Dataset Information

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

ABSTRACT: Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ? 40 kg/m(2)], but their contribution to common obesity (BMI ? 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (? = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (? = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

SUBMITTER: Nead KT

PROVIDER: S-EPMC4498155 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

Nead Kevin T KT Li Aihua A Wehner Mackenzie R MR Neupane Binod B Gustafsson Stefan S Butterworth Adam A Engert James C JC Davis A Darlene AD Hegele Robert A RA Miller Ruby R den Hoed Marcel M Khaw Kay-Tee KT Kilpeläinen Tuomas O TO Wareham Nick N Edwards Todd L TL Hallmans Göran G Varga Tibor V TV Kardia Sharon L R SL Smith Jennifer A JA Zhao Wei W Faul Jessica D JD Weir David D Mi Jie J Xi Bo B Quinteros Samuel Canizales SC Cooper Cyrus C Sayer Avan Aihie AA Jameson Karen K Grøntved Anders A Fornage Myriam M Sidney Stephen S Hanis Craig L CL Highland Heather M HM Häring Hans-Ulrich HU Heni Martin M Lasky-Su Jessica J Weiss Scott T ST Gerhard Glenn S GS Still Christopher C Melka Melkaey M MM Pausova Zdenka Z Paus Tomáš T Grant Struan F A SF Hakonarson Hakon H Price R Arlen RA Wang Kai K Scherag Andre A Hebebrand Johannes J Hinney Anke A Franks Paul W PW Frayling Timothy M TM McCarthy Mark I MI Hirschhorn Joel N JN Loos Ruth J RJ Ingelsson Erik E Gerstein Hertzel C HC Yusuf Salim S Beyene Joseph J Anand Sonia S SS Meyre David D

Human molecular genetics 20150317 12

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by ...[more]

PMID: 25784503

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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

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

Publications

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

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