OBJECTIVES: NOD2/CARD15 is involved in the innate immune response and three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with risk of the rare Crohn's disease. We tested the hypothesis that polymorphisms in NOD2/CARD15 associate with risk of nine common gastrointestinal diseases. DESIGN AND SETTING: We genotyped 43 596 white individuals from the Danish general population followed for 31 years, during which time 782 developed oesophagitis and reflux, 1395 ulcus ventriculi and duodeni, 1384 gastritis and dyspepsia, 1407 appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. RESULTS: Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95%CI 1.4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst homozygotes appeared to be similar amongst both men and women and amongst those below or above 60 years, and likely included both upper gastrointestinal cancer and colorectal cancer. CONCLUSIONS: NOD2/CARD15 polymorphisms are not major risk factors for common gastrointestinal diseases; however, we cannot completely exclude association with appendicitis, anal fissure, fistula and abscess, and gastrointestinal cancer.
OBJECTIVES: The NOD2/CARD15 gene is involved in the innate immune response, and thus in inflammation. Three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with increased risk of the inflammatory bowel disease, the Crohn's disease. We tested whether these polymorphisms are also associated with increased risk of cardiovascular disease and cancer, in which the innate immune system and inflammation may influence pathogenesis. DESIGN, SETTING AND SUBJECTS: We genotyped 43,596 white individuals from two large Danish general population cohorts followed for 31 years: the Copenhagen City Heart Study (n = 10,597) and the Copenhagen General Population Study (n = 32,999). We examined the risk of cardiovascular disease (2743 and 3890, respectively, in the two studies) and cancer (2144 and 3241, respectively) by NOD2/CARD15 genotype using Cox and logistic regressions in both studies. To maximize statistical power, the three NOD2/CARD15 genetic variants were analysed together as follows: noncarriers for all three variants, heterozygotes for one of the three variants and homozygotes for one of the three variants pooled with compound heterozygotes for two variants. RESULTS: Multifactorially adjusted hazard ratios for cardiovascular disease and cancer in NOD2/CARD15 heterozygotes or homozygotes/compound heterozygotes versus noncarries did not differ from 1.0 in the Copenhagen City Heart Study or in the Copenhagen General Population Study. The corresponding multifactorially adjusted odds ratios likewise did not differ from 1.0 in either study. CONCLUSIONS: The NOD2/CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms were not associated with increased risk of cardiovascular disease or cancer in the Danish general population.
We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal epoxide hydrolase gene (EPHX1), T113C and A139G, may influence susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. We genotyped participants from the Copenhagen City Heart Study (n = 10,038) and the Copenhagen General Population Study (n = 37,022) for the T113C and A139G variants in the EPHX1 gene and measured lung function and recorded COPD hospitalisation and asthma and smoking history. Finally, we meta-analysed results from 19 studies including 7,489 COPD cases and 42,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p-value for trend 0.46-0.98). In meta-analysis, random effects OR for COPD in T113C heterozygotes and homozygotes versus non-carriers were 1.17 (0.99-1.38) and 1.38 (1.09-1.74), respectively. Corresponding values for A139G were 0.93 (0.83-1.05) and 0.89 (0.78-1.02). Our results indicate that genetically reduced microsomal epoxide hydrolase activity is not a major risk factor for COPD or asthma in the Danish population; however, meta-analysis cannot completely exclude a minor effect on COPD risk.
Diabetes mellitus is believed to increase susceptibility to infectious diseases. The effects of hyperglycaemia per se on infectious disease risk are unknown and the influence of diabetes on infectious disease outcome is controversial.
We studied 10,063 individuals from the Danish general population, who were participants in The Copenhagen City Heart Study, over a follow-up period of 7 years. Risk of hospitalisation caused by any infectious disease, and subsequent risk of disease progression to death were estimated by Cox proportional hazards regression analysis.
At baseline, 353 individuals reported having diabetes. During 71,509 person-years of follow-up, a total of 1,194 individuals were hospitalised because of an infection. The risk of pneumonia (adjusted hazard ratio [aHR] 1.75, 95% CI 1.23-2.48), urinary tract infection (aHR 3.03, 95% CI 2.04-4.49) and skin infection (aHR 2.43, 95% CI 1.49-3.95) was increased in subjects with diabetes compared with subjects without. Each 1 mmol/l increase in plasma glucose at baseline was associated with a 6-10% increased relative risk of pneumonia, urinary tract infection and skin infection after adjustment for other possible confounders. Among patients hospitalised for urinary tract infection, diabetic patients were at an increased risk of death at 28 days after admission compared with non-diabetic subjects (HR 3.90, 95% CI 1.20-12.66).
In the Danish general population, diabetes and hyperglycaemia are strong and independent risk factors for hospitalisation as a result of pneumonia, urinary tract infection and skin infection. Further, diabetes has a negative impact on the prognosis of urinary tract infection.
Elevated CRP and matrix metalloproteinase-9 associate with increased risk of cardiovascular events, possibly because these plasma proteins mark vulnerable atherosclerotic plaques. We tested the hypothesis that levels of C-reactive protein (CRP) and matrix metalloproteinase-9 associate with prognosis in patients with stable coronary heart disease.
We measured baseline plasma CRP and matrix metalloproteinase-9 in 1090 patients with stable coronary heart disease and as the primary composite endpoint detected incident unstable angina, myocardial infarction and any death during 15 years of follow-up. CRP above versus below the median of 3.0 mg/L was associated with an increased cumulative incidence of unstable angina, myocardial infarction and any death combined (log-rank p
Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C(4) synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction.
