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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

ABSTRACT: BACKGROUND:High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS:We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS:Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION:Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING:US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

SUBMITTER: Voight BF

PROVIDER: S-EPMC3419820 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

Voight Benjamin F BF Peloso Gina M GM Orho-Melander Marju M Frikke-Schmidt Ruth R Barbalic Maja M Jensen Majken K MK Hindy George G Hólm Hilma H Ding Eric L EL Johnson Toby T Schunkert Heribert H Samani Nilesh J NJ Clarke Robert R Hopewell Jemma C JC Thompson John F JF Li Mingyao M Thorleifsson Gudmar G Newton-Cheh Christopher C Musunuru Kiran K Pirruccello James P JP Saleheen Danish D Chen Li L Stewart Alexandre F R A Schillert Arne A Thorsteinsdottir Unnur U Thorgeirsson Gudmundur G Anand Sonia S Engert James C JC Morgan Thomas T Spertus John J Stoll Monika M Berger Klaus K Martinelli Nicola N Girelli Domenico D McKeown Pascal P PP Patterson Christopher C CC Epstein Stephen E SE Devaney Joseph J Burnett Mary-Susan MS Mooser Vincent V Ripatti Samuli S Surakka Ida I Nieminen Markku S MS Sinisalo Juha J Lokki Marja-Liisa ML Perola Markus M Havulinna Aki A de Faire Ulf U Gigante Bruna B Ingelsson Erik E Zeller Tanja T Wild Philipp P de Bakker Paul I W PI Klungel Olaf H OH Maitland-van der Zee Anke-Hilse AH Peters Bas J M BJ de Boer Anthonius A Grobbee Diederick E DE Kamphuisen Pieter W PW Deneer Vera H M VH Elbers Clara C CC Onland-Moret N Charlotte NC Hofker Marten H MH Wijmenga Cisca C Verschuren W M Monique WM Boer Jolanda M A JM van der Schouw Yvonne T YT Rasheed Asif A Frossard Philippe P Demissie Serkalem S Willer Cristen C Do Ron R Ordovas Jose M JM Abecasis Gonçalo R GR Boehnke Michael M Mohlke Karen L KL Daly Mark J MJ Guiducci Candace C Burtt Noël P NP Surti Aarti A Gonzalez Elena E Purcell Shaun S Gabriel Stacey S Marrugat Jaume J Peden John J Erdmann Jeanette J Diemert Patrick P Willenborg Christina C König Inke R IR Fischer Marcus M Hengstenberg Christian C Ziegler Andreas A Buysschaert Ian I Lambrechts Diether D Van de Werf Frans F Fox Keith A KA El Mokhtari Nour Eddine NE Rubin Diana D Schrezenmeir Jürgen J Schreiber Stefan S Schäfer Arne A Danesh John J Blankenberg Stefan S Roberts Robert R McPherson Ruth R Watkins Hugh H Hall Alistair S AS Overvad Kim K Rimm Eric E Boerwinkle Eric E Tybjaerg-Hansen Anne A Cupples L Adrienne LA Reilly Muredach P MP Melander Olle O Mannucci Pier M PM Ardissino Diego D Siscovick David D Elosua Roberto R Stefansson Kari K O'Donnell Christopher J CJ Salomaa Veikko V Rader Daniel J DJ Peltonen Leena L Schwartz Stephen M SM Altshuler David D Kathiresan Sekar S

Lancet (London, England) 20120517 9841

<h4>Background</h4>High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.<h4>Methods</h4>We performed two mendelian randomisation analyses ...[more]

PMID: 22607825

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Project description:ObjectiveTo determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.DesignTwo sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.SettingReduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.Participants3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.Main outcome measuresThromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.ResultsOf the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.ConclusionsEndogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

Project description:BackgroundIncreased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.MethodsWe first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FindingsIn the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate.InterpretationConventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.FundingUK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

Project description:AimsPlasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A(1), the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear.Methods and resultsCase-control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA(1) than to HDL-C. The ratio apoB/apoA(1) was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8-9.2)] and varied little with age. The ratio apoB/apoA(1) was substantially more informative about risk (chi(1)(2) = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (chi(1)(2) = 407, 334, 204, and 105, respectively). Given apoB and apoA(1), the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA(1) and pre-onset HDL-C with risk in such retrospective case-control studies.ConclusionApolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Project description:Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results.We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits.A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels.Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.

Dataset Information

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

Publications

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

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