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Rare genetic variant analysis on blood pressure in related samples.

ABSTRACT: The genetic variants associated with blood pressure identified so far explain only a small proportion of the total heritability of this trait. With recent advances in sequencing technology and statistical methodology, it becomes feasible to study the association between blood pressure and rare genetic variants. Using real baseline phenotype data and imputed dosage data from Genetic Analysis Workshop 18, we performed a candidate gene association analysis. We focused on 8 genes shown to be associated with either systolic or diastolic blood pressure to identify the association with both common and rare genetic variants, and then did a genome-wide rare-variant analysis on blood pressure. We performed association analysis for rare coding and splicing variants within each gene region and all rare variants in each sliding window, using either burden tests or sequence kernel association tests accounting for familial correlation. With a sample size of only 747, we failed to find any novel associated genetic loci. Consequently, we performed analyses on simulated data, with knowledge of the underlying simulating model, to evaluate the type I error rate and power for the methods used in real data analysis.

SUBMITTER: Chen H

PROVIDER: S-EPMC4143757 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Rare genetic variant analysis on blood pressure in related samples.

Chen Han H Choi Seung Hoan SH Hong Jaeyoung J Lu Chen C Milton Jacqueline N JN Allard Catherine C Lacey Sean M SM Lin Honghuang H Dupuis Josée J

BMC proceedings 20140617 Suppl 1

The genetic variants associated with blood pressure identified so far explain only a small proportion of the total heritability of this trait. With recent advances in sequencing technology and statistical methodology, it becomes feasible to study the association between blood pressure and rare genetic variants. Using real baseline phenotype data and imputed dosage data from Genetic Analysis Workshop 18, we performed a candidate gene association analysis. We focused on 8 genes shown to be associa ...[more]

PMID: 25519320

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Project description:AimsActivation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown.MethodsTo examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic.ResultsExpression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1 μm, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 ± 1 mmHg (n = 204) vs. P16L carriers: 82 ± 1 mmHg (n = 127), 95% CI for difference: 0.6, 4.0 mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1 mmHg vs. P16L carriers: 108 ± 1 mmHg, 95% CI for difference:1.0, 5.1 mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 ± 0.5 mmHg vs. P16L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6 mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05).ConclusionsThe common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.

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Rare genetic variant analysis on blood pressure in related samples.

Publications

Rare genetic variant analysis on blood pressure in related samples.

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