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

ABSTRACT: In a recent clinical trial, the metabolite l-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To support 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 potential causal relationship between l-glutamine levels and painful crises (N = 1278, 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 were 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.

SUBMITTER: Ilboudo Y

PROVIDER: S-EPMC7686124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An understanding of whether homocysteine is a cause or a marker of increased blood pressure is relevant because blood homocysteine can be effectively lowered by safe and inexpensive interventions (e.g., vitamin B-6, B-9, and B-12 supplementation).The aim was to assess the causal influence of homocysteine on systolic and diastolic blood pressure (SBP and DBP, respectively) in adults with the use of Mendelian randomization (MR).Data from the 1982 Pelotas Birth Cohort (Brazil) were used. A total of 4297 subjects were evaluated in 2004-2005 (mean age: 22.8 y). The association of homocysteine concentration with SBP and DBP was assessed by conventional ordinary least-squares (OLS) linear regression and 2-stage least-squares (2SLS) regression (MR analysis). The single nucleotide polymorphism (SNP) methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) was used as proxy for homocysteine concentration. We also applied MR to data from the International Consortium for Blood Pressure (ICBP) genomewide association studies (>69,000 participants) using rs1801133 and additional homocysteine-associated SNPs as instruments.In OLS regression, a 1-SD unit increase in log homocysteine concentration was associated with an increase of 0.9 (95% CI: 0.4, 1.4) mm Hg in SBP and of 1.0 (95% CI: 0.6, 1.4) mm Hg in DBP. In 2SLS regression, for the same increase in homocysteine, the coefficients were -1.8 mm Hg for SBP (95% CI: -3.9, 0.4 mm Hg; P = 0.01) and 0.1 mm Hg for DBP (95% CI: -1.5, 1.7 mm Hg; P = 0.24). In the MR analysis of ICBP data, homocysteine concentration was not associated with SBP (? = 0.6 mm Hg for each 1-SD unit increase in log homocysteine; 95% CI: -0.8, 1.9 mm Hg) but was positively associated with DBP (? = 1.1 mm Hg; 95% CI: 0.2, 1.9 mm Hg). The association of genetically increased homocysteine with DBP was not consistent across different SNPs.Overall, the present findings do not corroborate the hypothesis that homocysteine has a causal role in blood pressure, especially in SBP.

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

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