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Measurement of absolute copy number variation reveals association with essential hypertension.

ABSTRACT: BACKGROUND:The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. METHODS:Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. RESULTS:A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). CONCLUSIONS:Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.

SUBMITTER: Marques FZ

PROVIDER: S-EPMC4107748 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Measurement of absolute copy number variation reveals association with essential hypertension.

Marques Francine Z FZ Prestes Priscilla R PR Pinheiro Leonardo B LB Scurrah Katrina K Emslie Kerry R KR Tomaszewski Maciej M Harrap Stephen B SB Charchar Fadi J FJ

BMC medical genomics 20140715

<h4>Background</h4>The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension ...[more]

PMID: 25027169

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Project description:BACKGROUND:Percent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer. Inherited factors are hypothesized to explain between 30 and 60% of the variance in this trait. However, previously identified common genetic variants account for less than 6% of the variance in PD, leaving much of the genetic contribution to this trait unexplained. We performed the first study to examine whether germline copy number variation (CNV) are associated with PD. Two genome-wide association studies (GWAS) of percent density conducted on the Illumina 660W-Quad were used to identify and replicate the association between candidate CNVs and PD: the Minnesota Breast Cancer Family Study (MBCFS) and controls from the Mayo Venous Thromboembolism (Mayo VTE) Case-Control Study, with 585 and 328 women, respectively. Linear models were utilized to examine the association of each probe with PD, adjusted for age, menopausal status and BMI. Segmentation was subsequently performed on the probe-level test statistics to identify candidate CNV regions that were associated with PD. RESULTS:Sixty-one probes from five chromosomal regions [3q26.1 (2 regions), 8q24.22, 11p15.3, and 17q22] were significantly associated with PD in MBCFS (p-values <0.0001). A CNV at 3q26.1 showed the greatest evidence for association with PD; a region without any known SNPs. Conversely, the CNV at 17q22 was largely due to the association between SNPs and PD in the region. SNPs in the 8q24.22 region have been shown to be associated with risk of many cancers; however, SNPs in this region were not responsible for the observed CNV association. While we were unable to replicate the associations with PD, two of the five CNVs (3q26.1 and 11p15.3) were also observed in the Mayo VTE controls. CONCLUSIONS:CNVs may help to explain some of the variability in PD that is currently unexplained by SNPs. While we were able to replicate the existence of two CNVs across the two GWAS studies, we were unable to replicate the associations with PD. Even so, the proximity of the identified CNV regions to loci known to be associated with breast cancer risk suggests further investigation and potentially shared genetic mechanisms underlying the PD and breast cancer association.

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Measurement of absolute copy number variation reveals association with essential hypertension.

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Measurement of absolute copy number variation reveals association with essential hypertension.

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