Dataset Information

Evidence for a Causal Role of the SH2B3-?2M Axis in Blood Pressure Regulation.

ABSTRACT: Genetic variants at SH2B3 are associated with blood pressure and circulating ?2M (?-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating ?2M is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7?065 Framingham Heart Study participants with measurements of plasma ?2M. Generalized estimating equations were used to test the association of ?2M with prevalent and new-onset hypertension. There were 2?145 (30%) cases of prevalent hypertension at baseline and 886 (21%) cases of incident hypertension during 6 years of follow-up. A 1-SD increase in baseline plasma ?2M was associated with a greater risk of prevalent (odds ratio 1.14, 95% CI 1.05-1.24) and new-onset (odds ratio 1.18, 95% CI 1.07-1.32) hypertension. Individuals within the top ?2M quartile had a greater risk than the bottom quartile for prevalent (odds ratio 1.29, 95% CI 1.05-1.57) and new-onset (odds ratio 1.59, 95% CI 1.20-2.11) hypertension. These associations remained essentially unchanged in analyses restricted to participants free of albuminuria and chronic kidney disease. Mendelian randomization demonstrated that lower SH2B3 expression is causal for increased circulating ?2M levels, and in a hypertensive mouse model, knockout of Sh2b3 increased ? 2 M gene expression. In a community-based study of healthy individuals, higher plasma ?2M levels are associated with increased risk of prevalent and incident hypertension independent of chronic kidney disease status. Overlapping genetic signals for hypertension and ?2M, in conjunction with mouse knockout experiments, suggest that the SH2B3-?2M axis plays a causal role in hypertension.

SUBMITTER: Keefe JA

PROVIDER: S-EPMC6334659 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Evidence for a Causal Role of the SH2B3-β2M Axis in Blood Pressure Regulation.

Keefe Joshua A JA Hwang Shih-Jen SJ Huan Tianxiao T Mendelson Michael M Yao Chen C Courchesne Paul P Saleh Mohamed A MA Madhur Meena S MS Levy Daniel D

Hypertension (Dallas, Tex. : 1979) 20190201 2

Genetic variants at SH2B3 are associated with blood pressure and circulating β2M (β-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating β2M is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7 065 Framingham Heart Study participants with measurements of plasma β2M. Generalized estimating equations were used to test the association of β2 ...[more]

PMID: 30624993

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Project description:BackgroundAn 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).ObjectiveThe 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).DesignData 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.ResultsIn 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 (β = 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 (β = 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.ConclusionOverall, the present findings do not corroborate the hypothesis that homocysteine has a causal role in blood pressure, especially in SBP.

Dataset Information

Evidence for a Causal Role of the SH2B3-?2M Axis in Blood Pressure Regulation.

Publications

Evidence for a Causal Role of the SH2B3-β<sub>2</sub>M Axis in Blood Pressure Regulation.

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