Association of vitamin D-binding protein polymorphisms and serum 25(OH)D concentration varies among Chinese healthy infants of different VDR-FokI genotypes: A multi-centre cross-sectional study
Hing Wai Tsang
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorKeith T. S. Tung
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorRosa S. Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorSiew Yan Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorJoanna Y. L. Tung
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Department of Paediatrics, Hong Kong Children's Hospital, Hospital Authority, Hong Kong SAR, China
Search for more papers by this authorGilbert T. Chua
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorMarco H. K. Ho
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorChi Pui Pang
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorWilfred H. S. Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorGodfrey C. F. Chan
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorIan C. K. Wong
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Patrick Ip
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Correspondence
Patrick Ip, The University of Hong Kong, Room 115, 1/F, New Clinical Building, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China.
Email: [email protected]
Search for more papers by this authorHing Wai Tsang
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorKeith T. S. Tung
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorRosa S. Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorSiew Yan Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorJoanna Y. L. Tung
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Department of Paediatrics, Hong Kong Children's Hospital, Hospital Authority, Hong Kong SAR, China
Search for more papers by this authorGilbert T. Chua
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorMarco H. K. Ho
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorChi Pui Pang
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorWilfred H. S. Wong
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorGodfrey C. F. Chan
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorIan C. K. Wong
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Patrick Ip
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Correspondence
Patrick Ip, The University of Hong Kong, Room 115, 1/F, New Clinical Building, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China.
Email: [email protected]
Search for more papers by this authorAbstract
Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2–12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no competing interests.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
Filename | Description |
---|---|
nbu12656-sup-0001-FigureS1.docxWord 2007 document , 390.9 KB |
Figure S1 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Abbas, S., Linseisen, J., Slanger, T., Kropp, S., Mutschelknauss, E.J., Flesch-Janys, D. 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 Epidemiology, Biomarkers & Prevention, 17, 1339–1343.
- Arguelles, L.M., Langman, C.B., Ariza, A.J., Ali, F.N., Dilley, K., Price, H. et al. (2009) Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins. The Journal of Clinical Endocrinology and Metabolism, 94, 3273–3281.
- Arnaud, J. & Constans, J. (1993) Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Human Genetics, 92, 183–188.
- Atoum, M.F., AlKateeb, D. & AlHaj Mahmoud, S.A. (2015) The Fok1 vitamin D receptor gene polymorphism and 25(OH) D serum levels and prostate cancer among Jordanian men. The Asian Pacific Journal of Cancer Prevention, 16, 2227–2230.
- Bhanushali, A.A., Lajpal, N., Kulkarni, S.S., Chavan, S.S., Bagadi, S.S. & Das, B.R. (2009) Frequency of fokI and taqI polymorphism of vitamin D receptor gene in Indian population and its association with 25-hydroxyvitamin D levels. Indian Journal of Human Genetics, 15, 108–113.
- Bikle, D.D. & Schwartz, J. (2019) Vitamin D binding protein, Total and free Vitamin D levels in different physiological and pathophysiological conditions. Frontiers in Endocrinology, 10, 317.
- Carter, G.D., Berry, J., Durazo-Arvizu, R., Gunter, E., Jones, G., Jones, J. et al. (2017) Quality assessment of vitamin D metabolite assays used by clinical and research laboratories. The Journal of Steroid Biochemistry and Molecular Biology, 173, 100–104.
- Cheung, C.L., Lau, K.S., Sham, P.C., Tan, K.C. & Kung, A.W. (2013) Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency in southern Chinese. Journal of Human Genetics, 58, 749–751.
- Cleve, H. & Constans, J. (1988) The mutants of the vitamin-D-binding protein: more than 120 variants of the GC/DBP system. Vox Sanguinis, 54, 215–225.
- Cooper, J.D., Smyth, D.J., Walker, N.M., Stevens, H., Burren, O.S., Wallace, C. et al. (2011) Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes, 60, 1624–1631.
- Cui, N. & Liu, J. (2018) Physical abuse, emotional abuse, and neglect and childhood behavior problems: a meta-analysis of studies in mainland China. Trauma, Violence, & Abuse, 21, 206–224.
- Engelman, C.D., Fingerlin, T.E., Langefeld, C.D., Hicks, P.J., Rich, S.S., Wagenknecht, L.E. et al. (2008) Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. The Journal of Clinical Endocrinology and Metabolism, 93, 3381–3388.
- Engelman, C.D., Meyers, K.J., Ziegler, J.T., Taylor, K.D., Palmer, N.D., Haffner, S.M. et al. (2010) Genome-wide association study of vitamin D concentrations in Hispanic Americans: the IRAS family study. The Journal of Steroid Biochemistry and Molecular Biology, 122, 186–192.
- Fink, C., Peters, R.L., Koplin, J.J., Brown, J. & Allen, K.J. (2019) Factors affecting vitamin D status in infants. Children, 6, 7.
- Focker, M., Antel, J., Ring, S., Hahn, D., Kanal, O., Ozturk, D. et al. (2017) Vitamin D and mental health in children and adolescents. European Child & Adolescent Psychiatry, 26, 1043–1066.
- Gozdzik, A., Zhu, J., Wong, B.Y., Fu, L., Cole, D.E. & Parra, E.J. (2011) Association of vitamin D binding protein (VDBP) polymorphisms and serum 25(OH)D concentrations in a sample of young Canadian adults of different ancestry. The Journal of Steroid Biochemistry and Molecular Biology, 127, 405–412.
- Hennessy, A., Hourihane, J.O., Malvisi, L., Irvine, A.D., Kenny, L.C., Murray, D.M. et al. (2018) Antenatal vitamin D exposure and childhood eczema, food allergy, asthma and allergic rhinitis at 2 and 5 years of age in the atopic disease-specific Cork BASELINE birth cohort study. Allergy, 73, 2182–2191.
- Karpiński, M., Galicka, A., Milewski, R., Popko, J., Badmaev, V. & Stohs, S.J. (2017) Association between vitamin D receptor polymorphism and serum vitamin D levels in children with low-energy fractures. Journal of the American College of Nutrition, 36, 64–71.
- Kiani, A., Mohamadi-Nori, E., Vaisi-Raygani, A., Tanhapour, M., Elahi-Rad, S., Bahrehmand, F. et al. (2019) Vitamin D-binding protein and vitamin D receptor genotypes and 25-hydroxyvitamin D levels are associated with development of aortic and mitral valve calcification and coronary artery diseases. Molecular Biology Reports, 46, 5225–5236.
- Kurylowicz, A., Ramos-Lopez, E., Bednarczuk, T. & Badenhoop, K. (2006) Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves' disease and the vitamin D status in a Polish population study. Experimental and Clinical Endocrinology & Diabetes, 114, 329–335.
- Lauridsen, A.L., Vestergaard, P., Hermann, A.P., Brot, C., Heickendorff, L., Mosekilde, L. et al. (2005) Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcified Tissue International, 77, 15–22.
- Lauridsen, A.L., Vestergaard, P. & Nexo, E. (2001) Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women. Clinical Chemistry, 47, 753–756.
- Lee, S.W., Chuang, T.Y., Huang, H.H., Liu, C.W., Kao, Y.H. & Wu, L.S. (2016) VDR and VDBP genes polymorphisms associated with susceptibility to tuberculosis in a Han Taiwanese population. Journal of Microbiology, Immunology and Infection, 49, 783–787.
- Li, L.H., Yin, X.Y., Wu, X.H., Zhang, L., Pan, S.Y., Zheng, Z.J. et al. (2014) Serum 25(OH)D and vitamin D status in relation to VDR, GC and CYP2R1 variants in Chinese. Endocrine Journal, 61, 133–141.
- Lu, L., Sheng, H., Li, H., Gan, W., Liu, C., Zhu, J. et al. (2012) Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans. Human Genetics, 131, 505–512.
- Lv, L., Tan, X., Peng, X., Bai, R., Xiao, Q., Zou, T. et al. (2020) The relationships of vitamin D, vitamin D receptor gene polymorphisms, and vitamin D supplementation with Parkinson's disease. Translational Neurodegeneration, 9, 1–13.
- Manousaki, D., Mitchell, R., Dudding, T., Haworth, S., Harroud, A., Forgetta, V. et al. (2020) Genome-wide association study for Vitamin D levels reveals 69 independent loci. American Journal of Human Genetics, 106, 327–337.
- Mathieu, C. (2015) Vitamin D and diabetes: where do we stand? Diabetes Research and Clinical Practice, 108, 201–209.
- McGrath, J.J., Saha, S., Burne, T.H. & Eyles, D.W. (2010) A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations. The Journal of Steroid Biochemistry and Molecular Biology, 121, 471–477.
- Nazemisalman, B., Vahabi, S., Sabouri, E., Hosseinpour, S. & Doaju, S. (2019) Association of vitamin D binding protein and vitamin D receptor gene polymorphisms in Iranian patients with chronic periodontitis. Odontology, 107, 46–53.
