Single Nucleotide Polymorphisms in the Gc Gene for Vitamin D Binding Protein in Common Cancers in Thailand

  • Published : 2015.04.29


Background: This case-control study aimed to determine if there were any associations between the two single nucleotide polymorphisms (SNPs) in Gc, rs7041 (Asp416Glu) and rs4588 (Thr420Lys) and 3 common cancers (breast, lung and colorectal) in Thai patients. Materials and Methods: Two hundred and eighty two colorectal, 101 breast and 113 lung cancer patients were recruited from one institute during 2011-2013. The controls were age-matched volunteers who had a negative history of index cancers. In addition, vitamin D levels were compared among different genotypes in the 2 SNPs. Results: The minor allele frequencies of rs7041 (G) and rs4588 (A) were 0.32 and 0.24, respectively. Under the dominant model, the study found significant associations between minor-allele genotypes of the SNP rs7041 (TG/GG) and lung cancer (odds ratio [OR] 1.78, 95% CI 1.05-3.03). When subgroup analysis was performed according to sex and age at diagnosis, the study found that the minor-allele genotypes of rs7041 (TG/GG) were significantly associated with colorectal cancer in patients whose age at diagnosis was more than 60 years (OR 1.67, 95%CI 1.06-2.61) and the minor-allele genotypes of rs4588 (CA/AA) were significantly associated with colorectal cancer in males aged 60 years or less (OR 2.34, 95%CI 1.25-4.37). When SNP combinations (rs7041-rs4588) were examined, the TT-CA combination had a significant protective association with lung cancer (OR 0.44, 95% CI 0.22-0.85). On evaluation of serum 25(OH)D levels in 205 individuals without cancer (males 144, females 61), the proportion of subjects with low serum vitamin D (< 20 ng/ml) in those harboring CA or AA genotypes of rs4588 (41.7%) was significantly higher than the CC genotype (15.5%, p-value < 0.01). Conclusions: Genetic polymorphisms in Gc were associated with lung and colorectal cancers in Thai patients. Lower serum 25(OH)D in minor variants of rs4588 may explain this association.


  1. Abbas S, Linseisen J, Slanger T, et al (2008). The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status. Cancer Epidemiol Biomarkers Prev, 17, 1339-43.
  2. Ahn J, Yu K, Stolzenberg-Solomon R, et al (2010). Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 19, 2739-45.
  3. Anderson LN, Cotterchio M, Cole DE, et al (2011). Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol Biomarkers Prev, 20, 1708-17.
  4. Anic GM, Weinstein SJ, Mondul AM, et al (2014). Serum vitamin D, vitamin D binding protein, and risk of colorectal cancer. PLoS One, 9, 102966.
  5. Bai Y, Yu Y, Yu B, et al (2009). Association of vitamin D receptor polymorphisms with the risk of prostate cancer in the Han population of Southern China. BMC Med Genet, 10, 125.
  6. Borradale D, Kimlin M (2009). Vitamin D in health and disease: an insight into traditional functions and new roles for the 'sunshine vitamin. Nutr Res Rev, 22, 118-36.
  7. Chupeerach C, Tungtrongchitr A, Phonrat B, et al (2012). Association of Thr420Lys polymorphism in DBP gene with fat-soluble vitamins and low radial bone mineral density in postmenopausal Thai women. Biomarkers Med, 6, 103-8.
  8. Engelman CD, Fingerlin TE, Langefeld CD, et al (2008). Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. J Clin Endocrinol Metab, 93, 3381-8.
  9. Gandini S, Gnagnarella P, Serrano D, et al (2014). Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol, 810, 69-105.
  10. Holick MF (2007). Vitamin D deficiency. N Engl J Med, 357, 266-81.
  11. Kidd LC, Paltoo DN, Wang S, et al (2005). Sequence variation within the 5' regulatory regions of the vitamin D binding protein and receptor genes and prostate cancer risk. Prostate, 64, 272-82.
  12. Mahmoudi T, Karimi K, Arkani M, et al (2014). Lack of associations between vitamin D metabolism-related gene variants and risk of colorectal cancer. Asian Pac J Cancer Prev, 15, 957-61.
  13. Malik S, Fu L, Juras DJ, et al (2013). Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci, 50, 1-22.
  14. McCullough ML, Stevens VL, Diver WR, et al (2007). Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Res, 1-9.
  15. Mocellin S (2011). Vitamin D and cancer: deciphering the truth. Biochim Biophys Acta, 1816, 172-8.
  16. National Cancer Institute of Thailand (2011). Cancer Registry.
  17. Oh JJ, Byun SS, Lee SE, et al (2014). Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population. Gene, 533, 86-93.
  18. Pani MA, Regulla K, Segni M, et al (2002). A polymorphism within the vitamin D-binding protein gene is associated with Graves' disease but not with Hashimoto's thyroiditis. J Clin Endocrinol Metab, 87, 2564-7.
  19. Poynter JN, Jacobs ET, Figueiredo JC, et al (2010). Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the colon cancer family registry. Cancer Epidemiol Biomarkers Prev, 19, 525-36.
  20. Powe CE, Evans MK, Wenger J, et al (2013). Vitamin D-Binding Protein and Vitamin D Status of Black Americans and White Americans. N Engl J Med, 369, 1991-2000.
  21. Robien K, Butler LM, Wang R, et al (2013). Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore. Br J Nutr, 109, 493-502.
  22. Santos BR, Mascarenhas LP, Boguszewski MC, et al (2013). Variations in the vitamin D-binding protein (DBP) gene are related to lower 25-hydroxyvitamin D levels in healthy girls: a cross-sectional study. Horm Res Paediatr, 79, 162-8.
  23. Sinotte M, Diorio C, Berube S, et al (2009). Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women. Am J Clin Nutr, 89, 634-40.
  24. Speeckaert M, Huang G, Delanghe JR, et al (2006). Biological and clinical aspects of the vitamin D binding protein (Gcglobulin) and its polymorphism. Clin Chim Acta, 372, 3-42.
  25. Taylor JA, Horvomen A, Watson M, et al (1996). Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res, 56, 4108-10.
  26. Wang TJ, Zhang F, Richards JB, et al (2010). Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 376, 180-8.
  27. Weinstein SJ, Mondul AM, Kopp W, et al (2013). Circulating 25-hydroxyvitamin D, vitamin D binding protein, and risk of prostate cancer. Int J Cancer, 132, 2940-7.
  28. Weinstein SJ, Purdue MP, Smith-Warner SA (2014). Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the prostate, lung, colorectal and ovarian cancer screening trial. Int J Cancer, 136, 654-64
  29. Yu K, Yang J, Jiang Y, et al (2014). Vitamin D receptor bsmi polymorphism and colorectal cancer risk: an updated analysis. Asian Pac J Cancer Prev, 15, 4801-7.
  30. Zhang Z, He JW, Fu WZ, et al (2013). An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population. J Bone Miner Res, 28, 1784-92.
  31. Zhao X, Yang B, Yu G, et al (2014). Polymorphisms in the vitamin D receptor (VDR) genes and skin cancer risk in European population: a meta-analysis. Arch Dermatol Res, 306, 545-53.
  32. Zhou L, Zhang X, Chen X, et al (2012). GC Glu416Asp and Thr420Lys polymorphisms contribute to gastrointestinal cancer susceptibility in a Chinese population. Int J Clin Exp Med, 5, 72-9.

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