Next Generation Sequencing of 502 Lifestyle and Nutrition related Genetic Polymorphisms reveals Independent Loci for Low Serum 25-hydroxyvitamin D Levels among Adult Respondents of the 2013 Philippine National Nutrition Survey
Objective. The study determined the relationship of serum vitamin D levels and 502 lifestyle and nutrition-related genetic polymorphisms among adult respondents of the 2013 Philippine National Nutrition Survey (NNS).
Methodology. A total of 1,160 adult respondents of the 2013 NNS living in the National Capital Region, Philippines were enrolled. Of the 1,160 sequenced samples, 833 passed the stringent quality control based on multiple parameters and were used for further analysis. Total serum 25-hydroxyvitamin D [25(OH)D] was determined using electro-chemiluminescence binding assay method. Genomic DNA was used for targeted next generation sequencing of 502 lifestyle and nutrition-related polymorphisms. Analysis of variance, followed by Tukey post hoc analysis, was employed to compare 25(OH)D serum levels across genotypes.
Results. Of the study participants, 56% was classified as having low serum 25(OH)D. The lower serum 25(OH)D was observed in the following gene/genotypes: KNG1 rs11924390 T/T; ANKH rs2454873 G/G; NPFFR2 rs4129733 T/G; SH2B1 rs4788102 G/A; RAP1A rs494453 T/T and CRHBP rs7728378 T/C. These genes were previously associated to the risk of osteoporosis, obesity, type 2 diabetes mellitus, and stress response.
Conclusion. Large-scale analysis of genes has shown great utility in the discovery of genetic factors that play a role in vitamin D nutrition. Interestingly, loci found in this Filipino population cohort were mostly independent from the canonical vitamin D synthesis and metabolism pathways. Understanding how genetic variations interact with nutrition and lifestyle may aid in the prevention of diseases through screening and identification of susceptible patients who would not benefit from regular supplementation with vitamin D because of genetic alterations and may also be used as basis for future development of functional food enriched with vitamin D.
Arabi A, El Rassi R, El-Hajj Fuleihan, G. Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. Nat Rev Endocrinol. 2010;6(10):550–61. https://www.ncbi.nlm.nih.gov/pubmed/20852586. https://doi.org/10.1038/nrendo.2010.146.
Kruger MC, Schollum LM, Kuhn-Sherlock B, et al. The effect of a fortified milk drink on vitamin D status and bone turnover in post-menopausal women from South East Asia. Bone. 2010;46(3):759-67. https://www.ncbi.nlm.nih.gov/pubmed/19895912. https://doi.org/10.1016/j.bone.2009.10.036.
Food and Nutrition Research Institute-Department of Science and Technology. Philippine Nutrition Facts and Figures 2013: Biochemical Survey, 2015.
Alshahrani F, Aljohani N. Vitamin D: Deficiency, sufficiency and toxicity. Nutrients. 2013;5(9):3605-16. https://www.ncbi.nlm.nih.gov/pubmed/24067388. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798924. https://doi.org/10.3390/nu5093605.
Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020;12(4):988. https://www.ncbi.nlm.nih.gov/pubmed/32252338. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231123. https://doi.org/10.3390/nu12040988.
Signorello LB, Shi J, Cai QC, et al. Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D levels among African Americans. PLoS One. 2011;(12):e28623. https://www.ncbi.nlm.nih.gov/pubmed/22205958. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244405. https://doi.org/10.1371/journal.pone.0028623.
Revez JA, Lin T, Qiao Z, et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat. Commun. 2020;11(1):1647. https://www.ncbi.nlm.nih.gov/pubmed/32242144. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118120. https://doi.org/10.1038/s41467-020-15421-7.
Sepulveda-Villegas M, Elizondo-Montemayor L, Trevino V. Identification and analysis of 35 genes associated with vitamin D deficiency: A systematic review to identify genetic variants. J Steroid Biochem Mol Biol. 2020;196:105516. https://www.ncbi.nlm.nih.gov/pubmed/31678109. https://doi.org/ 10.1016/j.jsbmb.2019.105516.
Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure. Circulation. 2005;111(5):697-716. https://www.ncbi.nlm.nih.gov/pubmed/15699287. https://doi.org/10.1161/01.CIR.0000154900.76284.F6.
Vesper HW, Sempos CT. Vitamin D standardization program. Clin Chem. 2011;57(10 Suppl 1):A177. Retrieved from https://meeting.aacc.org/-/media/Files/Meetings-and-Events/Annual-Meeting/2011/AACC_11_FullAbstract.pdf?la=en&hash=A762BB9A047239D3DB858A1DE4D0C21C4C378A7E.
Nimitphong H, Holick MF. Vitamin D status and sun exposure in southeast Asia. Dermatoendocrinol. 2013;5(1):34-7. https://www.ncbi.nlm.nih.gov/pubmed/24494040. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897596. https://doi.org/10.4161/derm.24054.
