» Articles » PMID: 25789079

The IGF1 P2 Promoter is an Epigenetic QTL for Circulating IGF1 and Human Growth

Overview
Publisher Biomed Central
Specialty Genetics
Date 2015 Mar 20
PMID 25789079
Citations 18
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.

Results: Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.

Conclusions: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

Citing Articles

The Role of Cow's Milk Consumption in Breast Cancer Initiation and Progression.

Melnik B, John S, Carrera-Bastos P, Cordain L, Leitzmann C, Weiskirchen R Curr Nutr Rep. 2023; 12(1):122-140.

PMID: 36729355 PMC: 9974716. DOI: 10.1007/s13668-023-00457-0.


Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through Igf1-Mediated Expansion of the Mammary Stem Cell Compartment.

Zheng Y, Luo L, Lambertz I, Conti C, Fuchs-Young R Cells. 2022; 11(16).

PMID: 36010633 PMC: 9406400. DOI: 10.3390/cells11162558.


GH Responsiveness Is not Correlated to P2 Promoter Methylation in Children With Turner Syndrome, GHD and SGA Short Stature.

Apel A, Iliev D, Urban C, Weber K, Schweizer R, Blumenstock G Front Endocrinol (Lausanne). 2022; 13:897897.

PMID: 35769084 PMC: 9235359. DOI: 10.3389/fendo.2022.897897.


Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects.

Hatmal M, Al-Hatamleh M, Olaimat A, Alshaer W, Hasan H, Albakri K Biomedicines. 2022; 10(6).

PMID: 35740242 PMC: 9219990. DOI: 10.3390/biomedicines10061219.


Differentially methylated CpGs in response to growth hormone administration in children with idiopathic short stature.

Shao X, Le Stunff C, Cheung W, Kwan T, Lathrop M, Pastinen T Clin Epigenetics. 2022; 14(1):65.

PMID: 35585611 PMC: 9118695. DOI: 10.1186/s13148-022-01281-z.


References
1.
Nili Gal-Yam E, Egger G, Iniguez L, Holster H, Einarsson S, Zhang X . Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc Natl Acad Sci U S A. 2008; 105(35):12979-84. PMC: 2529074. DOI: 10.1073/pnas.0806437105. View

2.
Ester W, Hokken-Koelega A . Polymorphisms in the IGF1 and IGF1R genes and children born small for gestational age: results of large population studies. Best Pract Res Clin Endocrinol Metab. 2008; 22(3):415-31. DOI: 10.1016/j.beem.2008.03.001. View

3.
Okada Y, Kamatani Y, Takahashi A, Matsuda K, Hosono N, Ohmiya H . A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum Mol Genet. 2010; 19(11):2303-12. DOI: 10.1093/hmg/ddq091. View

4.
Petronis A . Epigenetics and twins: three variations on the theme. Trends Genet. 2006; 22(7):347-50. DOI: 10.1016/j.tig.2006.04.010. View

5.
Cohen P . Controversy in clinical endocrinology: problems with reclassification of insulin-like growth factor I production and action disorders. J Clin Endocrinol Metab. 2006; 91(11):4235-6. DOI: 10.1210/jc.2006-1641. View