Potential causal role of l-glutamine in sickle cell disease painful crises: A Mendelian randomization analysis

ABSTRACTIn a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 – 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

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Estimating the causal role of C-reactive protein in coronary heart disease: Collaborative mendelian randomization analysis

Atherosclerosis ◽

10.1016/j.atherosclerosis.2010.08.024 ◽

2010 ◽

Vol 213 (1) ◽

pp. e12

Author(s):

F. Wensley

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Mendelian Randomization ◽

Causal Role ◽

C Reactive Protein ◽

Reactive Protein ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

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CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes: A Cross-Sectional Case Control Study

Mediators of Inflammation ◽

10.1155/2021/5521050 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yangyang Li ◽

Li Jin ◽

Jing Yan ◽

Hong Zhang ◽

Rong Zhang ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Mendelian Randomization ◽

Costimulatory Molecule ◽

Causal Role ◽

Chinese Patients ◽

Diabetic Kidney ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

Few studies have illuminated the genetic role of T cell costimulatory molecule CD28/CD80/CTLA4 variants in diabetic kidney disease (DKD) susceptibility. We aimed to investigate the causal role of genetic polymorphisms in CD28/CD80/CTLA4 with DKD susceptibility in patients with T2DM. A total of 3253 patients with T2DM were recruited for genotyping: including 204 DKD patients and 371 controls in stage 1 and 819 DKD patients and 563 controls in stage 2; besides, 1296 T2DM patients were selected for the analysis of association between loci and DKD-related traits. A subset of 227 T2DM patients (118 patients with DKD and 109 patients without DKD) from the total population above were selected to assess serum soluble CD28 (sCD28) levels. Then, we performed a candidate gene association study to identify single-nucleotide polymorphisms (SNPs) associated with DKD susceptibility and further used those SNPs to perform Mendelian randomization analyses of serum sCD28 level and DKD susceptibility. Under additive genetic models, CD28-rs3116494 ( OR = 1.29 [95% CI 1.11, 1.51], P = 0.0011 ) and CD80-rs3850890 ( OR = 1.16 [95% CI 1.02, 1.31], P = 0.0283 ) were associated with DKD susceptibility adjusted for age, gender, body mass index (BMI), duration of diabetes, and HbA1c. CD28-rs3116494 was associated with serum sCD28 level ( β = 0.26 [95% CI 0.08, 0.44], P = 0.0043 ). The Mendelian randomization analysis showed that CD28-rs3116494 played a causal role in DKD by influencing serum sCD28 levels ( β = 1.15 [95% CI 0.46, 1.83], P = 0.0010 ). In conclusion, we identified that two novel SNPs, CD28-rs3116494 and CD80-rs3850890, were associated with DKD susceptibility. Using the Mendelian randomization analysis, our study provided evidence for a causal relationship between serum CD28 levels and DKD with T2DM in the Chinese population.

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