 other genotypes did not affect the reduction in systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its components stroke, myocardial infarction, and cardiovascular death, or treatment differences between losartan and atenolol on these endpoints, as assessed by Cox proportional hazards models including baseline Framingham risk score and LVH.ACE insertion/deletion and 12 other polymorphisms of hypertension susceptibility genes did not affect blood pressure reduction, heart rate reduction, or cardiovascular events in patients with hypertension and LVH, or treatment differences between losartan and atenolol on these endpoints. These results suggest that the observed effects of losartan versus atenolol in the Losartan Intervention for Endpoint reduction in hypertension study do not depend on ACE and 12 other polymorphisms of hypertension susceptibility genes. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP) 1B1 enzymes metabolize tobacco-smoke polycyclic aromatic hydrocarbons and 17β-estradiol. CYP1B1∗3 (rs1056836 = Leu432Val = 4326C>G) and CYP1B1∗4 (rs1800440 = Asn453Ser = 4390A>G) influence this metabolism. We, therefore, hypothesized that these two polymorphisms associate with risk of myocardial infarction (MI), ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), chronic obstructive pulmonary disease (COPD), cancer overall, tobacco-related cancer, and female cancer, possibly dependent on tobacco exposure.We genotyped 10 391 adults from the Copenhagen City Heart Study, who had been followed prospectively for more than 30 years. Significant results were retested cross-sectionally in the Copenhagen General Population Study (CGPS) with 37 178 participants, and in the Copenhagen Ischemic Heart Disease Study with 2379 cases and 33 220 controls.In the Copenhagen City Heart Study, hazard ratio for MI among never smokers was 1.9 (95% confidence interval: 1.2-3.2) for CYP1B1∗3 GG (19%) versus CC (32%). These findings were, however, not confirmed when retested in CGPS and Copenhagen Ischemic Heart Disease Study. For tobacco-related cancer, we found decreasing risk with CYP1B1∗3 CG and GG versus CC; however, this could not be confirmed in the CGPS. For IHD, ICVD, COPD, cancer overall, and female cancer, we found no association with CYP1B1∗3 genotype, overall or according to smoking status. For CYP1B1∗4 genotype, we did not find any association with either endpoint, overall or according to smoking status.CYP1B1∗3 and CYP1B1∗4 genotypes did not associate with the risk of MI, IHD, ICVD, COPD, cancer overall, tobacco-related cancer, or female cancer. [ABSTRACT FROM AUTHOR]

Genetic variations are most likely an additional risk factor besides tobacco smoking per se for the risk of chronic obstructive pulmonary disease (COPD). In this study, we compared genetic variants influencing the effect of smoking on COPD, that is, the effect of the well-known splicing defect polymorphism, CYP3A5∗3 (rs776746), identified before genome-wide association studies, with the genome-wide association studies identified CHRNA3 (rs1051730) polymorphism on the risk of decreased lung function and COPD.In all, 10 605 participants from the general population were genotyped. Information on spirometry, hospital admissions and smoking behaviour was recorded. Endpoints were lung function and COPD.For CHRNA3, the percentage of forced expiratory volume in 1 s (FEV1%) predicted was 89.3, 90.6 and 92.4% in homozygous, heterozygous and noncarrier ever-smokers (P-trend<0.001). The corresponding values for forced vital capacity percentage (FVC%) predicted were 94.5, 95.2 and 96.7% (P-trend<0.001), and for FEV1/FVC ratio, the values were 0.753, 0.760 and 0.764 (P-trend=0.008). The odds ratio for COPD in homozygous versus noncarrier ever-smokers was 1.5 [95% confidence interval (CI) 1.3-1.9] for COPD hospitalization, 1.3 (95% CI 1.1-1.6) for COPD defined as FEV1/FVC less than lower limit of normal, 1.3 (95% CI 1.0-1.5) for the Global Initiative for Chronic Obstructive Lung Disease category 1-4 (GOLD 1-4), 1.2 (95% CI 1.0-1.5) for GOLD 2-4 and 1.5 (95% CI 1.1-2.2) for GOLD 3-4. This association could not be found in never-smokers. No association was found for CYP3A5∗3.The CHRNA3 genotype is associated with decreased lung function and risk of COPD among ever-smokers, whereas this was not the case for CYP3A5∗3. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin-angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding proteins in this system predict risk of atrial fibrillation.We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism in the ACE gene; rare allele frequencies were 0.16, 0.40, 0.12, 0.41, and 0.49, respectively. Participants had sinus rhythm at inclusion. During 26 years of follow-up, 968 individuals developed atrial fibrillation. Multifactorially adjusted hazard ratios for atrial fibrillation for a-20c ac and cc versus aa genotype were 1.1(95% confidence interval: 1.0-1.3; P=0.05) and 1.5(1.1-2.1; P=0.01). Compared with double noncarriers (angiotensinogen -20aa and ACE II), double heterozygotes (ac-I/D genotype), and double homozygotes (cc-DD) had hazard ratios for atrial fibrillation of 1.2(0.9-1.6; P=0.06) and 2.4(1.4-4.1; P=0.001). a-20c cc homozygotes above 70 years of age who were overweight, severely hypertensive, and had heart failure, had an absolute 10-year risk of atrial fibrillation of 61%.Angiotensinogen a-20c genotype alone and in combination with ACE I/D genotype predicts an increased risk of atrial fibrillation. Therefore, genetic variation in the renin-angiotensin system may influence effect of renin-angiotensin system blockers on atrial fibrillation. [ABSTRACT FROM AUTHOR]

