Application of Mendelian randomization in liver cancer / 临床肝胆病杂志

In recent years， the research method of Mendelian randomization based on genome-wide association studies has been widely used for etiological exploration in the medical field， which can effectively overcome the confounding biases and interference of reverse causalities in traditional observational researches with its unique advantages of the distributive randomness and timing priority of genetic variants. This article reviews the method of Mendelian randomization and its application in liver cancer， in order to provide new ideas for the research on causal association in liver cancer.

Application of Mendelian randomization analysis in exploring the etiology of nonalcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） is an abnormal lipid metabolic disorder of the liver characterized by accumulation of a large amount of lipids in the liver， and it is currently the most common liver disease around the world. Mendelian randomization （MR） incorporates genomic data into traditional epidemiological study designs to infer the causal relationship between exposure factors and disease risk. In recent years， MR has been widely used in studies on inference of the etiology of NAFLD. This article systematically summarizes the advances in the application of MR in NAFLD research， so as to provide new ideas for understanding the nature of the disease and scientific interventions.

Association between the risk of increase in total cholesterol and the risk of cholelithiasis： A bidirectional Mendelian randomization study / 临床肝胆病杂志

ObjectiveTo investigate the association between the risk of increase in total cholesterol （TC） and the risk of cholelithiasis by using bidirectional Mendelian randomization （MR）. MethodsThe open gwas public database was used to obtain the single nucleotide polymorphism data associated with TC and cholelithiasis， and a secondary data analysis was performed for all summary data of genome-wide association studies. The genetic loci closely associated with TC or cholelithiasis were selected as exposure or outcome variables， and the bidirectional MR analysis was performed using the methods such as Egger regression， Weighted median， IVW random effects model， and IVW fixed effects model， with odds ratio （OR） values for evaluating the causal relationship between TC and cholelithiasis. ResultsWith TC as the exposure and cholelithiasis as the outcome， TC-cholelithiasis had an overall OR value of 0.91 （95% confidence interval ［CI］： 0.85‍ ‍—‍ ‍0.97） before elimination of heterogeneity and 0.93 （95%CI： 0.89‍ ‍—‍ ‍0.97） after elimination of heterogeneity. With cholelithiasis as the exposure and TC as the outcome， TC-cholelithiasis had an overall OR value of 0.20 （95%CI： 0.06‍ ‍—‍ ‍0.65） before elimination of heterogeneity and 0.28 （95%CI： 0.10‍ ‍—‍ ‍0.83） after elimination of heterogeneity. There was a bidirectional causal relationship between genetically predicted TC and cholelithiasis. ConclusionThis study confirms the bidirectional causal relationship between TC and cholelithiasis. The risk of cholelithiasis decreases with the increase in alleles associated with the elevation of TC level； on the contrary， the risk of elevated TC level decreases with the increase in alleles associated with the onset of cholelithiasis.

Análisis mediante variables instrumentales para establecer causalidad en investigaciones observacionales / Analysis through instrumental variables to establish causality in observational research

La identificación de relaciones causales es uno de los problemas fundamentales de la investigación científica en medicina y es necesaria para poder ejercerla en forma efectiva. Sin embargo, desde el punto de vista práctico es difícil establecer la existencia de relaciones causales en estudios de carácter observacional, en gran parte por la presencia de factores de confusión. El análisis a través de variables instrumentales es una de las estrategias que permite controlar el efecto confundidor y documentar la presencia de relaciones causa-efecto en estas situaciones. En este artículo, el autor resume los principales supuestos del análisis a través de variables instrumentales, haciendo foco en la aleatorización mendeliana. (AU)

The identification of causal relationships is one of the fundamental challenges in scientific research in medicine and is necessary for its effective practice. However, from a practical standpoint, establishing the existence of causal relationships in observational studies is difficult, largely due to the presence of confounding factors. Analysis through instrumental variables is one of the strategies that allows to control the confounding effect and documenting the presence of cause-and-effect relationships in these situations. In this article, the author summarizes the main assumptions of analysis through instrumental variables, with a focus on Mendelian randomization. (AU)

Causal Association Between Unsaturated Fatty Acids and Inflammatory Bowel Disease: A Mendelian Randomization Analysis / 胃肠病学

