We reported previously that mice lacking ATP2B1 in vascular smooth muscle cells (VSMC ATP2B1 KO mice) exhibited high blood pressure and increased intracellular calcium concentration.
Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.
In conclusion, people with the major allele of ATP2B1rs17249754 are susceptible to hypertension especially in low intake of Ca and high ratio of Na and K.
Crossover analysis and stratified analysis indicated that BMI has a major effect on the development of hypertension, while ATP2B1 variants have a minor effect.
The present study confirmed the significant association of ATP2B1rs17249754 with risk of hypertension among Chinese children, but failed to replicate the association of CSK rs1378942, MTHFR rs1801133, CYP17A1 rs1004467, STK39 rs3754777 and FGF5 rs16998073 with BP/risk of hypertension.
Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 × 10(-14) to 4.46 × 10(-7) in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population.
We also observed a significant association of 4 SNPs and the GRS with hypertension (ATP2B1rs17249754: P = 0.02; CSK rs1378942: P = 0.02; CYP17A1 rs1004467: P = 0.02; MTHFR rs1801133: P = 0.03; GRS: P = 0.0004).
Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1).
Ex vivo mRNA expression analysis in umbilical artery smooth muscle cells indicated that reduced expression of this gene associated with the risk allele may be an underlying mechanism relating the ATP2B1 variant to hypertension.
Four loci-ATP2B1 (ATPase, Ca(++) transporting, plasma membrane 1), CSK (c-src tyrosine kinase), CYP17A1 (cytochrome P450 17A1) and PLEKHA7 (pleckstrin homology domain-containing family A member 7)-were associated with blood pressure and hypertension in the Korean population.
An additional hypertension case-control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 x 10(-9)) cohorts.
Significant associations were replicated for 7 loci-CASZ1, MTHFR, ITGA9, FGF5, CYP17A1-CNNM2, ATP2B1, and CSK-ULK3-with any or all of these 3 traits: systolic blood pressure (P=1.4x10(-14) to 0.05), diastolic blood pressure (P=1.9x10(-12) to 0.05), and hypertension (P=2.0x10(-14) to 0.006; odds ratio, 1.10 to 1.29).
Association analysis revealed significant association of the ATP2B1rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]).
For detection of polymorphisms all 22 PMCA1 exons from 44 patients with essential hypertension (based on rigorous clinical data in addition to a positive family history) and from 40 normotensives without a family history of hypertension were PCR amplified and subsequently subjected to combined single-strand conformation polymorphism (SSCP) and heteroduplex (HTX) analysis.