In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment.The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases and controls.The proportion of D-allele carriers was higher amongst cases than controls (83 vs. 73%; P=0.032). In contrast, AT2R genotype distribution was similar in cases and controls. In a multiple regression analysis, D-allele carriage remained a significant risk factor for being a case [odds ratio: 1.9 (1.0-3.6)] together with male sex, impaired symptomatic awareness of hypoglycaemia and presence of nephropathy.The D-allele of the ACE gene is associated with severe hypoglycaemia requiring emergency treatment in type 1 diabetic patients with preserved spontaneous ACE activity. This supports the association between high ACE activity and occurrence of severe hypoglycaemia. [ABSTRACT FROM AUTHOR]

Integrin αvβ3 is essential for mature osteoclast function and therefore important for the development of osteoporosis and osteoporotic fractures. Integrin αvβ3 antagonists have antiresorptive effects in bone. We tested the hypothesis that the Leu33Pro polymorphism in the integrin β3-subunit associates with risk of hip fracture.We included 9233 men and women selected at random to represent the Danish general population as participants in the Copenhagen City Heart Study. First-ever hip fractures (n=267) were registered during 25 years follow-up. Log-rank statistics and Cox regression were used to compare fracture incidences and risk estimates between genotypes.Genotyping rendered 69.9% noncarriers, 27.3% heterozygotes and 2.7% homozygotes. Incidence of hip fracture was 2.8 and 1.5 per 1000 person-years in homozygotes and noncarriers (log-rank: P=0.02), respectively. Multifactorial adjusted Cox regression revealed a hazard ratio of 2.0 (95% confidence interval: 1.1-3.5) for hip fracture in homozygotes versus noncarriers. After stratification by sex, equivalent hazard ratios were 2.0 (1.0-4.1) in women and 2.0 (0.8-5.0) in men. In the 2193 postmenopausal women, hazard ratio for hip fracture in homozygotes versus noncarriers after additional adjustment for age at menopause and use of hormone replacement therapy was 2.6 (1.2-5.3). Hazard ratio for hip fracture in heterozygotes versus noncarriers did not differ from 1.0.Individuals homozygous for the integrin β3 Leu33Pro polymorphism have a two-fold risk of hip fracture, mainly confined to postmenopausal women. Integrin β3 Leu33Pro homozygosity could prove a useful marker for risk of future hip fracture and may contribute to pharmacogenetic variation in effects of integrin αvβ3 antagonists. [ABSTRACT FROM AUTHOR]

Since β2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the β2-adrenergic receptor gene associated with elevated blood pressure.We genotyped 9185 individuals from the adult Danish general population.Allele frequencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively. Among women never treated with antihypertensive medication those heterozygous for Thr164Ile versus non-carriers had increased diastolic blood pressure (P=0.02). Women heterozygous for Thr164Ile versus non-carriers had an odds ratio for elevated blood pressure of 1.93 (95% CI: 1.30-2.86). Finally, women double heterozygous for Thr164Ile and Gln27Glu or Gly16Arg versus non-carriers at all 3 loci had an odds ratio for elevated blood pressure of 2.49 (1.28-4.85) or 3.19 (1.46-6.97). In men, blood pressure was not influenced by this genetic variation.In women Thr164Ile heterozygosity is associated with increased diastolic blood pressure, and represent a risk factor for elevated blood pressure in women in the general population. This was most pronounced in those women also heterozygous for Gln27Glu or Gly16Arg. [ABSTRACT FROM AUTHOR]