IGF-1 and cardiometabolic diseases: a Mendelian randomisation study.
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ABSTRACT:
SUBMITTER: Larsson SC
PROVIDER: S-EPMC7406523 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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IGF-1 and cardiometabolic diseases: a Mendelian randomisation study.
Larsson Susanna C SC Michaëlsson Karl K Burgess Stephen S
Diabetologia 20200616 9
<h4>Aims/hypothesis</h4>Abnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases.<h4>Methods</h4>Serum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 indi ...[more]
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Project description:AIMS/HYPOTHESIS:Observational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa. METHODS:We extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p?<?5?×?10-8). The random-effects inverse-variance weighted method was used for the main analyses. RESULTS:Genetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p?=?6?×?10-4) and 1.16 (95% CI 1.05, 1.29; p?=?0.0047) per one-unit increase in loge odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p?=?0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses. CONCLUSIONS/INTERPRETATION:The present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study. DATA AVAILABILITY:All data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/10283/3203; DIAGRAM: http://diagram-consortium.org/downloads.html; CARDIoGRAMplusCD4: www.cardiogramplusc4d.org/; HERMES: http://www.kp4cd.org/datasets/mi). Graphical abstract.
| S-EPMC7286869 | biostudies-literature
Project description:Recent advances in data analysis methods based on principles of Mendelian Randomisation, such as Egger regression and the weighted median estimator, add to the researcher's ability to infer cause-effect links from observational data. Now is the time to gauge the potential of these methods within specific areas of biomedical research. In this paper, we choose a study in metabolomics as an illustrative testbed. We apply Mendelian Randomisation methods in the analysis of data from the DILGOM (Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome) study, in the context of an effort to identify molecular pathways of cardiovascular disease. In particular, our illustrative analysis addresses the question whether body mass, as measured by body mass index (BMI), exerts a causal effect on the concentrations of a collection of 137 cardiometabolic markers with different degrees of atherogenic power, such as the (highly atherogenic) lipoprotein metabolites with very low density (VLDLs) and the (protective) high density lipoprotein metabolites.We found strongest evidence of a positive BMI effect (that is, evidence that an increase in BMI causes an increase in the metabolite concentration) on those metabolites known to represent strong risk factors for coronary artery disease, such as the VLDLs, and evidence of a negative effect on protective biomarkers.The methods discussed represent a useful scientific tool, although they assume the validity of conditions that are (at best) only partially verifiable. This paper provides a rigorous account of such conditions. The results of our analysis provide a proof-of-concept illustration of the potential usefulness of Mendelian Randomisation in genomic biobank studies aiming to dissect the molecular causes of disease, and to identify candidate pharmacological targets.
| S-EPMC6069804 | biostudies-other
Project description:BackgroundEarlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.Methods and findingsOne-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with -1.38 kg/m2 of BMI at age 18 y (or -0.34 SD units, 95% CI -0.46, -0.23; P = 9.77 × 10-09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI -0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or -0.39 SDs, 95% CI -0.50, -0.29; P = 6.28 × 10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26 y, 95% CI -0.37, -0.16; P = 1.16 × 10-06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI -0.21, -0.12; P = 4.00 × 10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10-15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.ConclusionsOur results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
| S-EPMC6112630 | biostudies-literature
Project description:OBJECTIVES:To investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and cardiometabolic health is causal. DESIGN:Two sample, bidirectional mendelian randomisation study. SETTING:Genetic data taken from various cohorts comprised of the general population (mostly individuals of European ancestry, plus a small proportion of other ancestries); follow-up analysis included individuals from the United Kingdom. PARTICIPANTS:Summary data were used from previous genome wide association studies (number of participants ranging from 83?198 to 339?224), which investigated traits related to cardiovascular or metabolic health, had the largest sample sizes, and consisted of the most similar populations while minimising sample overlap. A follow-up analysis included 337?112 individuals from the UK Biobank (54% female (n=181?363), mean age 56.87 years (standard deviation 8.00) at recruitment). MAIN OUTCOME MEASURES:Subjective wellbeing and 11 measures of cardiometabolic health (coronary artery disease; myocardial infarction; total, high density lipoprotein, and low density lipoprotein cholesterol; diastolic and systolic blood pressure; body fat; waist to hip ratio; waist circumference; and body mass index). RESULTS:Evidence of a causal effect of body mass index on subjective wellbeing was seen; each 1 kg/m2 increase in body mass index caused a -0.045 (95% confidence interval -0.084 to -0.006, P=0.02) standard deviation reduction in subjective wellbeing. Follow-up analysis of this association in an independent sample from the UK Biobank provided strong evidence of an effect of body mass index on satisfaction with health (?=-0.035 unit decrease in health satisfaction (95% confidence interval -0.043 to -0.027) per standard deviation increase in body mass index, P<0.001). No clear evidence of a causal effect was seen between subjective wellbeing and the other cardiometabolic health measures, in either direction. CONCLUSIONS:These results suggest that a higher body mass index is associated with a lower subjective wellbeing. A follow-up analysis confirmed this finding, suggesting that the effect in middle aged people could be driven by satisfaction with health. Body mass index is a modifiable determinant, and therefore, this study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher body mass index on subjective wellbeing.
| S-EPMC6155050 | biostudies-literature
Project description:The present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.
| S-EPMC8076146 | biostudies-literature
Project description:Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes ?5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma ?-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma ?-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.
| S-EPMC6950527 | biostudies-literature
Project description:OBJECTIVES:To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN:Mendelian randomisation study. SETTING:UK Biobank and international genome-wide association study data. PARTICIPANTS:Predominantly participants of European ancestry. EXPOSURE:Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE:The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS:Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS:BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.
| S-EPMC6529852 | biostudies-other
Project description:BackgroundTo investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation.MethodsWe created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants).FindingsFor each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 × 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1.7%; p = 3.5 × 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 × 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 × 10(-10)). Per-allele odds ratios were 0.97 (0.95-0.99; p = 9.9 × 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 × 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk.InterpretationHuman genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.
| S-EPMC4648058 | biostudies-literature
Project description:Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.
| S-EPMC5594424 | biostudies-literature
Project description:BackgroundAlthough epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.ObjectivesThrough a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF).MethodsThis study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls.ResultsSerum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations.ConclusionsEvidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.
| S-EPMC5503188 | biostudies-literature