Association of 20 potential ATP2B1-interacting genes with blood pressure in Koreans

Plasma membrane calcium-transporting ATPase 1 (ATP2B1) is associated significantly with blood pressure in Caucasians and Asians. ATP2B1 regulates calcium homeostasis and belongs to the P-type calcium pump family; several studies have identified diverse proteins that bind to ATP2B1. We hypothesized that ATP2B1 regulates blood pressure through ATP2B1 interacting genes. To this end, 20 potential ATP2B1-interacting genes were selected, 197 SNPs of which were analyzed for their association of systolic and diastolic blood pressure. These 20 genes were categorized into 2 groups: ATP2B1-binding genes and ATP2B1-cleaving calpain family members. Three ATP2B1-binding genes (CALM1, NOS1, and PDLIM1) were associated with blood pressure, and a SNP in CALM1 (rs2401887) generated the strongest association signal (beta=-3.60 ±0.92, p=8.9×10^-5 for systolic blood pressure and beta=-1.40 ±0.62, p=0.02 for diastolic blood pressure). Of the calpain family members, 3 genes (CAPN6, CAPN9, and CAPN10) were associated with blood pressure, and the CAPN10 SNP rs4676348 yielded the strongest association signal (beta=-0.88 ±0.27, p=0.001 for systolic blood pressure and beta=-0.58 ±0.18, p=0.015 for diastolic blood pressure). Further, the interaction of CALM1 to ATP2B1 was examined using the blood pressure of individuals who carried both variants of CALM1 and ATP2B1 genes. Similarly the interaction of CAPN10 to ATP2B1 was also examined. The CALM1 variant (rs2401887) and CAPN10 variants (rs4676348) appear to decrease blood pressure further in addition to the decrease by the variant (rs17249754) of ATP2B1, which suggests that ATP2B1 might regulate blood pressure through the ATP2B1-interacting genes CALM1 and CAPN10.