Common variants in PCSK1 influence blood pressure and body mass index

Proprotein convertase subtilisin/kexin-type 1 (PCSK1) activates precursors pro-opiomelanocortin (POMC), proinsulin and prorenin. We investigated if common variants in the PCSK1 gene influence blood pressure and risk of hypertension. Additionally, we investigated the risk of obesity and type 2 diabetes (T2D). In the Rotterdam Study (RS1), a prospective, population-based cohort (n=5974), four single-nucleotide polymorphisms (rs10515237, rs6232, rs436321 and rs3792747) in PCSK1 were studied. Linear and Cox regression models served to analyze associations between variants and end points. Replication was performed in the Rotterdam Study Plus1 (RSPlus1, n=1895). Rs436321 was significantly associated with systolic and diastolic blood pressure and risk of hypertension (odds ratio (OR): 1.1-1.3; P<0.05 in both populations). Rs6232 was associated with body mass index (BMI) (P=0.007 and P=0.04 in RS1 and RSPlus1, respectively). In RSPlus1, heterozygotes for rs6232 had 1.5 times higher risk of obesity (OR: 1.46; 95% confidence interval: 1.04-2.03; P=0.03). We did not find significant associations of PCSK1 with fasting insulin levels and T2D. We found an association of genetic variation in the PCSK1 gene with blood pressure and hypertension. Furthermore, we replicated the association of PCSK1 with BMI and obesity. No relationship was found between PCSK1 variants and fasting insulin levels and T2D. Our findings suggest that genetic variation in PCSK1 may contribute to, at least, some of these interrelated disorders.