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1.
Article in English | WPRIM | ID: wpr-927642

ABSTRACT

OBJECTIVE@#Traditional epidemiological studies have shown that C-reactive protein (CRP) is associated with the risk of cardiovascular diseases (CVDs). However, whether this association is causal remains unclear. Therefore, Mendelian randomization (MR) was used to explore the causal relationship of CRP with cardiovascular outcomes including ischemic stroke, atrial fibrillation, arrhythmia and congestive heart failure.@*METHODS@#We performed two-sample MR by using summary-level data obtained from Japanese Encyclopedia of Genetic association by Riken (JENGER), and we selected four single-nucleotide polymorphisms associated with CRP level as instrumental variables. MR estimates were calculated with the inverse-variance weighted (IVW), penalized weighted median and weighted median. MR-Egger regression was used to explore pleiotropy.@*RESULTS@#No significant causal association of genetically determined CRP level with ischemic stroke, atrial fibrillation or arrhythmia was found with all four MR methods (all Ps > 0.05). The IVW method indicated suggestive evidence of a causal association between CRP and congestive heart failure ( OR: 1.337, 95% CI: 1.005-1.780, P = 0.046), whereas the other three methods did not. No clear pleiotropy or heterogeneity were observed.@*CONCLUSIONS@#Suggestive evidence was found only in analysis of congestive heart failure; therefore, further studies are necessary. Furthermore, no causal association was found between CRP and the other three cardiovascular outcomes.


Subject(s)
C-Reactive Protein/metabolism , Cardiovascular Diseases/metabolism , Genetic Predisposition to Disease , Genotype , Humans , Japan , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Risk Factors
2.
Chinese Medical Journal ; (24): 1064-1069, 2021.
Article in English | WPRIM | ID: wpr-878160

ABSTRACT

BACKGROUND@#Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR).@*METHODS@#The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism.@*RESULTS@#The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids.@*CONCLUSION@#Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.


Subject(s)
Lipid Metabolism/genetics , Mendelian Randomization Analysis , Thyroid Function Tests , Thyroid Gland , Thyrotropin , Thyroxine , Triiodothyronine
3.
Article in English | WPRIM | ID: wpr-786229

ABSTRACT

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.


Subject(s)
Artifacts , Bias , Cardiovascular Diseases , Mendelian Randomization Analysis , Mortality , Precision Medicine , Random Allocation , Risk Factors
5.
Article in English | WPRIM | ID: wpr-766171

ABSTRACT

OBJECTIVE: This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with type 2 diabetes (T2D). METHODS: We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from a genome-wide association studies (GWAS) meta-analysis of 5,539 autoantibody-positive individuals with RA and 20,169 controls of European descent, and a GWAS dataset of 10,247 individuals with T2D and 53,924 controls, overwhelmingly of European descent as outcomes. RESULTS: We selected 10 single-nucleotide polymorphisms from GWAS data on RA as instrumental variables to improve the inference. The IVW method supported a causal association between RA and T2D (β=0.044, standard error [SE]=0.022, p=0.047). The MR-Egger analysis showed a causal association between RA and T2D (β=0.093, SE=0.033, p=0.023). In addition, the weighted median approach supported a causal association between RA and T2D (β=0.056, SE=0.025, p=0.028). The association between RA and T2D was consistently observed using IVW, MR Egger, and weighted median methods. Cochran's Q test indicated no evidence of heterogeneity between instrumental variable estimates based on individual variants and MR-Egger regression revealed that directional pleiotropy was unlikely to have biased the results (intercept=−0.030; p=0.101). CONCLUSION: MR analysis supports that RA may be causally associated with an increased risk of T2D.


Subject(s)
Arthritis, Rheumatoid , Bias , Dataset , Genome-Wide Association Study , Mendelian Randomization Analysis , Methods , Population Characteristics , Random Allocation
6.
Article in English | WPRIM | ID: wpr-765674

ABSTRACT

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.


Subject(s)
Bias , Case-Control Studies , Epidemiology , Genotype , Mendelian Randomization Analysis , Methods , Molecular Epidemiology , Phenotype , Pregnancy , Random Allocation , Risk Factors
7.
Article in English | WPRIM | ID: wpr-765672

ABSTRACT

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.


