S. M. Boekholdt

Triglyceride-mediated pathways and coronary disease: Collaborative analysis of 101 studies

Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the −1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2·79 million person-years at risk). We analysed −1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of −1131T>C was 8% (95% CI 7–9). −1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3·5% [95% CI 2·6–4·6]; 0·053 mmol/L [0·039–0·068]), lower apolipoprotein AI (1·3% [0·3–2·3]; 0·023 g/L [0·005–0·041]), and higher apolipoprotein B (3·2% [1·3–5·1]; 0·027 g/L [0·011–0·043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16·0% (95% CI 12·9–18·7), or 0·25 mmol/L (0·20–0·29), higher (p=4·4×10−24). The odds ratio for coronary heart disease was 1·18 (95% CI 1·11–1·26; p=2·6×10−7) per C allele, which was concordant with the hazard ratio of 1·10 (95% CI 1·08–1·12) per 16% higher triglyceride concentration recorded in prospective studies. −1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12·2 nmol/L [95% CI 7·7–16·7]; p=9·3×10−8) and smaller HDL particle size (0·14 nm [0·08–0·20]; p=7·0×10−5), factors that could mediate the effects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.

Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the −1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2·79 million person-years at risk). We analysed −1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of −1131T>C was 8% (95% CI 7–9). −1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3·5% [95% CI 2·6–4·6]; 0·053 mmol/L [0·039–0·068]), lower apolipoprotein AI (1·3% [0·3–2·3]; 0·023 g/L [0·005–0·041]), and higher apolipoprotein B (3·2% [1·3–5·1]; 0·027 g/L [0·011–0·043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16·0% (95% CI 12·9–18·7), or 0·25 mmol/L (0·20–0·29), higher (p=4·4×10−24). The odds ratio for coronary heart disease was 1·18 (95% CI 1·11–1·26; p=2·6×10−7) per C allele, which was concordant with the hazard ratio of 1·10 (95% CI 1·08–1·12) per 16% higher triglyceride concentration recorded in prospective studies. −1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12·2 nmol/L [95% CI 7·7–16·7]; p=9·3×10−8) and smaller HDL particle size (0·14 nm [0·08–0·20]; p=7·0×10−5), factors that could mediate the effects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.

Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study

Levels of IgG and IgM autoantibodies (AA) to malondialdehyde (MDA)-LDL and apoB-immune complexes (ICs) were measured in 748 cases and 1,723 controls in the EPIC-Norfolk cohort and their association to coronary artery disease (CAD) events determined. We evaluated whether AA and IC modify CAD risk associated with secretory phospholipase A2 (sPLA2) type IIA mass and activity, lipoprotein-associated PLA2 activity, lipoprotein (a) [Lp(a)], oxidized phospholipids on apoB-100 (OxPL/apoB), myeloperoxidase, and high sensitivity C-reactive protein. IgG ICs were higher in cases versus controls (P = 0.02). Elevated levels of IgM AA and IC were inversely associated with Framingham Risk Score and number of metabolic syndrome criteria (p range 0.02–0.001). In regression analyses adjusted for age, smoking, diabetes, LDL-cholesterol, HDL-cholesterol, and systolic blood pressure, the highest tertiles of IgG and IgM AA and IC were not associated with higher risk of CAD events compared with the lowest tertiles. However, elevated levels of IgM IC reduced the risk of Lp(a) (P = 0.006) and elevated IgG MDA-LDL potentiated the risk of sPLA2 mass (P = 0.018). This epidemiological cohort of initially healthy subjects shows that IgG and IgM AA and IC are not independent predictors of CAD events but may modify CAD risk associated with elevated levels of oxidative biomarkers.

Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study

Objective The value of a family history for coronary heart disease (CHD) in addition to established cardiovascular risk factors in predicting an individuals risk of CHD is unclear. In the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, the authors tested whether adding family history of premature CHD in first-degree relatives improves risk prediction compared with the Framingham risk score (FRS) alone. Methods and results This study comprised 10 288 men and 12 553 women aged 40–79 years participating in the EPIC-Norfolk cohort who were followed for a mean of 10.9±2.1 years (mean±SD). The authors computed the FRS as well as a modified score taking into account family history of premature CHD. A family history of CHD was indeed associated with an increased risk of future CHD, independent of established risk factors (FRS-adjusted HR of 1.74 (95% CI 1.56 to 1.95) for family history of premature CHD). However, adding family history of CHD to the FRS resulted in a negative net reclassification of 2%. In the subgroup of individuals estimated to be at intermediate risk, family history of premature CHD resulted in an increase in net reclassification of 2%. The sensitivity increased with 0.4%, and the specificity decreased 0.8%. Conclusion Although family history of CHD was an independent risk factor of future CHD, its use did not improve classification of individuals into clinically relevant risk categories based on the FRS. Among study participants at intermediate risk of CHD, adding family history of premature CHD resulted in, at best, a modest improvement in reclassification of individuals into a more accurate risk category.

