Objective Low serum 25(OH)D levels are associated with cardiovascular risk factors, and also predict future myocardial infarction (MI), type 2 diabetes (T2DM), cancer and all-cause mortality. Recently several single nucleotide polymorphisms (SNPs) associated with serum 25-hydroxyvitamin D (25(OH)D) level have been identified. If these relations are causal one would expect a similar association between these SNPs and health. Methods DNA was prepared from subjects who participated in the fourth survey of the Troms？ Study in 1994–1995 and who were registered with the endpoints MI, T2DM, cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2007–2010. Genotyping was performed for 17 SNPs related to the serum 25(OH)D level. Results A total of 9528 subjects were selected for genetic analyses which were successfully performed for at least one SNP in 9471 subjects. Among these, 2025 were registered with MI, 1092 with T2DM, 2924 with cancer and 3828 had died. The mean differences in serum 25(OH)D levels between SNP genotypes with the lowest and highest serum 25(OH)D levels varied from 0.1 to 7.8 nmol/L. A genotype score based on weighted risk alleles regarding low serum 25(OH)D levels was established. There was no consistent association between the genotype score or individuals SNPs and MI, T2DM, cancer, mortality or risk factors for disease. However, for rs6013897 genotypes (located at the 24-hydroxylase gene (CYP24A1)) there was a significant association with breast cancer (P<0.05). Conclusion Our results do not support nor exclude a causal relationship between serum 25(OH)D levels and MI, T2DM, cancer or mortality, and our observation on breast cancer needs confirmation. Further genetic studies are warranted, particularly in populations with vitamin D deficiency. Trial Registration ClinicalTrials.gov NCT01395303
References
[1]
DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80: 1689S–1696S.
[2]
Jorde R, Figenschau Y, Emaus N, Hutchinson M, Grimnes G (2010) Serum 25-hydroxyvitamin D levels are strongly related to systolic blood pressure but do not predict future hypertension. Hypertension 55: 792–798.
[3]
Jorde R, Sneve M, Emaus N, Figenschau Y, Grimnes G (2010) Cross-sectional and longitudinal relation between serum 25-hydroxyvitamin D and body mass index: the Troms？ study. Eur J Nutr 49: 401–407.
[4]
Hutchinson MS, Figenschau Y, Nj？lstad I, Schirmer H, Jorde R (2011) Serum 25-hydroxyvitamin D levels are inversely associated with glycated haemoglobin (HbA(1c)). The Troms？ Study. Scand J Clin Lab Invest 71: 399–406.
[5]
Jorde R, Figenschau Y, Hutchinson M, Emaus N, Grimnes G (2010) High serum 25- hydroxyvitamin D concentrations are associated with a favorable serum lipid profile. Eur J Clin Nutr 64: 1457–1464.
[6]
Grimnes G, Emaus N, Joakimsen RM, Figenschau Y, Jenssen T, et al. (2010) Baseline serum 25-hydroxyvitamin D concentrations in the Troms？ Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up. Diabet Med 27: 1107–1115.
[7]
Hutchinson MS, Grimnes G, Joakimsen RM, Figenschau Y, Jorde R (2010) Low serum 25-hydroxyvitamin D levels are associated with increased all-cause mortality risk in a general population: the Troms？ study. Eur J Endocrinol 162: 935–942.
[8]
Knekt P, Laaksonen M, Mattila C, H？rk？nen T, Marniemi J, et al. (2008) Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology 19: 666–671.
[9]
Melamed ML, Michos ED, Post W, Astor B (2008) 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168: 1629–1637.
[10]
Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, et al. (2006) Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98: 451–459.
[11]
Livshits G, Karasik D, Seibel MJ (1999) Statistical genetic analysis of plasma levels of vitamin D: familial study. Ann Hum Genet 63(Pt 5): 429–439.
[12]
Hunter D, De Lange M, Snieder H, MacGregor AJ, Swaminathan R, et al. (2001) Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J Bone Miner Res 16: 371–378.
[13]
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, et al. (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study Lancet 376: 180–188.
[14]
Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, et al. (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19: 2739–2745.
[15]
Thelle DS, F？rde OH, Try K, Lehmann EH (1976) The Troms？ heart study. Methods and main results of the cross-sectional study. Acta Med Scand 200: 107–118.
[16]
Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Nj？lstad I (2011) Cohort profile: The Tromso Study. Int J Epidemiol [Epub ahead of print]. doi:10.1093/ije/dyr049.
