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Kaplan, R.C.* ; Petersen, A.-K. ; Chen, M.H.* ; Teumer, A.* ; Glazer, N.L.* ; Döring, A. ; Lam, C.S.* ; Friedrich, N.* ; Newman, A.* ; Müller, M. ; Yang, Q.* ; Homuth, G.* ; Cappola, A.* ; Klopp, N. ; Smith, H.* ; Ernst, F.* ; Psaty, B.M.* ; Wichmann, H.-E. ; Sawyer, D.B.* ; Biffar, R.* ; Rotter, J.I.* ; Gieger, C. ; Sullivan, L.S.* ; Völzke, H.* ; Rice, K.* ; Spyroglou, A.* ; Kroemer, H.K.* ; Ida, Chen, Y.D.* ; Manolopoulou, J.* ; Nauck, M.* ; Strickler, H.D.* ; Goodarzi, M.O.* ; Reincke, M.* ; Pollak, M.N.* ; Bidlingmaier, M.* ; Vasan, R.S.* ; Wallaschofski, H.

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

Hum. Mol. Genet. 20, 1241-1251 (2011)

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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.

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