Audrey H.H. Merry

Body Mass Index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study

Background: In the last decades, the incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly in the Western world. We investigated the association between body mass index (BMI), height and risk of oesophageal and gastric cardia adenocarcinoma. Methods: The Netherlands Cohort Study was initiated in 1986. All participants (n = 120 852), aged 55–69 years, completed a self administered questionnaire. Cases were identified through annual record linkage with the Netherlands Cancer Registry. After 13.3 years of follow-up, excluding the first follow-up year, complete data from 4552 subcohort members, 133 oesophageal and 163 gastric cardia adenocarcinomas were available for case-cohort analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals were estimated using Cox proportional hazard models. Results: The RRs (95% CI) of oesophageal adenocarcinoma were 1.40 (0.95 to 2.04) and 3.96 (2.27 to 6.88) for overweight (BMI 25.0–29.9 kg/m2) and obese subjects (BMI ⩾30.0 kg/m2), respectively, compared to subjects with normal weight (BMI 20.0–24.9 kg/m2). For gastric cardia adenocarcinoma, these RRs were 1.32 (0.94 to 1.85) and 2.73 (1.56 to 4.79). Also change in BMI during adulthood was positively associated with the risk of oesophageal and gastric cardia adenocarcinoma (p trend 0.001 and 0.02, respectively), while no association was found with BMI in early adulthood (p trend 0.17 and 0.17, respectively). None of the tumour types investigated was significantly associated with height. Conclusions: These results confirm higher risks of oesophageal and gastric cardia adenocarcinoma with increasing BMI. This implies that the increasing prevalence of obesity may be one of the explanations for the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world.

Validity of coronary heart diseases and heart failure based on hospital discharge and mortality data in the Netherlands using the cardiovascular registry Maastricht cohort study

Incidence rates of cardiovascular diseases are often estimated by linkage to hospital discharge and mortality registries. The validity depends on the quality of the registries and the linkage. Therefore, we validated incidence rates of coronary heart disease (CHD), acute myocardial infarction, unstable angina pectoris, and heart failure, estimated by this method, against the disease registry of the cardiovascular registry Maastricht cohort study. The cohort consists of 21,148 persons, born between 1927 and 1977, who were randomly sampled from Maastricht and surrounding communities in 1987–1997. Incident cases were identified by linkage to the Netherlands causes of death registry and either the hospital discharge registry (HDR) or the cardiology information system (CIS) of the University Hospital Maastricht. Sensitivities and positive predictive values were calculated using the CIS-based registry as gold standard. Relatively high sensitivities and positive predictive values were found for CHD (72 and 91%, respectively) and acute myocardial infarction (84 and 97%, respectively). These values were considerably lower for unstable angina pectoris (53 and 78%, respectively) and heart failure (43 and 80%, respectively). A substantial number of cases (14–47%) were found only in the CIS-based registry, because they were missed or miscoded in the HDR-based registry. As a consequence, the incidence rates in the HDR-based registry were considerably lower than in the CIS-based registry, especially for unstable angina pectoris and heart failure. Incidence rates based on hospital discharge and mortality data may underestimate the true incidence rates, especially for unstable angina pectoris and heart failure.

Literature-based genetic risk scores for coronary heart disease: the Cardiovascular Registry Maastricht (CAREMA) prospective cohort study.

Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% (P=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% ( P =0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.

Markers of Endogenous Desaturase Activity and Risk of Coronary Heart Disease in the CAREMA Cohort Study