[17]
Joseph J, Svartberg J, Nj？lstad I, Schirmer H (2011) Risk factors of type 2 diabetes in groups stratified according to metabolic syndrome. A 10-year follow-up of The Troms？ Study. Eur J Epidemiol 26: 117–124.
[18]
Mannsverk J, Wilsgaard T, Nj？lstad I, Hopstock LA, L？chen ML, et al. (2011) Age and gender differences in incidence and case fatality trends for myocardial infarction: a 30-year follow-up. The Tromso Study. Eur J Cardiovasc Prev Rehabil [Epub ahead of print]. doi:10.1177/1741826711421081.
[19]
Kulathinal S, Karvanen J, Saarela O, Kuulasmaa K (2007) Case-cohort design in practice-experiences from the MORGAM Project. Epidemiol Perspect Innov 4: 15.
[20]
Giovannucci E, Liu Y, Hollis BW, Rimm EB (2008) 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 168: 1174–1180.
[21]
Grimnes G, Almaas B, Eggen AE, Emaus N, Figenschau Y, et al. (2010) Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed. Eur J Endocrinol 163: 339–348.
[22]
Jorde R, Svartberg J, Sundsfjord J (2005) Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens 23: 1639–1644.
[23]
Bu FX, Armas L, Lappe J, Zhou Y, Gao G, et al. (2010) Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet 128: 549–556.
[24]
Shen H, Bielak LF, Ferguson JF, Streeten EA, Yerges-Armstrong LM, et al. (2010) Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification. Arterioscler Thromb Vasc Biol 30: 2648–2654.
[25]
Rodriguez S, Gaunt TR, Day IN (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169: 505–514.
[26]
Lewontin RC (1964) The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics 49: 49–67.
[27]
Gaunt TR, Rodríguez S, Day IN (2007) Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool ‘CubeX’. BMC Bioinformatics 8: 428.
[28]
Engelman CD, Meyers KJ, Ziegler JT, Taylor KD, Palmer ND, et al. (2010) Genome-wide association study of vitamin D concentrations in Hispanic Americans: the IRAS family study. J Steroid Biochem Mol Biol 122: 186–192.
[29]
Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al. (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117: 503–511.
[30]
Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, et al. (2008) Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 358: 1336–1345.
[31]
Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7: 684–700.
[32]
Buttigliero C, Monagheddu C, Petroni P, Saini A, Dogliotti L, et al. (2011) Prognostic role of vitamin d status and efficacy of vitamin d supplementation in cancer patients: a systematic review. Oncologist 16: 1215–1227.
[33]
Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US).
[34]
Ramnath N, Kim S, Christensen PJ (2011) Vitamin D and lung cancer. Expert Rev Respir Med 5: 305–309.
[35]
Barnett CM, Beer TM (2011) Prostate cancer and vitamin d: what does the evidence really suggest? Urol Clin North Am 38: 333–342.
[36]
Yin L, Grandi N, Raum E, Haug U, Arndt V, et al. (2010) Meta-analysis: serum vitamin D and breast cancer risk. Eur J Cancer 46: 2196–2205.
[37]
Chen G, Kim SH, King AN, Zhao L, Simpson RU, et al. (2011) CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin Cancer Res 17: 817–826.
[38]
Anderson LN, Cotterchio M, Cole DE, Knight JA (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: 1708–1717.
[39]
Dorjgochoo T, Delahanty R, Lu W, Long J, Cai Q, et al. (2011) Common Genetic Variants in the Vitamin D Pathway Including Genome-Wide Associated Variants Are Not Associated with Breast Cancer Risk among Chinese Women. Cancer Epidemiol Biomarkers Prev 20: 2313–2316.
[40]
Ma Y, Zhang P, Wang F, Yang J, Liu Z, et al. (2011) Association Between Vitamin D and Risk of Colorectal Cancer: A Systematic Review of Prospective Studies. J Clin Oncol 29: 3775–3782.
[41]
Broderstad AR, Smith-Sivertsen T, Dahl IM, Ingebretsen OC, Lund E (2010) Low prevalence of hereditary hemochromatosis in multiethnic populations in Northern Norway. Scand J Gastroenterol 46: 350–357.
Constans J, Viau M, Bouissou C (1980) Affinity differences for the 25-OH-D3 associated with the genetic heterogeneity of the vitamin D-binding protein. FEBS Lett 111: 107–111.
[44]
Zintzaras E, Rodopoulou P, Koukoulis GN (2006) BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Dis Markers 22: 317–326.
[45]
Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, et al. (2011) Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60: 1624–1631.
