The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study

Kwok, Man Ki; Kawachi, Ichiro; Rehkopf, David H.; Schooling, CM

doi:10.1186/s12916-020-01831-3

Cited by 42 publications

(28 citation statements)

References 61 publications

(100 reference statements)

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“…However, in the two studies by Crawford et al, the positive estimate was found using IHD from the UK Biobank (33), but other estimates had CIs including the null using IHD from the CARDIoGRAMplusC4D (33) or the meta-analysis of the UK Biobank and CARDIoGRAMplusC4D (31), and in the other study by Pott et al, the sample was mainly patients with suspected or confirmed IHD (32), which is open to selection bias (34). Furthermore, our MR study in Westerners using more genetic variants for cortisol than those previous studies and found no association of cortisol with CVD and its risk factors (35). Replication using functionally relevant genetic variants for cortisol or conducting a meta-analysis of future MR studies on cortisol and CVD from China and elsewhere would help clarify the role of cortisol.…”

Section: Discussionmentioning

confidence: 65%

Relative Deprivation, Income Inequality, and Cardiovascular Health: Observational and Mendelian Randomization Studies in Hong Kong Chinese

Kwok

Kawachi

Rehkopf

et al. 2022

Front. Public Health

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The associations between absolute vs. relative income at the household or neighborhood level and cardiovascular disease (CVD) risk remain understudied in the Chinese context. Further, it is unclear whether stress biomarkers, such as cortisol, are on the pathway from income to CVD risk. We examined the associations of absolute and relative income with CVD risk observationally, as well as the mediating role of cortisol, and validated the role of cortisol using Mendelian Randomization (MR) in Hong Kong Chinese. Within Hong Kong's FAMILY Cohort, associations of absolute and relative income at both the individual and neighborhood levels with CVD risk [body mass index (BMI), body fat percentage, systolic blood pressure, diastolic blood pressure, self-reported CVD and self-reported diabetes] were examined using multilevel logistic or linear models (n = 17,607), the mediating role of cortisol using the mediation analysis (n = 1,562), and associations of genetically predicted cortisol with CVD risk using the multiplicative generalized method of moments (MGMMs) or two-stage least squares regression (n = 1,562). In our cross-sectional observational analysis, relative household income deprivation (per 1 SD, equivalent to USD 128 difference in Yitzhaki index) was associated with higher systolic blood pressure (0.47 mmHg, 95% CI 0.30–0.64), but lower BMI (−0.07 kg/m2, 95% CI −0.11 to −0.04), independent of absolute income. Neighborhood income inequality was generally unrelated to CVD and its risk factors, nor was absolute income at the household or neighborhood level. Cortisol did not clearly mediate the association of relative household income deprivation with systolic blood pressure. Using MR, cortisol was unrelated to CVD risk. Based on our findings, relative household income deprivation was not consistently associated with cardiovascular health in Hong Kong Chinese, nor were neighborhood income inequality and absolute income, highlighting the context-specific ways in which relative and absolute income are linked to CVD risk.

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Section: Discussionmentioning

confidence: 65%

Relative Deprivation, Income Inequality, and Cardiovascular Health: Observational and Mendelian Randomization Studies in Hong Kong Chinese

Kwok

Kawachi

Rehkopf

et al. 2022

Front. Public Health

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“…Instrumental SNPs of serotonin were retrieved from a GWAS for 486 metabolite concentrations, comprising up to 6,139 adult individuals from the Cooperative Health Research in the Region of Augsburg study and the TwinsUK cohort ( Shin et al, 2014 ). Since the lead SNP-serotonin pair, that is, the lowest association P -value (rs2742351, P = 3.23 × 10 –7 ) failed to reach the standard genome-wide significance signal, we relaxed the threshold as prior studies did ( Kwok et al, 2020 ; Ng and Schooling, 2020 ; Baumeister et al, 2021 ), and selected instrumental variants associated with serotonin at suggestive significance ( P ≤ 5 × 10 –6 ). Lotta et al (2021) performed a genome-wide meta-analysis of 174 circulating metabolites including a dozen of amino acids in 30,977 individuals from the Fenland, EPIC-Norfolk and INTERVAL studies ( Lindsay et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis

Deng

Lin

et al. 2022

Front. Aging Neurosci.