Resequencing the gene coding for leukotriene C(4) synthase in an extreme risk population with more than 1500 individuals revealed 17 new mutations, of which four are likely to change protein function (211G>A (minor allele frequency, 0.0001), IVS3 + 1G>A (0.002), 374G>A (0.0006) and 451_453+10del (0.0007)). Based on genotyping 50,000 individuals, age and sex adjusted odds ratios for venous thromboembolism were 2.0 (95% CI, 1.3-3.5) for IVS3+1G>A heterozygotes vs. wild type, and 1.9 (1.5-2.7) for any mutation heterozygote vs. wild type. Corresponding values were 2.0 (1.3-3.2) and 1.5 (1.1-2.1) for ischemic stroke, and 1.0 (0.8-1.3) and 1.2 (1.0-1.4) for myocardial infarction.
Four novel mutations that are likely to change the function of leukotriene C(4) synthase were associated with increased risk of venous thromboembolism and ischemic stroke. These findings need confirmation in other independent studies. In addition, the mechanism behind these findings deserves further investigation.
Active platelets are large and contribute to development of myocardial infarction (MI). Platelet size is measured automatically as mean platelet volume (MPV) together with platelet count.
We tested the hypothesis that increased MPV is associated with risk of MI in the general population independent of known cardiovascular risk factors.
We examined 39,531 men and woman from the Danish general population (the Copenhagen General Population Study), of whom 1300 developed MI.
After multifactorial adjustment for known cardiovascular risk factors, risk of MI was increased by 37% (95% CI, 18-59%) in the middle and 30% (12-52%) in the upper vs. the lower tertile of MPV. Compared with the 1st quintile of MPV, there was corresponding increased risk of MI of 13% (-7% to 39%), 35% (11-64%), 31% (8-59%) and 29% (6-57%) in the 2nd, 3rd, 4th and 5th quintile, respectively. Similar values for octiles were increases in MI risk of -3% (-25% to 26%), 15% (-10% to 46%), 31% (1- 69%), 32% (5-68%), 31% (2-67%), 27% (-1% to 62%) and 26% (-1% to 61%), respectively, in the 2nd through to the 8th octile vs. the 1st octile of MPV. Use of antiplatelet therapy did not modify these risk estimates. Finally, in prospective, multifactorially adjusted analyses, risk of MI increased by 38% (8-75%) in individuals with MPV = 7.4 vs.
Cytochrome P450 2C9 (CYP2C9) enzymes metabolize warfarin and arachidonic acid. We hypothesized that the CYP2C9(*)2 (rs.1799853) and CYP2C9(*)3 (rs.1057910) polymorphisms with decreased enzyme activity affect risk of subclinical atherosclerosis (reduced ankle brachial index and increased C-reactive protein), ischemic vascular diseases (ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease and ischemic stroke) and death after an ischemic heart disease diagnosis. We genotyped the Copenhagen City Heart Study, a prospective study including 10 398 participants with 30-32 years of follow-up; the Copenhagen General Population Study, a cross-sectional study including 21 629 participants; and the Copenhagen Ischemic Heart Disease Study, a case-control study including 5082 cases and 14 904 controls. CYP2C9 carriers versus noncarriers did not associate with subclinical atherosclerosis. Furthermore, the odds/hazard ratios for ischemic vascular disease did not differ from 1.0 for CYP2C9 carriers versus noncarriers. Finally, we found no altered risk of early death after a diagnosis of ischemic heart disease. For all end points, we could exclude even minor changes in risk of disease with 90% power. In conclusion, in three independent studies totaling more than 52 000 individuals, we found no association between CYP2C9(*)2 and CYP2C9(*)3 polymorphisms and risk of subclinical atherosclerosis, ischemic vascular disease or death after ischemic heart disease.
We hypothesized that common breast cancer risk alleles are associated with incidences of breast cancer and other cancers in the general population, and identify low risk women among those invited for screening mammography.
About 35 441 individuals from the Danish general population were followed in Danish health registries for up to 21 years after blood sampling. After genotyping 72 breast cancer risk loci, each with 0–2 alleles, the sum for each individual was calculated. We used the simple allele sum instead of the conventional polygenic risk score, as it is likely more sensitive in detecting associations with risks of other endpoints than breast cancer.
Breast cancer incidence in the 19 010 women was increased across allele sum quintiles (log-rank trend test; P?=?1×10?-?12), but not incidence of other cancers (P?=?0.41). Age- and study-adjusted hazard ratio for the fifth versus the first allele sum quintile was 1.82 (95% confidence interval; 1.53–2.18). Corresponding hazard ratios per allele were 1.04 (1.03–1.05) and 1.05 (1.02–1.08) for breast cancer incidence and mortality, similar across risk factors. In 50-year-old women, the starting age for screening mammography in Denmark, the average 5-year breast cancer risk was 1.5%, overall and 1.1%, 1.4%, 1.6%, 1.7%, 2.1%, for the first through fifth quintile, respectively. Based on age, nulliparity, familial history, and allele sum, 25% of women aged 50–69 years, and 94% of women aged 40–49 years, had absolute 5-year breast cancer risks?=?1.5%. Using polygenic risk score led to similar results.
Common breast cancer risk alleles are associated with incidence and mortality of breast cancer in the general population, but not with other cancers. After including breast cancer allele sum in risk assessment, 25% of women currently being offered screening mammography had an absolute 5-year risk below the cutoff of average risk for a 50-year-old woman.