Commentary: Does mortality from smoking have implications for future Mendelian randomization studies?
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ABSTRACT:
SUBMITTER: Taylor AE
PROVIDER: S-EPMC4190520 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Evidence from clinical and epidemiological studies indicates that asthma is associated with allergic diseases including hay fever, allergic rhinitis, and eczema. Genetic analysis demonstrated that asthma had a positive genetic correlation with allergic diseases. A Mendelian randomization (MR) analysis using the rs16969968 single-nucleotide variant as the instrumental variable indicated that smoking was associated with increased risk of asthma. However, in a different MR analysis, smoking was significantly associated with reduced hay fever and reduced allergic sensitization risk. These findings revealed inconsistencies in the association of smoking with asthma and allergic diseases. Hence, we conducted an updated MR analysis to investigate the causal association between lifetime smoking and asthma risk by using 124 genetic variants as the instrumental variables. No significant pleiotropy was detected using the MR-Egger intercept test. We found that increased lifetime smoking was significantly associated with decreased asthma risk by using the inverse variance weighted (IVW) method (OR = 0.97, 95% CI 0.956-0.986, and P = 1.77E-04), the weighted median regression method (OR = 0.976, 95% CI 0.96-0.994, and P = 8.00E-03), and the MR-Egger method (OR = 0.919, 95% CI 0.847-0.998, and P = 4.5E-02). Importantly, MR pleiotropy residual sum and outlier (MR-PRESSO) MR analysis also indicated a significant association between increased lifetime smoking and decreased asthma risk with OR = 0.971, 95% CI 0.956-0.986, and P = 2.69E-04. After the outlier was removed, MR-PRESSO outlier test further supported the significant association with OR = 0.971, 95% CI 0.959-0.984, P = 1.57E-05.
| S-EPMC7438748 | biostudies-literature
Project description: Not available
| S-EPMC5841830 | biostudies-literature
Project description:Background: Tobacco smoking and alcohol consumption have been associated with frailty in observational studies. We sought to examine whether these associations reflect causality using the two-sample Mendelian randomization (MR) design. Methods: We used summary genome-wide association statistics for smoking initiation (N = 2,669,029), alcohol consumption (N = 2,428,851), and the frailty index (FI, N = 175,226) in participants of European ancestry. Both univariable and multivariable MR were performed to comprehensively evaluate the independent effects of smoking and alcohol consumption on the FI, accompanied by multiple sensitivity analyses. Results were verified using lifetime smoking and alcohol use disorder. Reverse direction MR was undertaken to assess the potential for reverse causation. Results: Genetic predisposition to smoking initiation was significantly associated with increased FI (univariable MR: β = 0.345; 95% confidence interval [CI] = 0.316 to 0.374; p = 1.36E-113; multivariable MR: β = 0.219; 95% CI = 0.197 to 0.241; p = 2.44E-83). Genetically predicted alcohol consumption showed a suggestive association with the FI (univariable MR: β = −0.090; 95% CI = −0.151 to −0.029; p = 0.003; multivariable MR β = −0.153; 95% CI = −0.212 to −0.094; p = 2.03E-07), with inconsistent results in sensitivity analyses. In complementary analysis, genetic predicted lifetime smoking, but not alcohol use disorder was associated with the FI. There is no convincing evidence for reverse causation. Conclusion: The present MR study supported smoking as a causal risk factor of frailty. Further research is warranted to investigate whether alcohol consumption has a causal role in frailty.
| S-EPMC9935614 | biostudies-literature
Project description:BackgroundStriking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS.MethodsWe use genetic variants from the largest genome-wide association study for smoking phenotypes (initiation: N = 378, heaviness: N = 55, lifetime smoking: N = 126) and body mass index (BMI, N = 656) and apply these as instrumental variables in a two-sample MR analysis to the most recent meta-analysis for MS. We adjust for the genetic correlation between smoking and BMI in a multivariable MR.ResultsIn univariable and multivariable MR, smoking does not have an effect on MS risk nor explains part of the association between BMI and MS risk. In contrast, in both analyses each standard deviation increase in BMI, corresponding to roughly 5 kg/m2 units, confers a 30% increase in MS risk.ConclusionDespite observational studies repeatedly reporting an association between smoking and increased risk for MS, MR analyses on smoking phenotypes and MS risk could not confirm a causal relationship. This is in contrast with BMI, where observational studies and MR agree on a causal contribution. The reasons for the discrepancy between observational studies and our MR study concerning smoking and MS require further investigation.
