TY - JOUR
T1 - Integrated multiomics approach identifies calcium and integrin-binding protein-2 as a novel gene for pulse wave velocity
AU - Mangino, Massimo
AU - Cecelja, Marina
AU - Menni, Cristina
AU - Tsai, Pei Chien
AU - Yuan, Wei
AU - Small, Kerrin
AU - Bell, Jordana
AU - Mitchell, Gary F.
AU - AortaGen Consortium
AU - Chowienczyk, Phillip
AU - Spector, Tim D.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Background: Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV. Methods and results: We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [β = -0.359, standard error (SE) = 0.07, P = 4.8 × 10 -8 ]. The same variant was also associated with increased CIB2 expression in leucocytes (β = 0.034, SE = 0.008, P = 4.95 × 10 -5) and skin (β = 0.072, SE = 0.01, P = 2.35 × 10 -9) and with hypomethylation of the gene promoter (β = -0.899, SE = 0.098, P = 3.63 × 10 -20). Conclusion: Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms.
AB - Background: Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV. Methods and results: We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [β = -0.359, standard error (SE) = 0.07, P = 4.8 × 10 -8 ]. The same variant was also associated with increased CIB2 expression in leucocytes (β = 0.034, SE = 0.008, P = 4.95 × 10 -5) and skin (β = 0.072, SE = 0.01, P = 2.35 × 10 -9) and with hypomethylation of the gene promoter (β = -0.899, SE = 0.098, P = 3.63 × 10 -20). Conclusion: Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms.
KW - arterial stiffness
KW - arteriosclerosis
KW - association
KW - calcium and integrin-binding protein-2
KW - pulse wave velocity
KW - vascular calcification
UR - http://www.scopus.com/inward/record.url?scp=84950143638&partnerID=8YFLogxK
U2 - 10.1097/HJH.0000000000000732
DO - 10.1097/HJH.0000000000000732
M3 - Article
C2 - 26378684
SN - 0263-6352
VL - 34
SP - 79
EP - 87
JO - Journal of Hypertension
JF - Journal of Hypertension
IS - 1
ER -