Mendelian Randomization Analysis as a Tool to Gain Insights into Causes of Diseases: A Primer

2021 ◽  
pp. ASN.2020121760
Author(s):  
Adrienne Tin ◽  
Anna Köttgen
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mendelian Randomization ◽  
Mr Studies ◽  
Causal Relationships ◽  
Omics Technologies ◽  
Basic Concepts ◽  
Traditional Risk Factors ◽  
Randomization Analysis

Many Mendelian randomization (MR) studies have recently been published, with inferences on the causal relationships between risk factors and diseases that have potential implications for clinical research. In nephrology, MR methods have been applied to investigate potential causal relationships of traditional risk factors, lifestyle factors, and biomarkers from omics technologies with kidney function or chronic kidney disease. This primer summarizes the basic concepts of MR studies, highlighting methods employed in recent applications, and emphasizes key elements in conducting and reporting of MR studies that are important for interpreting the results.

scholarly journals ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis

2021 ◽  
Author(s):  
Pedrum Mohammadi-Shemirani ◽  
Michael Chong ◽  
Nicolas Perrot ◽  
Marie Pigeyre ◽  
Gregory R. Steinberg ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Whole Blood ◽  
Therapeutic Target ◽  
Mendelian Randomization ◽  
Atp Citrate Lyase ◽  
Mendelian Randomization Analysis ◽  
Citrate Lyase ◽  
Ckd Stage ◽  
Randomization Analysis

Background: ATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed. Methods: We constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we then evaluated the effect of genetically predicted ACLY expression on risk of CKD, estimated glomerular filtration rate (eGFR), and microalbuminuria using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls. Results: ACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of variation in whole blood ACLY gene expression. A 34% reduction in genetically predicted ACLY expression was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 x 10-4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (OR = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with eGFR nor microalbuminuria. Conclusion: Mendelian Randomization analysis provides cautious optimism regarding the possibility of ACLY as a therapeutic target for CKD.

scholarly journals SAT-LB96 Chronic Kidney Disease Incidence and Cardiorespiratory Fitness Association in Patients With Diabetes And/Or Hypertension

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Joseph Powell ◽  
Eric S Nylen ◽  
Jonathan Myers ◽  
Pamela Karasik ◽  
Hans Moore ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiorespiratory Fitness ◽  
Cox Regression ◽  
Disease Incidence ◽  
Metabolic Equivalents ◽  
Patients With Diabetes ◽  
Exercise Treadmill ◽  
Traditional Risk Factors

Abstract Introduction: Type 2 diabetes mellitus (T2DM) and hypertension (HTN) are considered strong risk factors for developing chronic kidney disease (CKD). Increased cardiorespiratory fitness (CRF) is associated with lower CKD risk. However, the CRF-CKD association in patients with T2DM and/or HTN has not been assessed.Methods: We identified 9,751 patients (age 58.6 + 10.1 years) with T2DM (N=1,444) or HTN (n=5,031) or both (n=3,276) prior to a maximal standardized exercise treadmill test (ETT) and no evidence of ischemia as indicated by the ETT. We established four CRF categories based on age-adjusted peak metabolic equivalents (METs) achieved: Least-Fit (4.6±1.2 METs; n=2,231); Low-Fit Fit (6.4±1.1 METs; n=2,693); Moderate-Fit (8.0±1.0 METs; n=2,432); and High-Fit (10.8±2.1 METs; n=2,395). We performed multivariable Cox Regression analyses to access the risk of CKD according to fitness. The models were adjusted for age, body mass index (BMI), traditional risk factors and medications. Results: During the median follow-up of 12.4 years, 1,118 patients developed CKD, accounting for 9.1 events/ 1,000 person-years of observation. The association between CRF and CKD was inverse and graded. The risk of CKD was 21% lower (Hazard Ratio [HR] 0.79; 95% confidence interval [CI] 0.77-0.81). When CRF categories were considered, the CKD risk was 44% lower for Moderate-Fit patients (HR 0.56; 95% CI 0.48-0.67) and 80% lower for High-Fit (HR 0.20; 95% CI 0.15-0.25). Similar findings were noted in patients with both T2DM and HTN. Conclusions: We noted an inverse and dose-response association between CRF and CKD incidence. The risk was attenuated significantly beyond a mean peak MET level of 8.0±1.0, suggesting that moderate increases in exercise capacity confers favorable health benefits in patients at high risk of developing CKD.

Independent, Non-traditional Risk Factors for Cardiovascular Events and Atherothrombosis in Chronic Kidney Disease and in Hemodialysis-dependent Patients

2006 ◽  
Vol 6 (3) ◽  
pp. 484-491 ◽  
Author(s):  
Mona Ezzat Madkour . ◽  
Iman William Bekheet . ◽  
Nagwa Abdel-Ghaffar . ◽  
Emam Waked . ◽  
Khaled Younes .
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiovascular Events ◽  
Traditional Risk Factors

scholarly journals Cardiovascular Risk Factors in Pre-dialysis Chronic Kidney Disease patients of Nepal

2020 ◽  
Vol 9 (2) ◽  
pp. 47-53
Author(s):  
Kashyap Dahal ◽  
A. Baral ◽  
K.K. Sah ◽  
J.R. Shrestha ◽  
A. Niraula ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Kidney Disease ◽  
Multiple Logistic Regression Analysis ◽  
Multiple Logistic Regression ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Traditional Risk Factors

