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Recently, the rs6232 (N221D) and rs6235 (S690T) SNPs in the  PCSK1  gene were associated with obesity in a meta-analysis comprising more than 13 000 individuals of European ancestry. Each additional minor allele of rs6232 or rs6235 was associated with a 1.34- or 1.22-fold increase in the risk of obesity, respectively. So far, only one relatively small study has aimed to replicate these findings, but could not confirm the association of the rs6235 SNP and did not study the rs6232 variant. In the present study, we examined the associations of the rs6232 and rs6235 SNPs with obesity in a population-based cohort consisting of 20 249 individuals of European descent from Norfolk, UK. Logistic regression and generalized linear models were used to test the associations of the risk alleles with obesity and related quantitative traits, respectively. Neither of the SNPs was significantly associated with obesity, BMI or waist circumference under the additive genetic model ( P  &gt; 0.05). However, we observed an interaction between rs6232 and age on the level of BMI ( P  = 0.010) and risk of obesity ( P  = 0.020). The rs6232 SNP was associated with BMI ( P  = 0.021) and obesity ( P  = 0.022) in the younger individuals [less than median age (59 years)], but not among the older age group ( P  = 0.81 and  P  = 0.68 for BMI and obesity, respectively). In conclusion, our data suggest that the  PCSK1  rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population. However, the effect of rs6232 may be age-dependent.

Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study