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It has been previously postulated that blood neurotransmitters might affect risks of neurodegenerative diseases. Here, a Mendelian Randomization (MR) study was conducted to explore whether genetically predicted concentrations of glycine, glutamate and serotonin were associated with risks of Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). From three genome-wide association studies of European ancestry, single nucleotide polymorphisms strongly associated with glycine, glutamate and serotonin were selected as genetic instrumental variables. Corresponding summary statistics were also obtained from the latest genome-wide association meta-analyses of AD, PD and ALS. The inverse-variance weighted MR and multiple sensitivity analyses were performed to evaluate causal effects of genetically predicted levels of neurotransmitters on risks of neurodegenerative diseases. The statistical significance threshold was set at P < 0.0056 using the Bonferroni-correction, while 0.0056 < P < 0.05 was considered suggestive evidence for a causal association. There was a causal association of elevated blood glutamate levels with higher AD risks. The odds ratio (OR) of AD was 1.311 [95% confidence interval (CI), 1.087–1.580; P = 0.004] per one standard deviation increase in genetically predicted glutamate concentrations. There was suggestive evidence in support of a protective effect of blood serotonin on AD (OR = 0.607; 95% CI, 0.396–0.932; P = 0.022). Genetically predicted glycine levels were not associated with the risk of AD (OR = 1.145; 95% CI, 0.939–1.396; P = 0.180). Besides, MR analyses indicated no causal roles of three blood neurotransmitters in PD or ALS. In conclusion, the MR study provided evidence supporting the association of elevated blood glutamate levels with higher AD risks and the association of increased blood serotonin levels with lower AD risks. Triangulating evidence across further study designs is still warranted to elucidate the role of blood neurotransmitters in risks of neurodegenerative diseases.

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“…Regarding LBP, however, there were no genome-wide significant loci identified outside the MHC locus. Therefore, we relaxed the threshold ( p < 5 × 10 –6 ), as previous studies did ( Schooling and Ng, 2019 ; Kwok et al, 2020 ; Ng and Schooling, 2020 ; Kwok and Schooling, 2021 ), to select 17 instrumental variants of LBP. For instrumental SNPs which were not present in the outcome datasets, we also searched for available proxies ( r 2 > 0.8, 1000 Genomes EUR).…”

Section: Methodsmentioning

confidence: 99%

Joint Analysis of Genome-Wide Association Data Reveals No Genetic Correlations Between Low Back Pain and Neurodegenerative Diseases

Wu¹,

Du²,

Wang³

et al. 2021

Front. Genet.

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Background: We aimed to explore the genetic correlation and bidirectional causal relationships between low back pain (LBP) and three neurodegenerative diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).Methods: Summary-level statistics were obtained from genome-wide association studies of LBP (n = 177,860), AD (n = 63,926), PD (n = 482,730), and ALS (n = 80,610). We implemented linkage disequilibrium score regression to calculate heritability estimates and genetic correlations. To investigate possible causal associations between LBP and three neurodegenerative diseases, we also conducted a bidirectional two-sample Mendelian randomization (MR) study. Inverse variance-weighted MR was employed as the primary method to generate overall estimates, whereas complementary approaches and sensitivity analyses were conducted to confirm the consistency and robustness of the findings.Results: There was no evidence of genetic correlations between LBP and AD (Rg = −0.033, p = 0.766). MR analyses did not support the causal effect of LBP on AD (OR = 1.031; 95% CI, 0.924–1.150; p = 0.590) or the effect of AD on LBP (OR = 0.963; 95% CI, 0.923–1.006; p = 0.090). Likewise, this study failed to identify genetic correlations between LBP and two other neurodegenerative diseases. MR results of the associations of LBP with PD and ALS, and the reverse associations, did not reach Bonferroni-corrected significance.Conclusion: The study did not support genetic correlations or causations between LBP and three common neurodegenerative diseases, AD, PD, and ALS in the European population.

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The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study

Cited by 42 publications

References 61 publications

Relative Deprivation, Income Inequality, and Cardiovascular Health: Observational and Mendelian Randomization Studies in Hong Kong Chinese

Relative Deprivation, Income Inequality, and Cardiovascular Health: Observational and Mendelian Randomization Studies in Hong Kong Chinese

Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis

Joint Analysis of Genome-Wide Association Data Reveals No Genetic Correlations Between Low Back Pain and Neurodegenerative Diseases

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