Background Intakes of n-3 polyunsaturated fatty acids (PUFAs), especially EPA (C20∶5n-3) and DHA (C22∶6n-3), are known to prevent fatal coronary heart disease (CHD). The effects of n-6 PUFAs including arachidonic acid (C20∶4n-6), however, remain unclear. δ-5 and δ-6 desaturases are rate-limiting enzymes for synthesizing long-chain n-3 and n-6 PUFAs. C20∶4n-6 to C20∶3n-6 and C18∶3n-6 to C18∶2n-6 ratios are markers of endogenous δ-5 and δ-6 desaturase activities, but have never been studied in relation to incident CHD. Therefore, the aim of this study was to investigate the relation between these ratios as well as genotypes of FADS1 rs174547 and CHD incidence. Methods We applied a case-cohort design within the CAREMA cohort, a large prospective study among the general Dutch population followed up for a median of 12.1 years. Fatty acid profile in plasma cholesteryl esters and FADS1 genotype at baseline were measured in a random subcohort (n = 1323) and incident CHD cases (n = 537). Main outcome measures were hazard ratios (HRs) of incident CHD adjusted for major CHD risk factors. Results The AA genotype of rs174547 was associated with increased plasma levels of C204n-6, C20∶5n-3 and C22∶6n-3 and increased δ-5 and δ-6 desaturase activities, but not with CHD risk. In multivariable adjusted models, high baseline δ-5 desaturase activity was associated with reduced CHD risk (P for trend = 0.02), especially among those carrying the high desaturase activity genotype (AA): HR (95% CI) = 0.35 (0.15–0.81) for comparing the extreme quintiles. High plasma DHA levels were also associated with reduced CHD risk. Conclusion In this prospective cohort study, we observed a reduced CHD risk with an increased C20∶4n-6 to C20∶3n-6 ratio, suggesting that δ-5 desaturase activity plays a role in CHD etiology. This should be investigated further in other independent studies.

A metabolomic profile is associated with the risk of incident coronary heart disease

BACKGROUND Metabolomics, defined as the comprehensive identification and quantification of low-molecular-weight metabolites to be found in a biological sample, has been put forward as a potential tool for classifying individuals according to their risk of coronary heart disease (CHD). Here, we investigated whether a single-point blood measurement of the metabolome is associated with and predictive for the risk of CHD. METHODS AND RESULTS We obtained proton nuclear magnetic resonance spectra in 79 cases who developed CHD during follow-up (median 8.1 years) and in 565 randomly selected individuals. In these spectra, 100 signals representing 36 metabolites were identified. Applying least absolute shrinkage and selection operator regression, we defined a weighted metabolite score consisting of 13 proton nuclear magnetic resonance signals that optimally predicted CHD. This metabolite score, including signals representing a lipid fraction, glucose, valine, ornithine, glutamate, creatinine, glycoproteins, citrate, and 1.5-anhydrosorbitol, was associated with the incidence of CHD independent of traditional risk factors (TRFs) (hazard ratio 1.50, 95% CI 1.12-2.01). Predictive performance of this metabolite score on its own was moderate (C-index 0.75, 95% CI 0.70-0.80), but after adding age and sex, the C-index was only modestly lower than that of TRFs (C-index 0.81, 95% CI 0.77-0.85 and C-index 0.82, 95% CI 0.78-0.87, respectively). The metabolite score was also associated with prevalent CHD independent of TRFs (odds ratio 1.59, 95% CI 1.19-2.13). CONCLUSION A metabolite score derived from a single-point metabolome measurement is associated with CHD, and metabolomics may be a promising tool for refining and improving the prediction of CHD.

Smoking, alcohol consumption, physical activity, and family history and the risks of acute myocardial infarction and unstable angina pectoris: a prospective cohort study

BackgroundFew studies investigated the association between smoking, alcohol consumption, or physical activity and the risk of unstable angina pectoris (UAP), while the strength of these associations may differ compared to other coronary diseases such as acute myocardial infarction (AMI). Therefore, we investigated whether the associations of these lifestyle factors with UAP differed from those with AMI. Additionally, we investigated whether these effects differed between subjects with and without a family history of myocardial infarction (MI).MethodsThe CAREMA study consists of 21,148 persons, aged 20-59 years at baseline and randomly sampled from the Maastricht region in 1987-1997. At baseline, all participants completed a self-administered questionnaire. After follow-up of maximally 16.9 years, 420 AMI and 274 UAP incident cases were registered. Incidence rate ratios (RRs) were estimated using Cox proportional hazards models.ResultsFor both diseases, smoking increased the risk while alcohol consumption was associated with a protective effect. Associations with both risk factors were stronger for AMI than UAP, although this difference was only statistically significant for smoking. In men, an inverse association was found with physical activity during leisure time which seemed to be stronger for the risk of UAP than of AMI. On the contrary, physical activity during leisure time was associated with an increased risk of both AMI and UAP in women which seemed to be weaker for UAP than for AMI. Except for occupational physical activity in women, no significant interactions on a multiplicative scale were found between the lifestyle factors and family history of MI. Nevertheless, the highest risks were found in subjects with both a positive family history and the most unfavorable level of the lifestyle factors.ConclusionsThe strength of the associations with the lifestyle factors did not differ between AMI and UAP, except for smoking. Furthermore, the effects of the lifestyle factors on the risk of both coronary diseases were similar for subjects with and without a positive family history.

