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Association of VDBP and CYP2R1 gene polymorphisms with vitamin D status in women with polycystic ovarian syndrome: a north Indian study

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Abstract

Purpose

Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age and is usually associated with oligo-ovulation/anovulation, obesity, and insulin resistance. Hypovitaminosis D may also be a primary factor in the initiation and development of PCOS. However, little is known about the role of genetic variation in vitamin D metabolism in PCOS aetiology. Therefore, we studied the genetic polymorphisms of CYP2R1 and vitamin D binding protein (VDBP) in an Indian population.

Methods

Serum vitamin D was measured by ELISA. Genotyping of VDBP single nucleotide polymorphisms (SNPs) rs7041 (HaeIII; G>T) and rs4588 (StyI; A>C) and CYP2R1 SNP rs2060793 (HinfI; A>G) was carried out by restriction fragment length polymorphism in 50 cases of PCOS that were compared with 50 age-matched healthy women.

Results

Vitamin D levels were found to be significantly lower in women with PCOS (p = 0.008) than in age-matched controls. There was no significant difference in genotype frequencies of all three polymorphisms (rs7041, rs4588, and rs2060793) between PCOS and control women. In women with a vitamin D deficiency (<20 ng/ml), the GT allele of the VDBP SNP rs7041 (p value =0.04), the VDBP allelic combination Gc1F/1F (T allele of rs4588 and C allele of rs7041) (p value =0.03), and the GA allele of the CYP2R1 SNP rs2060793 (p = 0.05) were associated with an increased risk of developing PCOS.

Conclusions

The present study shows that the GT allele of VDBP SNP rs7041, the VDBP allelic combination (GC1F/1F), and GA allele of CYP2R1 SNP rs2060793 in vitamin D deficient women increase the risk of PCOS.

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References

  1. Franks S (1997) Polycystic ovary syndrome. Arch Dis Child 77:89–90

    Article  CAS  Google Scholar 

  2. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236

    Article  CAS  Google Scholar 

  3. Escobar-Morreale HF, Asunción M, Calvo RM, Sancho J, San Millán JL (2001) Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies. Eur J Endocrinol 145:619–624

    Article  CAS  Google Scholar 

  4. Heutling D, Schulz H, Randeva H, Dodt C, Lehnert H (2007) Polycystic ovary syndrome. Prototype of a cardio-metabolic syndrome. Internist 48:144–153

    Article  CAS  Google Scholar 

  5. Repaci A, Gambineri A, Pasquali R (2011) The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol 335:30–41

    Article  CAS  Google Scholar 

  6. Seshadri KG, Tamilselvan B, Rajendran A (2011) Role of vitamin D in diabetes. J Endocrinol Metab 1:47–56

    CAS  Google Scholar 

  7. Kiyak Caglayan E, Engin-Üstun Y, Sari N, Göçmen AY, Seckin L, Kara M et al (2016) Is there association between vitamin D levels, apelin 36, and visfatin in PCOS? Gynecol Endocrinol 32(5):386–389

    Article  CAS  Google Scholar 

  8. Shahrokhi SZ, Ghaffari F, Kazerouni F (2016) Role of vitamin D in female reproduction. Clin Chim Acta 1(455):33–38

    Article  Google Scholar 

  9. Joham AE, Teede HJ, Cassar S, Stepto NK, Strauss BJ, Harrison CL et al (2016) Vitamin D in polycystic ovary syndrome: relationship to obesity and insulin resistance. Mol Nutr Food Res 60(1):110–118

    Article  CAS  Google Scholar 

  10. Rashidi B, Haghollahi F, Shariat M, Zayerii F (2009) The effects of calcium–vitamin D and metformin on polycystic ovary syndrome: a pilot study. Taiwan J Obstet Gynecol 48:142–147

    Article  Google Scholar 

  11. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D et al (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376:180–188

    Article  CAS  Google Scholar 

  12. Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park H-W (2008) Structural analysis of CYP2R1 in complex with vitamin D3. J Mol Biol 380:95–106

    Article  CAS  Google Scholar 

  13. Prosser DE, Jones G (2004) Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci 29:664–673

    Article  CAS  Google Scholar 

  14. Engelman CD, Meyers KJ, Iyengar SK, Liu Z, Karki CK, Igo RP et al (2013) Vitamin D intake and season modify the effects of the GC and CYP2R1 Genes on 25-hydroxyvitamin D concentrations. J Nutr 143:17–26

    Article  CAS  Google Scholar 

  15. Zhang Y, Wang X, Liu Y, Qu H, Qu S, Wang W et al (2012) The GC, CYP2R1 and DHCR7 genes are associated with vitamin D levels in northeastern Han Chinese children. Swiss Med Wkly 142:w13636

    Google Scholar 

  16. Speeckaert M, Huang G, Delanghe JR, Taes YE (2006) Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta 372:33–42

    Article  CAS  Google Scholar 

  17. White P, Cooke N (2000) The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 11:320–327

    Article  CAS  Google Scholar 

  18. Wehr E, Trummer O, Giuliani A, Gruber H-J, Pieber TR, Obermayer-Pietsch B (2011) Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol 164:741–749