Plasma levels of lecithin:cholesterol acyltransferase and risk of future coronary artery disease in apparently healthy men and women: a prospective case-control analysis nested in the EPIC-Norfolk population study

LCAT plays a key role in the maturation of HDL, as evidenced by low HDL-cholesterol levels in carriers of deleterious mutations in LCAT. However, the role of LCAT in atherosclerosis is unclear. We set out to study this in a prospective study. Plasma LCAT levels, which strongly correlate with LCAT activity, were measured in baseline nonfasting samples of 933 apparently healthy men and women who developed coronary artery disease (CAD) and 1,852 matched controls who remained free of CAD during 6 year follow-up. LCAT levels did not differ between cases and controls but were higher in women than men. Stratification into LCAT quartiles revealed a positive association with plasma LDL-cholesterol and triglyceride levels in the unexpected absence of an association with HDL-cholesterol. In mixed-gender analyses, the odds ratio (OR) for future CAD in the highest LCAT quartile versus the lowest was 1.00 [confidence interval (CI): 0.76–1.29, P for linearity = 0.902], although opposite trends were observed in men and women. In fact, high LCAT levels were associated with an increased CAD risk in women (unadjusted OR 1.45, CI: 0.94–2.22, P for linearity = 0.036). In contrast to our studies in carriers of LCAT mutations, the current data show that low LCAT plasma levels are not associated with increased atherosclerosis in the general population.

Impact of abdominal obesity and systemic hypertension on risk of coronary heart disease in men and women: the EPIC-Norfolk Population Study.

Background: The objective of our study was to determine the respective contributions of waist circumference and systemic hypertension (HTN) to coronary heart disease (CHD) risk in a large population-based cohort representative of a contemporary European population. Methods and results: A total of 9580 men and 12 250 women aged 45–79 years were followed for 11.4 years. Over the follow-up, 2191 CHD events were recorded. After adjusting for traditional CHD risk factors, individuals with high blood pressure (BP) and high waist circumference were at an increased CHD risk [hazard ratio 3.04; 95% confidence interval (CI) 2.06–4.48 and 2.90 (1.85–4.55) in men and women, respectively], compared with individuals with both low waist circumference and BP. Among individuals with normal BP, those in the top waist circumference tertile were at an increased CHD risk compared with those in the bottom waist circumference tertile (hazard ratio 2.66; 95% CI 1.59–4.45 and 2.11; 95% CI 1.12–3.97 in men and women, respectively). Within each physical activity category, a linear positive association was observed between waist circumference tertiles and both SBP (P for trend <0.001) and DBP (P for trend <0.001). Within each waist circumference tertile, inactive individuals had higher SBP than active individuals (P for trend <0.001). Conclusion: Our results show that abdominal obesity (measured by waist circumference) and HTN had both independent and additive contributions to CHD risk. We also found that physical inactivity and abdominal obesity contribute to elevated BP in primary prevention settings.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women.

Background We aimed to examine the association between chocolate intake and the risk of incident heart failure in a UK general population. We conducted a systematic review and meta-analysis to quantify this association. Methods and results We used data from a prospective population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Chocolate intake was quantified based on a food frequency questionnaire obtained at baseline (1993–1997) and incident heart failure was ascertained up to March 2009. We supplemented the primary data with a systematic review and meta-analysis of studies which evaluated risk of incident heart failure with chocolate consumption. A total of 20,922 participants (53% women; mean age 58 ± 9 years) were included of whom 1101 developed heart failure during the follow up (mean 12.5 ± 2.7 years, total person years 262,291 years). After adjusting for lifestyle and dietary factors, we found 19% relative reduction in heart failure incidence in the top (up to 100 g/d) compared to the bottom quintile of chocolate consumption (HR 0.81 95%CI 0.66–0.98) but the results were no longer significant after controlling for comorbidities (HR 0.87 95%CI 0.71–1.06). Additional adjustment for potential mediators did not attenuate the results further. We identified five relevant studies including the current study (N = 75,408). The pooled results showed non-significant 19% relative risk reduction of heart failure incidence with higher chocolate consumption (HR 0.81 95%CI 0.66–1.01). Conclusions Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure.