Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis: A Systematic Review / 生物医学与环境科学（英文）

OBJECTIVE@#This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD.@*METHODS@#We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation.@*RESULTS@#The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression.@*CONCLUSION@#This study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

Associations of cholecystectomy with the risk of colorectal cancer: a Mendelian randomization study / 中华医学杂志(英文版)

BACKGROUND@#Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases, while the causal effects of cholecystectomy on colorectal cancer (CRC) and other complications are still unknown.@*METHODS@#We obtained genetic variants associated with cholecystectomy at a genome-wide significant level ( P value <5 × 10 -8 ) as instrumental variables (IVs) and performed Mendelian randomization (MR) to identify the complications of cholecystectomy. Furthermore, the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy, and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis. The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines.@*RESULTS@#The selected IVs explained 1.76% variance of cholecystectomy. Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC (odds ratio [OR] =1.543, 95% confidence interval [CI]: 0.607-3.924). Also, it was not significant in either colon or rectum cancer. Intriguingly, cholecystectomy might decrease the risk of Crohn's disease (OR = 0.078, 95% CI: 0.016-0.368) and coronary heart disease (OR = 0.352, 95% CI: 0.164-0.756). However, it might increase the risk of irritable bowel syndrome (IBS) (OR = 7.573, 95% CI: 1.096-52.318). Cholelithiasis could increase the risk of CRC in the largest population (OR = 1.041, 95% CI: 1.010-1.073). The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population (OR = 1.061, 95% CI: 1.002-1.125) after adjustment of cholecystectomy.@*CONCLUSIONS@#The study indicated that cholecystectomy might not increase the risk of CRC, but such a conclusion needs further proving by clinical equivalence. Additionally, it might increase the risk of IBS, which should be paid attention to in clinical practice.

Tea consumption and cancer: a Mendelian randomization study / 中华流行病学杂志

Objective: A Mendelian randomization (MR) analysis was performed to assess the relationship between tea consumption and cancer. Methods: There were 100 639 participants with the information of gene sequencing of whole genome in the China Kadoorie Biobank. After excluding those with cancer at baseline survey, a total of 100 218 participants were included in this study. The baseline information about tea consumption were analyzed, including daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption. We used the two-stage least square method to evaluate the associations between three tea consumption variables and incidence of cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer. Multivariable MR and analysis only among nondrinkers were used to control the impact of alcohol consumption. Sensitivity analyses were also performed, including inverse variance weighting, weighted median, and MR-Egger. Results: We used 54, 42, and 28 SNPs to construct non-weighted genetic risk scores as instrumental variables for daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption, respectively. During an average of (11.4±3.0) years of follow-up, 6 886 cases of cancer were recorded. After adjusting for age, age2, sex, region, array type, and the first 12 genetic principal components, there were no significant associations of three tea consumption variables with the incidence of cancer and cancer subtypes. Compared with non-daily tea drinkers, the HR (95%CI) of daily tea drinkers for cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer, are respectively 0.99 (0.78-1.26), 1.17 (0.58-2.36), 0.86 (0.40-1.84), 0.85 (0.42-1.73), 1.39 (0.85-2.26) and 0.63 (0.28-1.38). After controlling the impact of alcohol consumption and performing multiple sensitivity analyses, the results were similar. Conclusion: There is no causal relationship between tea consumption and risk of cancer in population in China.

Associations between vitamin D levels and systemic lupus erythematosus risk:a Mendelian randomized study / 中华预防医学杂志

Objective: To explore the causal effects of the serum Vitamin D levels on the risk of systemic lupus erythematosus (SLE). Methods: A two-sample Mendelian randomization (MR) study was performed to infer the causality. Three Genome-wide association studies (GWAS) for circulating Vitamin D levels, including 25-hydroxyvitamin D [25(OH)D], 25-hydroxyvitamin D3 [25(OH)D3] and C3-epimer of 25-hydroxyvitamin D3 [C3-epi-25(OH)D3] published in 2020, and one GWAS for SLE published in 2015 were utilized to analyze the causal effects of the serum Vitamin D levels on the risk of SLE. MR analyses were conducted using the inverse-variance weighted method (IVW), weighted median, MR-Egger methods, MR-pleiotropy residual sum and outlier (MR-PRESSO) method. Results: 34, 29 and 6 SNPs were respectively selected as instrumental variables to analyze the causal association of total 25 (OH) D level, 25 (OH) D3 level and C3-epi-25 (OH) D3 level with the risk of SLE. The MR results showed that each standard deviation decrease in the level of 25(OH)D3 would result in 14.2% higher risk of SLE (OR, 0.858; 95%CI, 0.753-0.978; P=0.022). The levels of 25(OH)D and C3-epi-25(OH)D3 had null associations with risk of SLE (OR, 0.849; 95%CI, 0.653-1.104; P=0.222; OR, 0.904; 95%CI, 0.695-1.176; P=0.452). Conclusion: This study have identified a causal effect of 25(OH)D3 on increased risk of SLE. These findings highlighted the significance of active monitoring and prevention of SLE in population of low Vitamin D levels.