    Article  CAS  Google Scholar 

  19. Group TREP consensus workshop (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19:41–47

    Article  Google Scholar 

  20. Daly AK, Steen VM, Fairbrother KS, Idle JR (1996) CYP2D6 multiallelism. Meth Enzymol 272:199–210

    Article  CAS  Google Scholar 

  21. Lim SS, Davies MJ, Norman RJ, Moran LJ (2012) Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 18:618–637

    Article  CAS  Google Scholar 

  22. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR (2002) Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 30:771–777

    Article  CAS  Google Scholar 

  23. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D (2008) Vitamin D status in Andhra Pradesh: a population based study. Indian J Med Res 127:211–218

    CAS  Google Scholar 

  24. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716

    Article  CAS  Google Scholar 

  25. Grant WB, Holick MF (2005) Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev 10:94–111

    Google Scholar 

  26. Hollis BW (2005) Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 135:317–322

    Article  CAS  Google Scholar 

  27. Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR et al (2009) Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol 161:575–582

    Article  CAS  Google Scholar 

  28. Yildizhan R, Kurdoglu M, Adali E, Kolusari A, Yildizhan B, Sahin HG et al (2009) Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet 280:559–563

    Article  Google Scholar 

  29. Li HWR, Brereton RE, Anderson RA, Wallace AM, Ho CKM (2011) Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metab Clin Exp 60:1475–1481

    Article  CAS  Google Scholar 

  30. Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S et al (2006) Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 114:577–583

    Article  CAS  Google Scholar 

  31. Goswami R, Mishra SK, Kochupillai N (2008) Prevalence & potential significance of vitamin D deficiency in Asian Indians. Indian J Med Res 127:229–238

    CAS  Google Scholar 

  32. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690–693

    Article  CAS  Google Scholar 

  33. Compston JE, Vedi S, Ledger JE, Webb A, Gazet JC, Pilkington TR (1981) Vitamin D status and bone histomorphometry in gross obesity. Am J Clin Nutr 34:2359–2363

    Article  CAS  Google Scholar 

  34. Lerchbaum E, Obermayer-Pietsch B (2012) Mechanisms in endocrinology: vitamin D and fertility: a systematic review. Eur J Endocrinol 166(5):765–778

    Article  CAS  Google Scholar 

  35. Kotsa K, Yavropoulou MP, Anastasiou O, Yovos JG (2009) Role of vitamin D treatment in glucose metabolism in polycystic ovary syndrome. Fertil Steril 92:1053–1058

    Article  CAS  Google Scholar 

  36. Pittas AG, Lau J, Hu FB, Dawson-Hughes B (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029

    Article  CAS  Google Scholar 

  37. Johnson JA, Grande JP, Roche PC, Kumar R (1994) Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28 k in human and rat pancreas. Am J Physiol 267:E356–E360

    CAS  Google Scholar 

  38. Milner RD, Hales CN (1967) The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia 3:47–49

    Article  CAS  Google Scholar 

  39. Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26–34

    Article  CAS  Google Scholar 

  40. Grzegorzewska AE, Ostromecki G, Mostowska A, Sowińska A, Jagodziński PP (2015) Clinical aspects of vitamin D-binding protein gene polymorphisms in hemodialysis patients. Pol Arch Med Wewn 125:8–17

    Google Scholar 

  41. Sinotte M, Diorio C, Bérubé S, Pollak M, Brisson J (2009) Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women. Am J Clin Nutr 89:634–640

    Article  CAS  Google Scholar 

  42. Zhang Y, Yang S, Liu Y, Ren L (2013) Relationship between polymorphisms in vitamin D metabolism-related genes and the risk of rickets in Han Chinese children. BMC Med Genet 14:101

    Article  CAS  Google Scholar 

  43. Kitanaka S, Isojima T, Takaki M, NumakuraC HayasakaK, Igarashi T (2012) Association of vitamin D-related gene polymorphisms with manifestation of vitamin D deficiency in children. Endocr J 59:1007–1014

    Article  CAS  Google Scholar 

  44. Arunabh S, Pollack S, Yeh J, Aloia JF (2003) Body fat content and 25-hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab 88:157–161

    Article  CAS  Google Scholar 

  45. Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G et al (2009) The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest 33:234–238

    Article  Google Scholar 

  46. Belenchia AM, Tosh AK, Hillman LS, Peterson CA (2013) Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr 97(4):774–781

    Article  CAS  Google Scholar 

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Acknowledgements

Immense thanks to Indian Council of Medical Research (ICMR), New Delhi for the financial support. We also thank all the patients for their participation and all the working staff of the departments of Biochemistry and Obstetrics and Gynaecology of V.M.M.C. and Safdarjang Hospital, New Delhi.

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Authors and Affiliations

  1. Department of Biochemistry, Room No. 302, Third Floor, Casualty Building, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India

    Deepa Haldar, Nitin Agrawal, Seema Patel, Kanchan Arora, Aditi Sharma & Bhaskar C. Kabi

  2. Department of Biochemistry, S.M.B.T. Institute of Medical Science and Research Centre, Nashik, Maharashtra, India

    Pankaj Ramrao Kambale

  3. Department of Anaesthesia, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India

    Manish Tripathi

  4. Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India

    Aruna Batra

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  1. Deepa Haldar
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Haldar, D., Agrawal, N., Patel, S. et al. Association of VDBP and CYP2R1 gene polymorphisms with vitamin D status in women with polycystic ovarian syndrome: a north Indian study. Eur J Nutr 57, 703–711 (2018). https://doi.org/10.1007/s00394-016-1357-z

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