The Effect of PCSK1 Variants on Waist, Waist-Hip Ratio and Glucose Metabolism Is Modified by Sex and Glucose Tolerance Status

Anette P. Gjesing,Daniel R. Witte,Torben Hansen,Martin Heni,Oluf Pedersen,Jens J. Holst,Marie A. Vestmar,Torben Jørgensen,Nicholas John Timpson

doi:10.1371/journal.pone.0023907

Abstract

BackgroundWe aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans.Methodology/Principal FindingsRs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test.Conclusions/Significance PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status.

Highlights

PCSK1 encodes the proprotein convertase 1/3 (PC1/3) which is involved in the tissue-specific processing of several prohormones and neuropeptide precursors [1,2]
For the present study DNA was available from 6,164 individuals of the Inter99 participants including 4,568 individuals with normal glucose tolerance (NGT), 508 individuals with impaired fasting glucose (IFG), 707 individuals with impaired glucose tolerance (IGT), 256 individuals with screen detected diabetes mellitus (SDM), and 125 with known diabetes mellitus (KDM)
Neither variant was associated with measures of obesity among Danes (Table 1); when we combined our results with two previous studies [11,13], the rs6232 G-allele was significantly associated with increased waist/hip ratio (p = 0.02) and the rs6235 C-allele with increased waist circumference (p = 0.01) (Figure 1)

Summary

Introduction

PCSK1 encodes the proprotein convertase 1/3 (PC1/3) which is involved in the tissue-specific processing of several prohormones and neuropeptide precursors [1,2]. Rare mutations in PCSK1 are leading to PC1/3 deficiency. This results in obesity as well as other abnormalities such as dysregulated glucose homeostasis and small intestinal dysfunction confirming the importance of PC1/3 for the maturation of hormones regulating body weight and glucose homeostasis [4,5,6]. In a meta-analysis combining eight independent studies and comprising a total of 13,659 Europeans two common non-synonymous variants, rs6232, encoding. Data were included in meta-analyses of additional Europeans

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