Risk prediction of incident coronary heart disease in The Netherlands: re-estimation and improvement of the SCORE risk function.

Aims: To re-estimate the SCORE risk function using individual data on risk factors and coronary heart disease (CHD) incidence from the Dutch Cardiovascular Registry Maastricht (CAREMA) population-based cohort study; to evaluate changes that may improve risk prediction after re-estimation; and to compare the performance of the resulting CAREMA risk function with that of existing risk scores. Methods and results: The cohort consisted of 21,148 participants, born in 1927–1977 and randomly sampled from the Maastricht region in 1987–1997. After follow-up (median 10.9 years), 783 incident CHD cases occurred. Model performance was assessed by discrimination and calibration. The additional value of including other risk factors or current risk factors in a different manner was evaluated using the net reclassification index (NRI). The c statistic of the re-estimated SCORE model was 0.799 (95% CI 0.782–0.816). Separating the total/high-density lipoprotein (HDL) cholesterol ratio into total and HDL cholesterol levels did not improve the c statistic (p = 0.22), but reclassified 6.0% of the participants into a more appropriate risk category (p < 0.001) compared with the re-estimated model. The resulting CAREMA function reclassified 28% of the participants into a more appropriate risk category than the Framingham score. Compared with the SCORE functions for high- and low-risk regions, the NRIs were 28% and 35%, respectively, which can largely be explained by the difference in outcome definition (CHD incidence vs. CHD mortality). Conclusion: In this Dutch population, a re-estimated SCORE function with total and HDL cholesterol levels instead of the cholesterol ratio can be used for the risk prediction of CHD incidence.

Literature-Based Genetic Risk Scores for Coronary Heart Disease; The CAREMA Prospective-Cohort Study

Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% (P=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% ( P =0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.

Co-occurrence of metabolic factors and the risk of coronary heart disease: a prospective cohort study in the Netherlands.

BACKGROUND Prevalence of metabolic factors such as diabetes, hypertension, obesity, HDL and total cholesterol that are associated with an increased risk of coronary heart disease (CHD) is increasing worldwide. However, less is known about combinations of these factors that are associated with the highest CHD risk. Therefore, the associations between combinations of these metabolic factors and the incidence of CHD, acute myocardial infarction (AMI), and unstable angina pectoris (UAP) were studied in the Cardiovascular Registry Maastricht (CAREMA) cohort study. METHODS The CAREMA study consists of 21,148 participants, born in 1927-1977 and randomly sampled from Maastricht and surrounding communities in 1987-1997. At baseline, all participants completed a self-administered questionnaire. Height, weight, blood pressure, total and HDL cholesterol levels were measured during a physical examination. After follow-up of maximally 16.9 years, 780 CHD, 437 AMI, and 286 UAP cases of first occurrence were registered. Incidence rate ratios (RRs) were estimated using Cox proportional hazards models adjusted for age, sex, smoking, and alcohol consumption. RESULTS Compared with subjects without any of the metabolic factors, the RRs of CHD were 2.37, 4.34, and 7.36 for subjects with 1, 2, or ≥ 3 metabolic factors, respectively. These RRs were higher for AMI but lower for UAP. Especially combinations of metabolic factors that included diabetes or both a low HDL (≤ 0.9 mmol/L in men; ≤ 1.0 mmol/L in women) and high total cholesterol (≥ 6.21 mmol/L) were associated with increased risks. CONCLUSION The risk of total CHD, AMI, and UAP varies considerably between different combinations of metabolic factors.

Literature-Based Genetic Risk Scores for Coronary Heart DiseaseClinical Perspective: The Cardiovascular Registry Maastricht (CAREMA) Prospective Cohort Study

Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% (P=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.Background— Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. Methods and Results— Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% ( P =0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS. Conclusions— A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.