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. 2014 Oct 2;9(10):e109155.
doi: 10.1371/journal.pone.0109155. eCollection 2014.

Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study

Alanna C Morrison  1 , Joshua C Bis  2 , Shih-Jen Hwang  3 , Georg B Ehret  4 , Thomas Lumley  5 , Kenneth Rice  2 , Donna Muzny  6 , Richard A Gibbs  6 , Eric Boerwinkle  7 , Bruce M Psaty  8 , Aravinda Chakravarti  9 , Daniel Levy  3
Affiliations

Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study

Alanna C Morrison et al. PLoS One. .

Abstract

Background: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

Methods and results: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

Conclusion: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and an author of this manuscript has the following competing interests: Dr. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor), and on the Steering Committee for the Yale Open-Data Access Project funded by Medtronic. Dr. Psaty, co-author, has indicated a potential competing interest for the purpose of transparency, but this disclosure does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Forest plot for rs11191416 in relation to SBP.
The beta estimate and standard error are reported from the unconditional weighted analyses. P-values are reported from unconditional unweighted analyses.
Figure 2
Figure 2. Regional association plot for CYP17A1 in relation to SBP.
Each circle represents a single variant. The triangle denotes the index variant. The color coding corresponds to the correlation (r2) between index variant and the other variants.
Figure 3
Figure 3. Forest plot for rs12806040 in relation to DBP.
The beta estimate and standard error are reported from the unconditional weighted analyses. P-values are reported from unconditional unweighted analyses.
Figure 4
Figure 4. Regional association plot for PLEKHA7 in relation to DBP.
Each circle represents a single variant. The triangle denotes the index variant. The color coding corresponds to the correlation (r2) between index variant and the other variants.
See this image and copyright information in PMC

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