Zella LA, Kim S, Shevde NK, Pike JW. Enhancers located within two introns of the vitamin d receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D 3. Mol Endocrinol. 2006;20(6):1231-47. https://www.ncbi.nlm.nih.gov/pubmed/16497728. https://doi.org/10.1210/me.2006-0015.
Grübler MR, März W, Pilz S, et al. Vitamin-D concentrations, cardiovascular risk and events - A review of epidemiological evidence. Rev Endocr Metab Disord. 2017;18(2):259-72. https://www.ncbi.nlm.nih.gov/pubmed/28451877. https://doi.org/10.1007/s11154-017-9417-0.
Nissen J, Vogel U, Ravn-Haren G, et al. Common variants in CYP2R1 and GC genes are both determinants of serum 25-hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D3-fortified bread and milk during winter in Denmark. Am J Clin Nutr. 2015;101(1):218-27. https://www.ncbi.nlm.nih.gov/pubmed/25527766. https://doi.org/10.3945/ajcn.114.092148.
Wu Y, Li Y, Lange EM, et al. Genome-wide association study for adiponectin levels in Filipino women identifies CDH13 and a novel uncommon haplotype at KNG1-ADIPOQ. Hum Mol Genet. 2010;19(24):4955-64. https://www.ncbi.nlm.nih.gov/pubmed/20876611. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989895. https://doi.org/10.1093/hmg/ddq423.
Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D. Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1(Suppl 1):S14. https://www.ncbi.nlm.nih.gov/pubmed/17903296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995606. https://doi.org/10.1186/1471-2350-8-S1-S14.
Hunt SC, Hasstedt SJ, Xin Y, et al. Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects. Obesity (Silver Spring). 2011;19(11):2241-7. https://www.ncbi.nlm.nih.gov/pubmed/21818152. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733173. https://doi.org/10.1038/oby.2011.239.
Fu LW, Zhang MX, Wu LJ, Gao LW, Mi J. Gene-gene interaction on central obesity in school-aged children in China. Zhongzhua Liu Xing Bing Xue Za Zhi. 2017;38(7):883-8. https://www.ncbi.nlm.nih.gov/pubmed/28738459. https://doi.org/10.3760/cma.j.issn.0254-6450.2017.07.007.
Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes. 2014;5(4):511-26. https://www.ncbi.nlm.nih.gov/pubmed/25126397. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127586. https://doi.org/10.4239/wjd.v5.i4.511.
Croteau-Chonka DC, Marvelle AF, Lange EM, et al. Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women. Obesity. 2011;19(5):1019-27. https://www.ncbi.nlm.nih.gov/pubmed/20966902. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046220. https://doi.org/10.1038/oby.2010.256.
Hsu YH, Zillikens MC, Wilson SG, et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. PLoS Genet. 2010;6(6):e1000977. https://www.ncbi.nlm.nih.gov/pubmed/20548944. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883588. https://doi.org/10.1371/journal.pgen.1000977.
Enoch MA, Shen PH, Ducci F, et al. Common genetic origins for EEG, alcoholism and anxiety: The role of CRH-BP. PLoS One. 2008;3(10):e3620. https://www.ncbi.nlm.nih.gov/pubmed/18974851. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575401. https://doi.org/10.1371/journal.pone.0003620.
Trummer O, Schweighofer N, Haudum CW, et al. Genetic components of 25-hydroxyvitamin D increase in three randomized controlled trials. J Clin Med. 2020;9(2):570. https://www.ncbi.nlm.nih.gov/pubmed/32093012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074051. https://doi.org/10.3390/jcm9020570.
Food and Nutrition Research Institute-Department of Science and Technology. Philippine Nutrition Facts and Figures 2013: Food Consumption Survey Title, 2015.
Yan X, Zhang N, Cheng S, Wang Z, Qin Y. Gender differences in vitamin D status in China. Med Sci Monit. 2019;25:7094-9. https://www.ncbi.nlm.nih.gov/pubmed/31541605. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767943. https://doi.org/10.12659/MSM.916326.
Manousaki D, Mitchell R, Dudding T, et al. Genome-wide association study for vitamin D levels reveals 69 independent loci. Am J Hum Genet. 2020;106(3):327-37. https://www.ncbi.nlm.nih.gov/pubmed/32059762. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058824. https://doi.org/10.1016/j.ajhg.2020.01.017.
Dahlman I, Dicker A, Jiao H, et al. A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis. Am J Hum Genet. 2007 ;80(6):1115-24. https://www.ncbi.nlm.nih.gov/pubmed/17503329. PMCID: PMC1867099. https://doi.org/10.1086/518445.
Hong J, Hatchell KE, Bradfield JP, et al. Transethnic evaluation identifies low-frequency loci associated with 25-hydroxyvitamin D concentrations. J Clin Endocrinol Metab. 2018;103(4):1380-92. https://www.ncbi.nlm.nih.gov/pubmed/29325163. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276579. https://doi.org/10.1210/jc.2017-01802.
Angeles-Agdeppa I, Perlas LA, Capanzana MV. Vitamin D status of Filipino adults: Evidence from the 8th National Nutrition Survey 2013. Malays J Nutr. 2018;24:395-406.
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