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Functional and clinical relevance of novel and known PCSK1 variants for childhood obesity and glucose metabolism.

ABSTRACT: OBJECTIVE:Variants in Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) may be causative for obesity as suggested by monogenic cases and association studies. Here we assessed the functional relevance in experimental studies and the clinical relevance through detailed metabolic phenotyping of newly identified and known PCSK1 variants in children. RESULTS:In 52 obese children selected for elevated proinsulin levels and/or impaired glucose tolerance, we found eight known variants and two novel heterozygous variants (c.1095 + 1G > A and p.S24C) by sequencing the PCSK1 gene. Patients with the new variants presented with extreme obesity, impaired glucose tolerance, and PCOS. Functionally, c.1095 + 1G > A caused skipping of exon8 translation and a complete loss of enzymatic activity. The protein was retained within the endoplasmic reticulum (ER) causing ER stress. The p.S24C variant had no functional effect on protein size, cell trafficking, or enzymatic activity. The known variants rs6230, rs35753085, and rs725522 in the 5' end did not affect PCSK1 promoter activity. In clinical association studies in 1673 lean and obese children, we confirmed associations of rs6232 and rs6234 with BMI-SDS and of rs725522 with glucose stimulated insulin secretion and Matsuda index. We did not find the new variants in any other subjects. CONCLUSIONS:We identified and functionally characterized two rare novel PCSK1 variants of which c.1095 + 1G > A caused complete loss of protein function. In addition to confirming rs6232 and rs6234 in PCSK1 as polygenic risk variants for childhood obesity, we describe an association of rs725522 with insulin metabolism. Our results support the contribution of PCSK1 variants to obesity predisposition in children.

SUBMITTER: Loffler D

PROVIDER: S-EPMC5323889 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Functional and clinical relevance of novel and known <i>PCSK1</i> variants for childhood obesity and glucose metabolism.

Löffler Dennis D Behrendt Susanne S Creemers John W M JWM Klammt Jürgen J Aust Gabriela G Stanik Juraj J Kiess Wieland W Kovacs Peter P Körner Antje A

Molecular metabolism 20161208 3

<h4>Objective</h4>Variants in <i>Proprotein Convertase Subtilisin/Kexin Type 1</i> (<i>PCSK1</i>) may be causative for obesity as suggested by monogenic cases and association studies. Here we assessed the functional relevance in experimental studies and the clinical relevance through detailed metabolic phenotyping of newly identified and known <i>PCSK1</i> variants in children.<h4>Results</h4>In 52 obese children selected for elevated proinsulin levels and/or impaired glucose tolerance, we found ...[more]

PMID: 28271036

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Project description:Common PCSK1 variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common PCSK1 variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (P?=?0.006) and obesity (P?=?0.018) but also increased the obesity incidence during the 20 years of follow-up (HR?=?1.53 [1.07-2.19], P?=?0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (P?=?0.028) and obesity (P?=?0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR?=?1.23 [1.05-1.45], P?=?9.5×10(-3)). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (P?=?4.2×10(-3)) and obesity (P?=?3.4×10(-3)) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (P?=?0.756 and P?=?0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full PCSK1 locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings.

Dataset Information

Functional and clinical relevance of novel and known PCSK1 variants for childhood obesity and glucose metabolism.

Publications

Functional and clinical relevance of novel and known <i>PCSK1</i> variants for childhood obesity and glucose metabolism.

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