Background and Aims: Cardiovascular disease (CVD) is the commonest cause of morbidity and mortality in patients with chronic kidney disease (CKD) due to increased prevalence of traditional and nontraditional CVD risk factors. Our study aimed to evaluate these risk factors in pre-dialysis Nepalese CKD patients. Methods: This was a cross-sectional study conducted in Department of Nephrology, Bir hospital. Total 100 consecutive pre-dialysis CKD patients were enrolled. Ten traditional and six nontraditional CVD risk factors were analyzed and compared between CKD stages. Descriptive statistics was used to illustrate the socio-demographic and clinical characteristics, chi square test for categorical variables and multiple logistic regression analysis was done to determine the risk factors of CVD in CKD patients. p-value<0.05 was considered to be statistically significant. Results: Mean patient age was 52.03}13.64 years with majority (60%) of the patients being male. Comparison of traditional risk factors in different stages depicted similar trend except for old age in Stage 3 CKD (p=0.002). Anemia (p<0.001), hyperphosphatemia (p=0.01), hyperparathyroidism (p<0.01) and cumulative nontraditional risk factors were significantly higher (p=0.01) in stage 5 CKD. The predicted CVD events by Framingham risk score showed high risk in 37% with no significant difference among the stages. Multiple logistic regression analysis showed increased body mass index, low serum albumin and increased serum phosphate as the three significant predictors for left ventricular hypertrophy. Conclusion: Our study shows that the CVD risk factors were prevailing along the various stages of CKD. The occurrence of non-traditional risk factors increased with increasing stage of CKD.

scholarly journals Framing Cause-Effect Relationship of Acute Coronary Syndrome in Patients with Chronic Kidney Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1518
Author(s):  
Mădălina Ioana Moisi ◽  
Simona Gabriela Bungau ◽  
Cosmin Mihai Vesa ◽  
Camelia Cristina Diaconu ◽  
Tapan Behl ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Approach ◽  
Coronary Syndrome ◽  
Inflammatory Status ◽  
Ischemic Coronary Artery Disease ◽  
Improper Use ◽  
Traditional Risk Factors ◽  
Artery Disease

The main causes of death in patients with chronic kidney disease (CKD) are of cardiovascular nature. The interaction between traditional cardiovascular risk factors (CVRF) and non-traditional risk factors (RF) triggers various complex pathophysiological mechanisms that will lead to accelerated atherosclerosis in the context of decreased renal function. In terms of mortality, CKD should be considered equivalent to ischemic coronary artery disease (CAD) and properly monitored. Vascular calcification, endothelial dysfunction, oxidative stress, anemia, and inflammatory syndrome represents the main uremic RF triggered by accumulation of the uremic toxins in CKD subjects. Proteinuria that appears due to kidney function decline may initiate an inflammatory status and alteration of the coagulation – fibrinolysis systems, favorizing acute coronary syndromes (ACS) occurrence. All these factors represent potential targets for future therapy that may improve CKD patient’s survival and prevention of CV events. Once installed, the CAD in CKD population is associated with negative outcome and increased mortality rate, that is the reason why discovering the complex pathophysiological connections between the two conditions and a proper control of the uremic RF are crucial and may represent the solutions for influencing the prognostic. Exclusion of CKD subjects from the important trials dealing with ACS and improper use of the therapeutical options because of the declined kidney functioned are issues that need to be surpassed. New ongoing trials with CKD subjects and platelets reactivity studies offers new perspectives for a better clinical approach and the expected results will clarify many aspects.

scholarly journals Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease

2019 ◽  
Vol 8 (7) ◽  
pp. 1034 ◽  
Author(s):  
Chrysan J. Mohammed ◽  
Yanmei Xie ◽  
Pamela S. Brewster ◽  
Subhanwita Ghosh ◽  
Prabhatchandra Dube ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Outcomes ◽  
Prognostic Value ◽  
Oxidant Stress ◽  
Adverse Outcomes ◽  
Protein Levels ◽  
Traditional Risk Factors ◽  
Apparently Healthy

The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.

scholarly journals Cardiovascular Biomarkers in Chronic Kidney Disease

2010 ◽  
Vol 29 (4) ◽  
pp. 298-303 ◽  
Author(s):  
Mirjana Đerić ◽  
Velibor Čabarkapa
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Disease ◽  
Left Ventricular ◽  
Calcium Phosphorus ◽  
Traditional Risk Factors ◽  
Cardiovascular Biomarkers

Cardiovascular Biomarkers in Chronic Kidney DiseaseCardiovascular morbidity and mortality are markedly increased in chronic renal failure patients. Although it cannot be regarded as a cardiovascular disease risk equivalent, kidney dysfunction is considered an independent predictor of increased cardiovascular risk that increases with deteriorating kidney function. The association is a very complex one, and the term cardiorenal syndrome is now widely used. Cardiovascular disease in chronic kidney disease patients usually manifests as ischemic heart disease (in the form of angina, acute coronary syndrome or sudden cardiac death), cerebrovascular disease, peripheral vascular disease, and congestive heart failure. Vascular disease includes atherosclerosis and vascular calcifications, and cardiomyopathy comprises left ventricular hypertrophy, cardiac fibrosis and left ventricular systolic and diastolic dysfunction. In addition to the well-established traditional risk factors such as hypertension, hyperlipidemia, insulin resistance and diabetes mellitus, the association is supported by synergistic action of non-traditional risk factors such as excessive calcium-phosphorus load, hyperparathyroidism, anemia, hemodynamic overload, malnutrition, inflammation, hyperhomocysteinemia, altered nitric oxide synthase and increased oxidative stress. This paper summarizes the current understanding of the significance of specific uremic retention solutes, natriuretic peptides, biochemical markers of disorders in calcium-phosphorus homeostasis, systemic inflammation, oxidative stress, and dyslipidemia.

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