Background: Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It is unclear whether there is a causal association between unsaturated fatty acids and IBD. Aims: A two⁃sample Mendelian randomization analysis was used to explore the causal association between unsaturated fatty acids and IBD. Methods: The data of the genome⁃wide association study (GWAS) of unsaturated fatty acids and IBD were obtained from web⁃based public databases. Two⁃sample Mendelian randomization analysis was performed by using inverse⁃variance weighted analysis, and weight median estimator and MR⁃Egger regression were conducted to validate the association of the causal effect. The causality of unsaturated fatty acids on the risk of IBD was evaluated by OR and 95% CI. Results: No direct causal association was found between ω⁃6 fatty acids and CD, and a direct causal association was found with UC. Inverse⁃variance weighted analysis showed a 16% increase in the risk of UC for each standard deviation increase in ω⁃6 fatty acid gene levels (OR=1.16, 95% CI: 1.00⁃1.36, P=0.04). However, no causal association was found between ω⁃3 fatty acids, monounsaturated fatty acids and IBD. Conclusions: ω⁃6 fatty acids may be only causally associated with UC, and no causal association is found between ω⁃3 fatty acids, monounsaturated fatty acids and IBD.

Association between primary sclerosing cholangitis and the risk of colorectal cancer: A two-sample Mendelian randomization study / 临床肝胆病杂志

Objective To investigate the association between primary sclerosing cholangitis (PSC) and colorectal cancer (CRC) by using two-sample Mendelian randomization (TSMR). Methods The single nucleotide polymorphism (SNP) data associated with PSC and CRC were obtained from Finland Biobank and UK Biobank, respectively. A secondary data analysis was performed for all pooled data based on genome-wide association studies to select the genetic loci closely associated with PSC as instrumental variables, and TSMR was conducted by seven methods, i.e., Egger regression in Mendelian randomization, weighted median, inverse variance weighted (IVW) random effects model, maximum likelihood, linear weighted median, IVW radial method, and IVW fixed effects model. Odds ratio (OR) value was used to evaluate the causal relationship between PSC and the risk of CRC. Results There was a positive causal relationship between gene predicted PSC and CRC, and with the IVW fixed effects model as an example, genetically determined patients with PSC could increase the risk of CRC ( OR =1.002 243, 95% confidence interval: 1.001 319-1.003 167). TSMR results showed no heterogeneity ( P =0.87) or horizontal pleiotropy ( P =0.95). The three instrumental variables selected for PSC were strong instrumental variables ( F =11.86). Conclusion TSMR shows the genetic evidence for the association between PSC and the risk of CRC. Regardless of the presence or absence of inflammatory bowel disease, active enteroscopy screening among patients with PSC may help with the early identification and timely intervention of CRC.

Precision Medicine and Cardiovascular Health: Insights from Mendelian Randomization Analyses

Cardiovascular disease (CVD) is considered a primary driver of global mortality and is estimated to be responsible for approximately 17.9 million deaths annually. Consequently, a substantial body of research related to CVD has developed, with an emphasis on identifying strategies for the prevention and effective treatment of CVD. In this review, we critically examine the existing CVD literature, and specifically highlight the contribution of Mendelian randomization analyses in CVD research. Throughout this review, we assess the extent to which research findings agree across a range of studies of differing design within a triangulation framework. If differing study designs are subject to non-overlapping sources of bias, consistent findings limit the extent to which results are merely an artefact of study design. Consequently, broad agreement across differing studies can be viewed as providing more robust causal evidence in contrast to limiting the scope of the review to a single specific study design. Utilising the triangulation approach, we highlight emerging patterns in research findings, and explore the potential of identified risk factors as targets for precision medicine and novel interventions.

The Uric Acid and Gout have No Direct Causality With Osteoarthritis: A Mendelian Randomization Study

OBJECTIVE: To examine whether uric acid level or gout is causally associated with the risk of osteoarthritis.METHODS: We performed a two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW), MR-Egger regression, and weighted median methods. We used the publicly available summary statistics datasets of uric acid level or gout genome-wide association studies (GWASs) as the exposure, and a GWAS in 3,498 patients with osteoarthritis in the arcOGEN study and 11,009 controls of European ancestry as the outcome.RESULTS: Six single nucleotide polymorphisms (SNPs) from the GWAS data on uric acid level and 12 SNPs from the GWAS data on gout were selected as instrumental variables (IVs). The IVW analysis did not support a causal association between uric acid level or gout and risk of osteoarthritis (beta=−0.026, standard error [SE]=0.096, p=0.789; beta=−0.018, SE=0.025, p=0.482). MR-Egger regression revealed no causal association between uric acid level or gout and risk of osteoarthritis (beta=0.028, SE=0.142, p=0.852; beta=−0.056, SE=0.090, p=0.548). Similarly, no evidence of a casual association was provided by the weighted median approach (beta=0.004, SE=0.064, p=0.946; beta=−0.005, SE=0.025, p=0.843).CONCLUSION: The results of MR analysis demonstrates that uric acid level and gout may be not causally associated with the increased risk of osteoarthritis. Considering MR study is not susceptible to bias from unmeasured confounders or reverse causation, the epidemiological evidence for an association between uric acid level or gout and a higher risk of osteoarthritis may be due to residual confounding or reverse causation rather than direct causality.

