Background: We 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 Findings: Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middleaged
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% (20.7–9%, 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.