SNP rs1024750 polymorphism in the EGFR gene significantly influences serum calcium levels in postmenopausal Caucasian women

Abstract

Abstract: AIM: To study the effect of genetic polymorphisms of EGFR gene on the body composition, including blood calcium level, in postmenopausal Caucasian women through analyzing the data of a 4-year longitudinal supplementation of calcium and vitamin D. METHODS:A total of 201 postmenopausal non-Hispanic Caucasian women were recruited from rural Midwest area of the USA. They were administrated with calcium (either calcium citrate 1 400 mg/d or calcium carbonate 1 500 mg/d) and vitamin D (1 100 IU/d) supplementation three times per day for 4 years. One hundred-seventy subjects completed the 4-year clinical trial. A total of 35 candidate SNPs were selected with Haploview software 4.2 and genotyped. The cohort's body compositions after calcium and vitamin D intervention were measured every year. Association analysis between target SNPs and phenotypes of body composition was conducted.RESULTS: Among the cohort's body compositions, only serum calcium level at the baseline was significantly associated with rs1024750 SNP in EGFR gene (P<0.05), carriers of AA genotype had the highest baseline level while the GG genotype was the lowest. The annual changes of the serum calcium levels were significantly associated with rs1024750 SNP from Year 1 to Year 4 with calcium and vitamin D intervention (P<0.05), the serum calcium level of GG genotype had tremendous change, it was more than the total of AA and GA genotypes. CONCLUSION: The rs1024750 polymorphism in EGFR gene was significantly correlated with the changes of serum calcium level after calcium and vitamin D supplement in postmenopausal Caucasian women.

Key words: EGFR, genetics, single nucleotide polymorphism, calcium, vitamin D

CLC Number:

R969.1

WANG Ping, XU Xiao-jing, BU Feng-xiao, ZHOU Yu, YE An, ZHOU Bo-ting. SNP rs1024750 polymorphism in the EGFR gene significantly influences serum calcium levels in postmenopausal Caucasian women[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(7): 772-779.

References

[1] Kim SH, Kim KH, Seo BM, et al.Alveolar bone regeneration by transplantation of periodontal ligament stem cells and bone marrow stem cells in a canine peri-implant defect model: a pilot study[J]. J Periodontol, 2009,80(11):1815-1823.
[2] Hamano T, Oseto S, Fujii N, et al.Impact of lowering dialysate calcium concentration on serum bone turnover markers in hemodialysis patients[J]. Bone, 2005,36(5):909-916.
[3] Kurajoh M, Inaba M, Yamada S, et al.Association of increased active PTH(1-84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D[J]. Osteoporos Int, 2008,19(11):709-716.
[4] Kuo J, Hariri OR, Bondar G, et al.Membrane estrogen receptor-alpha interacts with metabotropic glutamate receptor type 1a to mobilize intracellular calcium in hypothalamic astrocytes[J]. Endocrinology, 2009,150(3):1369-1376.
[5] Dick IM, Devine A, Beilby J, et al.Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women[J]. Am J Physiol Endocrinol Metab, 2005,288(2):E430-435.
[6] Normanno N, De Luca A, Bianco C, et al.Epidermal growth factor receptor (EGFR) signaling in cancer[J]. Gene ,2006,366(1):2-16.
[7] Salomon DS, Brandt R, Ciardiello F, et al.Epidermal growth factor-related peptides and their receptors in human malignancies[J]. Crit Rev Oncol Hematol, 1995,19(3):183-232.
[8] Normanno N, Bianco C, De Luca A, et al.The role of EGF-related peptides in tumor growth[J]. Front Biosci, 2001,6:D685-707.
[9] Salomon DS, Kim N, Saeki T, et al.Transforming growth factor-alpha: an oncodevelopmental growth factor[J]. Cancer cells, 1990,2(12):389-397.
[10] Downward J, Parker P, Waterfield MD.Autophosphorylation sites on the epidermal growth factor receptor[J]. Nature, 1984,311(5985):483-485.
[11] Fallon JH, Seroogy KB, Loughlin SE, et al.Epidermal growth factor immunoreactive material in the central nervous system: location and development[J]. Science, 1984,224(4653):1107-1109.
[12] Li H, Panina S, Kaur A, et al.Regulation of the ligand-dependent activation of the epidermal growth factor receptor by calmodulin[J]. J Biol Chem, 2012,287(5):3273-3281.
[13] Dong LM, Brennan P, Karami S, et al.An analysis of growth, differentiation and apoptosis genes with risk of renal cancer[J]. PloS one, 2009,4(3):e4895.
[14] Woodburn JR.The epidermal growth factor receptor and its inhibition in cancer therapy[J]. Pharmacol Ther, 1999,82(2/3):241-250.
[15] Zhao LJ, Zhou Y, Bu F, et al.Factors predicting vitamin D response variation in non-Hispanic white postmenopausal women[J]. J Clin Endocrinol Metab, 2012,97(8):2699-2705.
[16] Lappe JM, Davies KM, Travers-Gustafson D, et al.Vitamin D status in a rural postmenopausal female population[J]. J Am Coll Nutr, 2006,25(5):395-402.
[17] De La Vega FM, Isaac HI, Scafe CR. A tool for selecting SNPs for association studies based on observed linkage disequilibrium patterns[J]. Pac Symp Biocomput, 2006:487-498.
[18] Purcell S, Neale B, Todd-Brown K, et al.PLINK: a tool set for whole-genome association and population-based linkage analyses[J]. Am J Hum Genet,2007,81(3):559-575.
[19] Park JY, Amankwah EK, Anic GM, et al.Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression[J]. Cancer Epidemiol Biomarkers Prev, 2013,22(5):827-834.
[20] Walker F, Abramowitz L, Benabderrahmane D, et al.Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus[J]. Hum Pathol, 2009,40(11):1517-1527.
[21] Kuan CT, Wikstrand CJ, Bigner DD.EGF mutant receptor vIII as a molecular target in cancer therapy[J]. Endocr Relat Cancer, 2001,8(2):83-96.
[22] Lynch TJ, Bell DW, Sordella R, et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib[J]. N Engl J Med, 2004,350(21):2129-2139.
[23] Bryant JA, Finn RS, Slamon DJ, et al.EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells[J]. Cancer Biol Ther, 2004,3(12):1243-1249.
[24] Tveteraas IH, Muller KM, Aasrum M, et al.Mechanisms involved in PGE2-induced transactivation of the epidermal growth factor receptor in MH1C1 hepatocarcinoma cells[J]. J Exp Clin Cancer Res, 2012 ,31:72. doi: 10.1186/1756-9966-31-72.