Douglas Sawyer
Faculty Member
Last active: 7/21/2014

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

Kaplan RC, Petersen AK, Chen MH, Teumer A, Glazer NL, Döring A, Lam CS, Friedrich N, Newman A, Müller M, Yang Q, Homuth G, Cappola A, Klopp N, Smith H, Ernst F, Psaty BM, Wichmann HE, Sawyer DB, Biffar R, Rotter JI, Gieger C, Sullivan LS, Völzke H, Rice K, Spyroglou A, Kroemer HK, Ida Chen YD, Manolopoulou J, Nauck M, Strickler HD, Goodarzi MO, Reincke M, Pollak MN, Bidlingmaier M, Vasan RS, Wallaschofski H
Hum Mol Genet. 2011 20 (6): 1241-51

PMID: 21216879 · PMCID: PMC3043664 · DOI:10.1093/hmg/ddq560

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.

MeSH Terms (11)

Aged Chromosomes, Human, Pair 7 Cohort Studies European Continental Ancestry Group Female Genome-Wide Association Study Humans Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Male Polymorphism, Single Nucleotide

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