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A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Kaplan, RC, Petersen, A-K, Chen, M-H, Teumer, A, Glazer, NL, Döring, A, Lam, CSP, Friedrich, N, Newman, A, Müller, M, Yang, Q, Homuth, G, Cappola, A, Klopp, N, Smith, H, Ernst, F, Psaty, BM, Wichmann, H-E, Sawyer, DB, Biffar, R, Rotter, JI, Gieger, C, Sullivan, LS, Völzke, H, Rice, K, Spyroglou, A, Kroemer, HK, Chen, Y-DIda, Manolopoulou, J, Nauck, M, Strickler, HD, Goodarzi, MO, Reincke, M, Pollak, MN, Bidlingmaier, M, Vasan, RS, Wallaschofski, H |
| Journal | Hum Mol Genet |
| Volume | 20 |
| Issue | 6 |
| Pagination | 1241-51 |
| Date Published | 2011 Mar 15 |
| ISSN | 1460-2083 |
| Keywords | 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 |
| Abstract | <p>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.</p> |
| DOI | 10.1093/hmg/ddq560 |
| Alternate Journal | Hum. Mol. Genet. |
| PubMed ID | 21216879 |
| PubMed Central ID | PMC3043664 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States UL1 TR000005 / TR / NCATS NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R01 AG031890 / AG / NIA NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01 HL077447 / HL / NHLBI NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States |