Research progress of Mendelian randomization analysis in intensive care medicine / 中华危重病急救医学

The condition of critically ill patients changes rapidly, involving pathological changes in multiple systems and organs throughout the body. Exploring the causal relationship of mechanisms can further reveal etiology, treatment, and prognosis of diseases. However, traditional prospective studies in the field of critical care are still subject to numerous limitations. As an emerging research method, Mendelian randomization (MR) analysis uses genetic variation to provide causal evidence for instrumental variables, which is expected to provide clues in critical diseases. This article systematically describes the research progresson the application of MR analysis in critical care medicine from four aspects: the principle of MR analysis, the difference between MR analysis and randomized controlled trial (RCT), the use of MR analysis in the field of critical illness, and the possible methods of application, aiming to provide possible directions for the research in this field.

Neutrophil extracellular trap increase the risk of sepsis: a two-sample, one-way Mendelian randomization study / 中华危重病急救医学

OBJECTIVE@#To investigate the causal relationship between neutrophil extracellular trap (NET) and sepsis based on Mendelian randomization analysis.@*METHODS@#The genome wide association study (GWAS) dataset for the NET biomarker myeloperoxidase (MPO)-DNA complex based on Donkel et al. 's Rotterdam study (RS) and GWAS dataset for identifying sepsis from the UK biobank were selected to screen single nucleotide polymorphisms (SNPS) associated with MPO-DNA complex as instrumental variable (IV) for genetic variation, using MPO-DNA complex as exposure factor. Potential causal associations between MPO-DNA complex and the risk of occurrence of sepsis, 28-day death from sepsis, need for intensive care due to sepsis, and 28-day death from sepsis requiring intensive care were analyzed using a two-sample, one-way Mendelian randomization analysis primary analysis method of inverse analysis of variance (IVW). Potential pleiotropy was assessed using the MR Egger regression intercept test. Sensitivity analysis was performed using the "leave one out" test.@*RESULTS@#The GWAS data were obtained from a European population of both sexes, and the screening criteria was based on the three main assumptions of Mendelian randomization, resulting in 22 SNP entering the Mendelian randomization analysis. The results of the Mendelian randomization causal association effect analysis using the IVW method showed that for every standard deviation increase in the level of the MPO-DNA complex, the risk of sepsis increased by approximately 18% [odds ratio (OR) = 1.18, 95% confidence interval (95%CI) was 1.07-1.29, P < 0.001], the risk of 28-day death from sepsis increased by approximately 51% (OR = 1.51, 95%CI was 1.27-1.81, P < 0.001), an increase of approximately 38% in the risk of occurrence of needing intensive care due to sepsis (OR = 1.38, 95%CI was 1.12-1.70, P = 0.002), and an increase of approximately 125% in the risk of 28-day death from sepsis requiring intensive care (OR = 2.25, 95%CI was 1.21-4.18, P = 0.01). MR Egger regression intercept test suggested that there was no horizontal pleiotropy in the included SNP, and the MR-PRESSO test did not find outliers. Sensitivity analysis suggested that the results of Mendelian randomization were robust.@*CONCLUSIONS@#Rising NET can increase the risk of sepsis onset, progression and death as derived from Mendelian randomization analysis.

Trans-ethnic Mendelian randomization study of systemic lupus erythematosus and common female hormone-dependent malignancies / 中华医学杂志(英文版)

BACKGROUND@#Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis.@*METHODS@#We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results.@*RESULTS@#We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P  = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P  = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P  = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P  = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P  = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P  = 0.002). The statistical powers of positive MR results were all >0.9.@*CONCLUSION@#This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.