| S-EPMC7501136 | biostudies-literature
Project description:BackgroundThe association between cigarette smoking and thyroid cancer has been reported in prospective cohort studies, but the relationship remains controversial. To investigate this potential correlation further, we employed Mendelian randomization methodology to evaluate the causative impact of smoking on thyroid cancer incidence.MethodsFrom the genome-wide association study and Sequencing Consortium of Alcohol and Nicotine use, we obtained genetic variants associated with smoking initiation and cigarettes per day (1.2 million individuals). We also extracted genetic variants associated with past tobacco smoking from the UK Biobank (424,960 individuals). Thyroid cancer outcomes were selected from the FinnGen GWAS (989 thyroid cancer cases and 217,803 control cases). Sensitivity analyses employing various approaches such as weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) have been executed, as well as leave-one-out analysis to identify pleiotropy.ResultsUsing the IVW approach, we did not find evidence that any of the three smoking phenotypes were related to thyroid cancer (smoking initiation: odds ratio (OR) = 1.56, p = 0.61; cigarettes per day: OR = 0.85, p = 0.51; past tobacco smoking: OR = 0.80, p = 0.78). The heterogeneity (p > 0.05) and pleiotropy (p > 0.05) testing provided confirmatory evidence for the validity of our MR estimates.ConclusionsThe MR analysis revealed that there may not exist a causative link between smoking exposure and elevated incidence rates of thyroid malignancies.
| S-EPMC10587937 | biostudies-literature
Project description:BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER- breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91-0.97)], cg0760265 [OR = 1.07, 95% CI (1.03-1.11)], cg0420946 [OR = 0.95, 95% CI (0.93-0.98)], and cg2037583 [OR =1.09, 95% CI (1.04-1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10-11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER- breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.
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Project description:In this study, we aimed to investigate the causal effect of smoking on social isolation among older adults in England. Data from older adults of European ancestry who participated in 1 or more waves of the English Longitudinal Study of Ageing, from wave 1 (2002/2003) to wave 9 (2018/2019), were analyzed (n = 43,687 observations from 7,008 individuals; mean age = 68.50 years). The effect of current smoking on social isolation (ranging from 0 to 5) was estimated by 2-stage least squares regression using a polygenic score (PGS) for smoking cessation as the instrument. A low PGS for smoking cessation predicted current smoking (per 1-standard-deviation lower PGS, coefficient = 0.023, 95% confidence interval (CI): 0.015, 0.030; F = 36.420). The second-stage regression showed that current smoking increased social isolation by 1.205 points (95% CI: 0.308, 2.101). The association was larger for persons with higher socioeconomic backgrounds: 2.501 (95% CI: -0.024, 5.026) and 0.696 (95% CI: -0.294, 1.686) for those with higher and lower educational levels, respectively. This study showed that current smoking instrumented by a PGS for smoking cessation was associated with social isolation. Assuming that the PGS served as a valid instrument in this study, the findings support an effect of smoking on social isolation.
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Project description:The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.
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Project description:Habitual coffee and caffeine consumption has been reported to be associated with numerous health outcomes. This perspective focuses on Mendelian Randomization (MR) approaches for determining whether such associations are causal. Genetic instruments for coffee and caffeine consumption are described, along with key concepts of MR and particular challenges when applying this approach to studies of coffee and caffeine. To date, at least fifteen MR studies have investigated the causal role of coffee or caffeine use on risk of type 2 diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease, gout, osteoarthritis, cancers, sleep disturbances and other substance use. Most studies provide no consistent support for a causal role of coffee or caffeine on these health outcomes. Common study limitations include low statistical power, potential pleiotropy, and risk of collider bias. As a result, in many cases a causal role cannot confidently be ruled out. Conceptual challenges also arise from the different aspects of coffee and caffeine use captured by current genetic instruments. Nevertheless, with continued genome-wide searches for coffee and caffeine related loci along with advanced statistical methods and MR designs, MR promises to be a valuable approach to understanding the causal impact that coffee and caffeine have in human health.
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Project description:Ovarian cancer (OC) is one of the deadliest gynecological cancers worldwide. Previous observational epidemiological studies have revealed associations between modifiable environmental risk factors and OC risk. However, these studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) analysis has been established as a reliable method to investigate the causal relationship between risk factors and diseases using genetic variants to proxy modifiable exposures. Over recent years, MR analysis in OC research has received extensive attention, providing valuable insights into the etiology of OC as well as holding promise for identifying potential therapeutic interventions. This review provides a comprehensive overview of the key principles and assumptions of MR analysis. Published MR studies focusing on the causality between different risk factors and OC risk are summarized, along with comprehensive analysis of the method and its future applications. The results of MR studies on OC showed that higher BMI and height, earlier age at menarche, endometriosis, schizophrenia, and higher circulating β-carotene and circulating zinc levels are associated with an increased risk of OC. In contrast, polycystic ovary syndrome; vitiligo; higher circulating vitamin D, magnesium, and testosterone levels; and HMG-CoA reductase inhibition are associated with a reduced risk of OC. MR analysis presents a2 valuable approach to understanding the causality between different risk factors and OC after full consideration of its inherent assumptions and limitations.
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