Genome-wide association study for incident myocardial infarction and coronary heart disease in prospective cohort studies: The CHARGE Consortium

Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders

Cardiorespiratory fitness but not physical activity are associated with pulse wave velocity and arterial stiffness in the general population

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BMBF Background Higher cardiorespiratory fitness (CRF) and physical activity (PA) are associated with lower cardiovascular morbidity and all-cause mortality. Pulse wave velocity (PWV) and augmentation index (AIx) are vascular parameters associated with aging and end-organ damage and provide reliable information about arterial stiffness. Therefore, PWV and AIx could represent attractive parameters for cardiovascular risk stratification. Purpose To improve our understanding of the relationship between CRF/PA and PWV and arterial stiffness, we associated CRF and PA with central and peripheral PWVs and AIx as outcomes using multivariable regression analysis using data from the population-based Study of Health in Pomerania (SHIP Trend 1). Methods CRF was assessed using cardiopulmonary exercise testing (CPET) on a bicycle ergometer. CRF was defined as peak oxygen uptake (VO2peak), VO2peak per kg fat free mass (VO2peak_ffm) and metabolic equivalent tasks (METs). PA was measured using the Baecke questionnaire. Aortic PWV (aoPWV), carotid-femoral PWV (cfPWV) and brachial-ankle PWV (baPWV) in m/s were determined non-invasively using the Vascular Explorer. Aortic AIx (aoAIx), aortic AIx at a heart rate of 75 bpm (aoAIx@75) and brachial-ankle AIx (brAIx) were measured using the same device. We used linear regression models adjusted for age, sex, smoking status, mean arterial pressure, antihypertensive medication, diabetic medication, HbA1c, fat mass, fat-free-mass and height. Fat-free mass was not included when VO2peak_ffm was the exposure. Fat-free mass and fat mass were not used in models with METs. Results We analysed data of 1,677 individuals which included 840 men (median age 56 years; inter-quartile range [IQR] 47 to 65) and 837 women (median age 54 years; IQR 46 to 65). A one l/min greater VO2peak was related to lower aoPWV (β - 0.22; 95% confidence interval (CI) -0.37 to -0.06, p &amp;lt; 0.01), cfPWV (β - 0.32; 95%CI -0.55 to -0.09; p &amp;lt; 0.01), baPWV (β -0.02; 95%CI -0.03 to 0.00, p &amp;lt; 0.05) and brAIx (β -3.49; 95%CI -6.95 to -0.03, p &amp;lt; 0.01). VO2peak was not related to aoAIx and aoAIx@75. VO2peak_ffm was associated with lower aoPWV (β -0.01; 95%CI -0.02 to -0.00, p &amp;lt; 0.05) and cfPWV (β -0.02; 95%CI -0.03 to -0.00, p &amp;lt; 0.05). VO2peak_ffm was not associated with baPWV, aoAIx, aoAIx@75 or brAIx. METs were positively associated with aoAIx@75 (β 0.30; 95%CI 0.02 to 0.59, p &amp;lt; 0.01). Sport and work related PA were not related to PWV or AIx. Sensitivity analysis with further adjustment for heart rate did not significantly change the results. Conclusions We found an association between CRF and central as well as peripheral PWV and AIx values in the adult general population. Interestingly, body composition had an impact on the relationship between CRF and peripheral but not central parameters. Further, PA was not related to these vascular markers which highlights the important difference between CRF and PA. </jats:sec

Sex-specific associations of ceramides with cardiopulmonary fitness in the general population

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Federal Ministry of Education &amp; Research (BMBF) Introduction According to the WHO 17.9 million people die because of cardiovascular diseases (CVD) each year, being the 3rd leading cause of death worldwide. Low cardiorespiratory fitness (CRF) is an important risk factor for CVD. Recent research showed that long-chain unsaturated ceramides are associated with higher risk of cardiovascular events, thus identifying ceramides as a potential novel and independent risk factor. However, not all ceramides are equal. We previously showed beneficial effects of very-long-chain ceramides (i.e. C24:0 and C24:0/C16:0 ratio) with higher concentrations being inversely associated with all-cause mortality and CVD events. Purpose We would like to investigate, if ceramides mediated their effects on developing CVD by affecting CRF. Therefore, we explored the association of three specific ceramides (C16:0, C22:0 and C24:0) and their ratios with different parameters of CRF. Methods We used data of the population-based Study of Health in Pomerania (SHIP-1) from North Germany (N: 1,247/men: 583, median age: 50.8 years/women: 664, median age: 50.2 years). Ceramides and CRF were assessed by LC/MS assay and symptom-limited cardiopulmonary exercise testing, respectively. VO2peak, VO2@AT, Wmax and respective indexing per kg body weight were used as outcomes. We used sex-stratified, multiple adjusted linear regression models. Participants with asthma, chronic lung disease, LVEF &amp;lt; 40% and cancer were excluded. Results In men, a 1-unit higher C24:0/C16:0 ratio was associated with higher VO2peak/kg (0.199 ml/min/kg [95% CI: 0.032, 0.365], P = 0.019), Wmax (1.368 W [0.033, 2.404], P = 0.010) and Wmax/kg (0.018 W/kg [0.007, 0.029], P = 0.002). In addition, a 1 µg/ml higher C24:0 concentration was related to greater Wmax/kg (0.054 W/kg [0.009, 0.099], P = 0.018). In women, a 1-unit greater C24:0/C16:0 ratio was associated with greater VO2peak (8.603 ml/min [0.019, 17.013], P = 0.045), VO2peak/kg (0.186 ml/min/kg [0.054, 0.319], P = 0.006), VO2@AT/kg (0.136 ml/min/kg [0.040, 0.231], P = 0.005) as well as higher Wmax/kg (0.015 W/kg [0.004, 0.026], P = 0.007). Furthermore, a 1 µg/ml higher C16:0 concentration was related to lower Wmax (-55.447 W [-101.775, -9.119], P = 0.019) and Wmax/kg (-0.736 W/kg [-1.341, -0.130], P = 0.017). Conclusions We report sex-specific associations between ceramides and CRF. In women, C24:0/C16:0 ratio was associated with more CRF parameters than in men. Furthermore, the single species C16:0 was significantly associated with lower maximal power in women only, whereas in men the single species C24:0 was significantly associated with higher maximal power. The positive association of the C24:0/C16:0 ratio with maximal CRF capacity is in agreement with previous findings of beneficial effects on the risk for CVD events and mortality. Future studies should explore the reason for different sex-specific ceramide profiles and whether ceramides are causally mediating their effects on CVD through CRF. </jats:sec