The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population

Abstract

Proprotein convertase subtilisin/kexin-type 1 (PCSK1) is a prohormone convertase that has an important role in prohormone maturation including the process of prorenin to renin. We studied the association of the PCSK1 single-nucleotide polymorphism (SNP) rs6235 (encoding an S690T substitution) with essential hypertension (EH), obesity and related traits in the Han Chinese population. The rs6235 SNP in the PCSK1 gene was investigated using a case-control study design, with 1034 hypertension cases and 1112 normotensive controls. In this study, the rs6235 SNP was significantly associated with hypertension (OR ¼ 1.26, 95% CI (1.10-1.46), P ¼ 0.001); the odds ratios of GC vs GG and CC vs GG were 1.30 (95% CI (1.06-1.58), P ¼ 0.010) and 1.55 (95% CI (1.12-2.13), P ¼ 0.007), respectively. In the controls, the C-allele was associated with increased systolic (P ¼ 0.010) and diastolic (P ¼ 0.010) blood pressure levels. In all of the EH patients and EH patients without a history of renin-angiotensin-aldosterone (RAA) system-related antagonists, the C-allele was associated with increased plasma renin activity (P ¼ 0.00004 and 0.002, respectively) and aldosterone levels (P ¼ 0.018 and 0.005, respectively). The C-allele was also associated with increased body mass index (BMI) (P ¼ 0.010) in the normotensive controls. In conclusion, the PCSK1 SNP rs6235 was associated with EH and blood pressure in the Han Chinese population, and this association may be mediated by the SNP's effect on RAA levels. rs6235 was also associated with BMI in this population.

Association of PCSK1 and PPARG1 Allelic Variants with Obesity and Metabolic Syndrome in Mexican Adults

“…In addition, PCSK1 variants may affect HDL cholesterol; one study showed that the livers of PCSK1 mutant mice had 2.0-fold lower levels of serum apolipoprotein A1, the primary component of HDL, but HDL cholesterol concentration was unaffected [ 46 ]. The effect of PCSK1 on metabolic syndrome traits could be due to (1) its activity in energy metabolism, as mentioned above, (2) regulation of blood pressure by the renin–angiotensin–aldosterone system (RAAS), as PCSK1 is involved in the processing of prorenin to renin, and variants in this gene could affect the RAAS [ 47 ], or (3) the involvement of PCSK1 in glucose and lipid metabolism by modulating insulin and APOA1 production [ 48 , 49 ]. On the other hand, the lack of association of the other SNPs ( TMEM18 rs6548238 C allele, GPX5 rs445870 G allele, ZPR1 rs964184 G allele, and ZBTB16 rs7106340 T allele) with metabolic diseases (obesity or metabolic syndrome) in this work could have been influenced by the sample size.…”

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

“…The results by Benzinou et al were subsequently only partly confirmed in different case-control studies from different ethnic origins (99 -106). Similarly, in individual studies for BMI or genome wide association studies (GWAS) for BMI, either weak associations or no association were identified (99,102,105,(107)(108)(109)(110)(111)(112). To challenge the evidence on the associations of PCSK1 SNPs with obesity and BMI, two meta-analyses were conducted independently (95,113).…”

<p>PCSK1 Overexpression in Rectal Cancer Correlates with Poor Response to Preoperative Chemoradiotherapy and Prognosis</p>

“…As a member of the proprotein convertase family, the PCSK1 protein (also known as PC1/3) plays a vital role in the proteolytic processing of mature bioactive proteins from large prohormones, including proopiomelanocortin, proinsulin, proglucagon, pro-islet amyloid polypeptide, and prorenin. 5,6 The resulting end products are widely involved in energy balance, glucose metabolism, and blood pressure regulation. In humans, loss-of-function mutations in the PCSK1 gene cause monogenic obesity, impaired glucose tolerance, hypertension, cardiac remodeling, and microvascular damage.…”