Mendelian Randomization Analysis in Observational Epidemiology

Mendelian randomization (MR) in epidemiology is the use of genetic variants as instrumental variables (IVs) in non-experimental design to make causality of a modifiable exposure on an outcome or disease. It assesses the causal effect between risk factor and a clinical outcome. The main reason to approach MR is to avoid the problem of residual confounding. There is no association between the genotype of early pregnancy and the disease, and the genotype of an individual cannot be changed. For this reason, it results with randomly assigned case-control studies can be set by regressing the measurements. IVs in MR are used genetic variants for estimating the causality. Usually an outcome is a disease and an exposure is risk factor, intermediate phenotype which may be a biomarker. The choice of the genetic variable as IV (Z) is essential to a successful in MR analysis. MR is named ‘Mendelian deconfounding’ as it gives to estimate of the causality free from biases due to confounding (C). To estimate unbiased estimation of the causality of the exposure (X) on the clinically relevant outcome (Y), Z has the 3 core assumptions (A1-A3). A1) Z is independent of C; A2) Z is associated with X; and A3) Z is independent of Y given X and C; The purpose of this review provides an overview of the MR analysis and is to explain that using an IV is proposed as an alternative statistical method to estimate causal effect of exposure and outcome under controlling for a confounder.

Genetically Mediated Lipid Metabolism and Risk of Insulin Resistance: Insights from Mendelian Randomization Studies

Dysregulated lipid metabolism, characterized by higher levels of circulating triglycerides, higher levels of small, low density lipoprotein, and accumulation of intracellular lipids, is linked to insulin resistance and related complications such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Considering that various metabolic, genetic, and environmental factors are involved in the development of T2DM and CVD, the causalities of these diseases are often confounded. In recent years, Mendelian randomization (MR) studies coupling genetic data in population studies have revealed new insights into the risk factors influencing the development of CVD and T2DM. This review briefly conceptualizes MR and summarizes the genetic traits related to lipid metabolism by evaluating their effects on the indicators of insulin resistance based on the results of recent MR studies. The data from the MR study cases referred to in this review indicate that the causal associations between lipid status and insulin resistance in MR studies are not conclusive. Furthermore, available data on Asian ethnicities, including Korean, are very limited. More genome-wide association studies and MR studies on Asian populations should be conducted to identify Asian- or Korean-specific lipid traits in the development of insulin resistance and T2DM. The present review discusses certain studies that investigated genetic variants related to nutrient intake that can modify lipid metabolism outcomes. Up-to-date inferences on the causal association between lipids and insulin resistance using MR should be interpreted with caution because of several limitations, including pleiotropic effects and lack of information on genotype and ethnicity.

Application of mendelian randomization methods in causal inference of observational study / 中华预防医学杂志

Mendelian randomization (MR) approach follows the Mendel′s law of inheritance, which is called "Parental alleles randomly assigned to the offspring", and refers to use genetic variants as an instrumental variable to develop causal inference between the exposure factor and the outcome from observational study. In recent years, with the rapid development of genome-wide association study (GWAS) and various omics data,the disclosure of a large number of aggregated data provides an opportunity for the wide application of MR approach in causal inference. We introduce three methods widely used in MR and then apply them to explore causal relationship between blood metabolites and depressive. The advantages and disadvantages of three methods in causal inference are compared in order to provide reference for the application of MR in observational studies.

Mendelian randomization analysis of the relationship between obesity and DNA methylation / 中华预防医学杂志

Objective@#To explore the association between DNA methylation and body mass index (BMI) using Mendelian randomization analysis.@*Methods@#A total of 469 participants were selected from the Chinese National Twin Registry in 2013, who were living in Shandong, Jiangsu, Zhejiang, and Sichuan provinces, and at least 18 years of age. A questionnaire survey and physical examination were conducted to collect demographic, clinical, and behavioral information. Peripheral blood cells were collected to detect genotype and methylation status. Association analyses between DNA methylation and BMI and between CpGs and cis-SNP were conducted. With rs748212 as the instrumental variable, the association between cg15053022 and BMI was explored using the Mendelian randomization method.@*Results@#A total of 469 participants were selected. The mean age of participants was (44.8±13.2) years and the BMI was (25.0±3.8) kg/m2. Nine BMI-related DNA methylation sites were found and DNA methylation site cg15053022 in the ATP4A gene was negatively associated with cis-SNP rs748212 (β=-0.020); the mean methylation level of AA, AC, and CC were 0.212±0.025, 0.242±0.024, and 0.264±0.028, respectively. rs748212 was associated with BMI (β=0.04, P=0.007) and closely related to cg15053022 (F=237.66, P=0.143). Mendelian randomization analysis showed lower methylation levels at cg15053022 were associated with higher BMI (β=-1.97, P<0.001).@*Conclusion@#This study supported the impact of cg15053022 methylation in the ATP4A gene on BMI using Mendelian randomization analysis and provided the basis for using Mendelian randomization analysis in methylation studies.

Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea

Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required.

El papel de lasffracciones lipídicas, lipoproteínas y apolipoproteínas en preeclampiaa / The role f lipidd fractions, lipoproteins and apolipoproteins in preeclampsia / O papel das raçõões lipídicas, lipoproteínas e apolipoproteínas na preeclampsia

La Preeclampsia (PE) es un trastorno multisistémico, exclusivo de la gestación humana y responsable de aproximadamente 44.000 muertes maternas anuales a nivel mundial; esta enfermedad está asociada a múltiples complicaciones tanto en la madre como en el feto, sin embargo, su etiología no se encuentra totalmente dilucidada y en consecuencia ha sido difícil definir estrategias válidas de predicción. La PE es una enfermedad compleja y comparte diferentes factores de riesgo con las enfermedades cardiovasculares; como la obesidad, hipertensión arterial, resistencia a la insulina y dislipidemias. Con esto se evidencia que algunas alteraciones en los niveles lípidos y apolipoproteínas, se asocian con mayor peroxidación lipídica y estrés oxidativo lo cual puede desencadenar en disfunción endotelial para ambas patologías. Por tanto, la exploración de la evidencia de una asociación entre las fracciones lipídicas y riesgo de PE, puede aportar nuevo conocimiento en torno a la etiología de esta enfermedad. En la presente revisión, se plantearán las principales implicaciones biológicas de las alteraciones del perfil lipídico y apolipoproteínas en la génesis de la PE. Se describirán los estudios observacionales que se han aproximado a su evaluación y se identificarán sus principales debilidades metodológicas, con el fin de plantear estrategias para una evaluación integral de esta vía fisiopatológica, con posibles implicaciones predictivas de la enfermedad.

Preeclampsia (PE) is a multisystemic disorder unique to human pregnancy and responsible for about 44,000 maternal deaths worldwide. This disease is associated with multiple complications for both mother and fetus; however, its etiology is not totally clear and it has therefore been difficult to define valid prediction strategies. PE is a complex disease and it shares different risk factors with cardiovascular disease, such as obesity, hypertension, insulin resistance and dyslipidemia, evidencing that the presence of disturbances in lipid and apolipoprotein levels are associated with increased lipid peroxidation and oxidative stress which can lead to endothelial dysfunction in both diseases. Therefore, exploring the evidence of an association between lipid fractions and PE risk can provide new knowledge about the etiology of this disease. In this review, the major biological implications of lipid profile and apolipoproteins alterations in the genesis of PE will be presented, describing the observational studies and identifying its main methodological weaknesses in order to create strategies for comprehensive assessment of the pathophysiological pathway with potential predictive implications of the disease.

A Preeclampsia (PE) é um transtorno multissistêmico, exclusivo da gestação humana e responsável por aproximadamente 44.000 mortes maternas anuais a nível mundial; esta doença esta associada a múltiplas complicações tanto na mãe como no feto, porém, sua etiologia não está totalmente esclarecida e consequentemente tem sido difícil definir estratégias válidas de predição. A PE é uma doença complexa e compartilha diferentes fatores de risco com as doenças cardiovasculares, como a obesidade, hipertensão arterial, resistência à insulina e dislipidemias; evidenciando que alterações nos níveis dos lipídios e apolipoproteínas, se associam com maior peroxidação lipídica e estresse oxidativo que pode desencadear disfunção endotelial para ambas patologias. Portanto, a exploração da evidência de uma associação entre las frações lipídicas e risco de PE, pode contribuir com novo conhecimento ao redor da etiologia desta doença. Na presente revisão, serão apresentadas as principais implicações biológicas das alterações do perfil lipídico e apolipoproteínas na gênese da PE, descrevendo os estudos observacionais que se aproximaram à sua avaliação e identificando suas principais fraquezas metodológicas, com o objetivo de propor estratégias para uma avaliação integral desta via fisiopatológica, com possíveis implicações preditivas da doença.