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)

Genetic variants, circulating levels of monocyte chemoattractant protein-1 with risk of breast cancer: a case-control study and Mendelian randomization analysis / 中华预防医学杂志

Objective: To assess the association of genetic polymorphisms and circulating levels of chemokine monocyte chemoattractant protein-1 (MCP1) with risk of breast cancer. Methods: A total of 820 patients with pathologically confirmed breast cancer and 900 age-and area-of-residence-matched healthy controls who visited the hospital for routine health screening during the same period were included in this case-control study. Mendelian randomization analysis was performed using three widely followed functional single nucleotide polymorphisms (SNPs) of the MCP1 gene rs1024611, rs2857656 and rs4586 to construct instrumental variables . Results: MCP1 rs1024611 (OR=1.26, P=0.002), rs2857656 (OR=1.23, P=0.006) and rs4586 (OR=1.23, P=0.003) were significantly associated with increased risk of breast cancer. SNP rs1024611 (β=1.194, P<0.001), rs2857656 (β=1.221, P<0.001) and rs4586 (β=1.137, P<0.001) were positively correlated with higher circulating level of MCP1. The case-control study showed that an increase of 23.7 pg/ml of circulating levels of MCP1 was associated with a 0.25-fold increased risk of breast cancer. MR analysis confirmed that the genetic predicted circulating levels of MCP1 were associated with an increased risk of breast cancer, and the risk of breast cancer increased by 0.20 times with an increase of 23.7 pg/ml in MCP1. Conclusion: Genetic variants and circulating levels of MCP1 are significantly associated with the risk of breast cancer and can be used as a biomarker for early prediction of breast cancer.

Association of C-reactive Protein with Cardiovascular Outcomes: A Mendelian Randomization Study in the Japanese Population / 生物医学与环境科学（英文）

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.

Genetic study of cardiovascular disease subtypes defined by International Classification of Diseases / 北京大学学报(医学版)

OBJECTIVE@#To study the molecular connection among cardiovascular diseases (CVD) subtypes defined by the International Classification of Diseases (ICD) version 10 (ICD-10).@*METHODS@#Both phenotypic data and genotypic data used in this study were obtained from the UK Biobank. A total of 380 083 participants aged between 40 and 69 years were included. Those without any cardiovascular disease (either no ICD-10 code at all or no ICD-10 code containing letter I) were assigned to the control group. The five CVD subtypes were: ischaemic heart diseases (IHD), pulmonary heart disease and diseases of pulmonary circulation (PHD), cerebrovascular diseases (CRB), diseases of arteries, arterioles and capillaries (AAC), diseases of veins, lymphatic vessels and lymph nodes, and diseases not elsewhere classified (VLL). We first performed a genome-wide association study (GWAS) for each of the five subtypes. We summarized novel loci using genome-wide significance threshold P=5×10-8. Next, we used linkage disequilibrium score regression (LDSC) method to assess genetic correlation among the five subtypes. Lastly, we applied mendelian randomization (MR) approach to assess the causal relationship among the subtypes. The particular software that we used was generalised summary-data-based mendelian randomisation (GSMR).@*RESULTS@#Through GWAS, we identified hundreds of genome-wide significant SNPs: 672 for IHD, 241 for PHD, 31 for CRB, 48 for AAC, and 193 for VLL. By comparing with published literature, we found 28 novel loci, for PHD (n=14), CRB (n =7) and AAC (n =7). Eight of these 28 loci were rare, where the lead SNP had minor allele frequency (MAF) less than 1%. LDSC analyses indicated IHD had significant genetic correlation with VLL (P=2.52×10-7), PHD (P=3.77×10-3) and AAC (P=4.90×10-3), respectively. Bidrectional GSMR analyses showed that IHD had a positive causal relationship with VLL (P=7.40×10-5) and AAC (P=1.50×10-3), while reverse causality was not supported.@*CONCLUSION@#This study adopted an innovative approach to study the molecular connection among CVD subtypes that are defined by ICD. We identified potentially positive genetic correlation and causal effects among some of these subtypes. Research along this line will provide scientific insights and serve as a guidance for future ICD standards.

Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study / 中华医学杂志(英文版)

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.

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.

Causal Association between Rheumatoid Arthritis with the Increased Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

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.

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.