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A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.

ABSTRACT: Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

SUBMITTER: Kaplan RC

PROVIDER: S-EPMC3043664 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.

Kaplan Robert C RC Petersen Ann-Kristin AK Chen Ming-Huei MH Teumer Alexander A Glazer Nicole L NL Döring Angela A Lam Carolyn S P CS Friedrich Nele N Newman Anne A Müller Martina M Yang Qiong Q Homuth Georg G Cappola Anne A Klopp Norman N Smith Holly H Ernst Florian F Psaty Bruce M BM Wichmann H-Erich HE Sawyer Douglas B DB Biffar Reiner R Rotter Jerome I JI Gieger Christian C Sullivan Lisa S LS Völzke Henry H Rice Kenneth K Spyroglou Ariadni A Kroemer Heyo K HK Ida Chen Y-D YD Manolopoulou Jenny J Nauck Matthias M Strickler Howard D HD Goodarzi Mark O MO Reincke Martin M Pollak Michael N MN Bidlingmaier Martin M Vasan Ramachandran S RS Wallaschofski Henri H

Human molecular genetics 20110107 6

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known associa ...[more]

PMID: 21216879

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A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.

Publications

A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.

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