Subject(s)
Asians , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Genotype , Humans , Insulin Resistance , Insulin , Lipid Metabolism , Lipoproteins , Mendelian Randomization Analysis , Random Allocation , Risk Factors , Triglycerides
9.
Frontiers of Medicine ; (4): 678-687, 2018.
Article in English | WPRIM | ID: wpr-771273

ABSTRACT

Type 2 diabetes (T2D) has been associated with a high prevalence of depression.We aimed to determine the causal relation by performing a Mendelian randomization (MR) study using 34 T2D risk genetic variants validated in East Asians as the instrumental variable (IV). An MR analysis was performed involving 11 506 participants from a large longitudinal study. The T2D genetic risk score (GRS) was built using the 34 typical T2D common variants. We used T2D_GRS as the IV estimator and performed inverse-variance weighted (IVW) and Egger MR analysis. The T2D_GRS was found to be associated with depression with an OR of 1.21 (95% CI: 1.07-1.37) after adjustments for age, sex, body mass index, current smoking and drinking, physical activity, education, and marital status. Using T2D_GRS as the IV, we similarly found a causal relationship between genetically determined T2D and depression (OR: 1.84, 95% CI: 1.25-2.70). Though we found no association between the combined effect of the genetic IVs for T2D and depression with EggerMR(OR: 0.95, 95%CI: 0.42-2.14), we found an association for T2D and depression with IVW (OR: 1.75, 95% CI: 1.31-2.46) after excluding pleiotropic SNPs. Overall, the MR analyses provide evidence inferring a potential causal relationship between T2D and depression.


Subject(s)
Aged , Causality , China , Epidemiology , Depression , Epidemiology , Diabetes Mellitus, Type 2 , Genetics , Psychology , Female , Genetic Variation , Genotype , Humans , Linear Models , Longitudinal Studies , Male , Mendelian Randomization Analysis , Middle Aged , Polymorphism, Single Nucleotide , Psychiatric Status Rating Scales , Risk Factors , Sensitivity and Specificity
11.
Yonsei Medical Journal ; : 689-696, 2017.
Article in English | WPRIM | ID: wpr-21754

ABSTRACT

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.


Subject(s)
Acetaldehyde , Acetic Acid , Alcohol Drinking , Alcoholism , Aldehyde Dehydrogenase , Asians , Drinking , Genotype , Heterozygote , Homozygote , Humans , Korea , Mendelian Randomization Analysis , Metabolism , Mortality , Point Mutation , Random Allocation
12.
Rev. méd. hondur ; 81(1): 18-28, ene.-mar. 2013. tab, graf, mapas
Article in Spanish | LILACS | ID: lil-750049

ABSTRACT

Antecedentes: La búsqueda de aislamientos genéticos, i.e. poblaciones humanas aisladas, es importante para la salud pública puesto que la endogamia aumenta la prevalencia de enfermedades mendelianas. Además, la frecuencia de alelos deletéreos en general podría verse aumentada por efecto fundador y deriva génica. El aislamiento genético puede ser estimado mediante análisis de las proporciones de apellidos con las técnicas de isonimia.Objetivos: Determinar la estructura genética aproximada, la presencia de aislamientos genéticos y la proporción de hijos ilegítimos mediante el análisis de frecuencias de apellidos e isonimia en 60 comunidades de cinco municipios rurales Hondureños.Método: Los apellidos se obtuvieron de la base de datos del TSE. Se determinaron los coeficientes de endogamia FST, FIT y FIS a partir de las proporciones de apellidos por los métodos matemáticos descritos por Crowy Mange. Se calculó la tasa de ilegitimidad como la proporción de sujetos con un solo apellido. Resultados: Las comunidades más aisladas fueron las del municipio de Trinidad, seguidas por Orica. Las menos aisladas correspondieron a los municipios de predominio afrodescendiente. Orica presentó la tasa de ilegitimidad más elevada. Discusión: El método de isonimia utilizado reveló la presencia de aislamientos genéticos que deberán ser estudiados más a fondo desde el punto de vista de la epidemiología genética. La diversidad encontrada en las comunidades afrodescendientes tiene como origen la contribución anglosajona. La alta proporción de ilegitimidad en Orica podría estar relacionada con paternidad irresponsable y bajo estatus socioeconómico con consecuencias adversas para el bienestar social y la salud pública...


Subject(s)
Humans , Male , Female , Mendelian Randomization Analysis/methods , Consanguinity , Names , Indigenous Peoples , Illegitimacy/legislation & jurisprudence
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