Abstract
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.
Highlights
Obesity is a common disorder which affects more than 35% of American adults [1] and involves multiple genetic factors [2,3]
The results of this study indicate that common PCSK1 variants, notably the rs6232 and rs6235 polymorphisms contribute modestly to obesity in multi-ethnic American population
Rs6232 was associated with body mass index (BMI) variation and obesity risk in EuropeanAmerican subjects from the Coronary Artery Risk Development in Young Adults (CARDIA) study
Summary
Obesity is a common disorder which affects more than 35% of American adults [1] and involves multiple genetic factors [2,3]. The PCSK1 (Prohormone Convertase Subtilisin/Kexin type 1) gene is involved in regulation of appetite and in obesity via the biochemical activities of its protein (PC1/3) on key peptides in the leptin-melanocortin pathway [4]. Rare PCSK1 variants causing total or partial PC1/3 deficiency have been reported to be associated with extreme obesity [5,6,7,8,9]. Common PCSK1 variants (notably rs6232 and rs6234-rs6235) have been shown to contribute to obesity risk in a study of 13,659 European subjects [10]. There is mixed evidence for the association of the rs6232, rs6234 and rs6235 PCSK1 variants with overweight, obesity and body mass index (BMI)
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