- Newton, D.A., Baatz, J.E., Kindy, M.S., Gattoni-Celli, S., Shary, J.R., Hollis, B.W. et al. (2019) Vitamin D binding protein polymorphisms significantly impact vitamin D status in children. Pediatric Research, 86, 662–669.
- Nykjaer, A., Dragun, D., Walther, D., Vorum, H., Jacobsen, C., Herz, J. et al. (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell, 96, 507–515.
- Ogunkolade, B.W., Boucher, B.J., Prahl, J.M., Bustin, S.A., Burrin, J.M., Noonan, K. et al. (2002) Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes, 51, 2294–2300.
- Orton, S.M., Morris, A.P., Herrera, B.M., Ramagopalan, S.V., Lincoln, M.R., Chao, M.J. et al. (2008) Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. The American Journal of Clinical Nutrition, 88, 441–447.
- Powe, C.E., Evans, M.K., Wenger, J., Zonderman, A.B., Berg, A.H., Nalls, M. et al. (2013) Vitamin D-binding protein and vitamin D status of black Americans and white Americans. The New England Journal of Medicine, 369, 1991–2000.
- Rozmus, D., Ciesielska, A., Płomiński, J., Grzybowski, R., Fiedorowicz, E., Kordulewska, N. et al. (2020) Vitamin D binding protein (VDBP) and its gene polymorphisms—the risk of malignant tumors and other diseases. International Journal of Molecular Sciences, 21, 7822.
- Sadat-Ali, M., Al-Turki, H.A., Azam, M.Q. & Al-Elq, A.H. (2016) Genetic influence on circulating vitamin D among Saudi Arabians. Saudi Medical Journal, 37, 996–1001.
- Safadi, F.F., Thornton, P., Magiera, H., Hollis, B.W., Gentile, M., Haddad, J.G. et al. (1999) Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. The Journal of Clinical Investigation, 103, 239–251.
- Santos, B.R., Mascarenhas, L.P., Satler, F., Boguszewski, M.C. & Spritzer, P.M. (2012) Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants. BMC Pediatrics, 12, 1–7.
- Shea, M.K., Benjamin, E.J., Dupuis, J., Massaro, J.M., Jacques, P.F., D'Agostino, R.B., Sr. et al. (2009) Genetic and non-genetic correlates of vitamins K and D. European Journal of Clinical Nutrition, 63, 458–464.
- Tan, M.L., Abrams, S.A. & Osborn, D.A. (2020) Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health. Cochrane Database of Systematic Reviews, 12, CD013046.
- Vitamin D Roundtable on the NHANES Monitoring of Serum 25D: Assay Challenges Options for Resolving Them. (2010) NHANES monitoring of serum 25-Hydroxyvitamin D: a roundtable summary. The Journal of Nutrition, 140, 2030S–2045S.
- Whitfield, G.K., Remus, L.S., Jurutka, P.W., Zitzer, H., Oza, A.K., Dang, H.T. et al. (2001) Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Molecular and Cellular Endocrinology, 177, 145–159.
- Wjst, M., Altmuller, J., Braig, C., Bahnweg, M. & Andre, E. (2007) A genome-wide linkage scan for 25-OH-D(3) and 1,25-(OH)2-D3 serum levels in asthma families. The Journal of Steroid Biochemistry and Molecular Biology, 103, 799–802.
- Yousefzadeh, P., Shapses, S.A. & Wang, X. (2014) Vitamin D binding protein impact on 25-Hydroxyvitamin D levels under different physiologic and pathologic conditions. International Journal of Endocrinology, 2014, 981581.
- Zaki, M., Kamal, S., Basha, W.A., Youness, E., Ezzat, W., El-Bassyouni, H. et al. (2017) Association of vitamin D receptor gene polymorphism (VDR) with vitamin D deficiency, metabolic and inflammatory markers in Egyptian obese women. Genes & Diseases, 4, 176–182.
- Zella, L.A., Shevde, N.K., Hollis, B.W., Cooke, N.E. & Pike, J.W. (2008) Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology, 149, 3656–3667.
- Zhou, J.C., Zhu, Y., Gong, C., Liang, X., Zhou, X., Xu, Y. et al. (2019) The GC2 haplotype of the vitamin D binding protein is a risk factor for a low plasma 25-hydroxyvitamin D concentration in a Han Chinese population. Nutrition & Metabolism, 16, 5.