Calcified Tissue International

, Volume 84, Issue 3, pp 195–202 | Cite as

Serum 25-Hydroxyvitamin D Levels Are Not Associated with Subclinical Vascular Disease or C-Reactive Protein in the Old Order Amish

  • Erin D. Michos
  • Elizabeth A. Streeten
  • Kathleen A. Ryan
  • Evadnie Rampersaud
  • Patricia A. Peyser
  • Lawrence F. Bielak
  • Alan R. Shuldiner
  • Braxton D. Mitchell
  • Wendy Post
Article

Abstract

The relationship between vitamin D metabolites and subclinical vascular disease is controversial. Because low serum levels of 25-hydroxyvitamin D (25(OH)D) have been associated with many cardiovascular disease (CVD) risk factors, we hypothesized that serum 25(OH)D levels would be inversely associated with inflammation as measured by C-reactive protein (CRP) and with subclinical vascular disease as measured by carotid intimal medial thickness (cIMT) and coronary artery calcification (CAC). We measured 25(OH)D levels in 650 Amish participants. CAC was measured by computed tomography and cIMT by ultrasound. The associations of 25(OH)D levels with natural log(CAC + 1), cIMT, and natural log(CRP) levels were estimated after adjustment for age, sex, family structure, and season of examination. Additional analyses were carried out adjusting for body mass index (BMI) and other CVD risk factors. 25(OH)D deficiency (<20 ng/ml) and insufficiency (21–30 ng/ml) were common among the Amish (38.2% and 47.7%, respectively). 25(OH)D levels were associated with season, age, BMI, and parathyroid hormone levels. In neither the minimally or fully adjusted analyses were significant correlations observed between 25(OH)D levels and CAC, cIMT, or CRP (R2 < 0.01 for all). Contrary to our hypothesis, this study failed to detect a cross-sectional association between serum 25(OH)D levels and CAC, cIMT, or CRP. Either there is no causal relationship between 25(OH)D and CVD risk, or if there is, it may be mediated through mechanisms other than subclinical vascular disease severity.

Keywords

Steroid hormones Vitamin D Coronary artery calcification Vascular disease Inflammation 

References

  1. 1.
    Streeten EA, Levine MA (2002) Vitamin D metabolism or action. In: Emery AE, Rimoin D (eds) Principles and practice of medical genetics, 4th edn. Churchill Livingston, London, pp 2566–2623Google Scholar
  2. 2.
    Spina CS, Tangpricha V, Uskokovic M et al (2006) Vitamin D and cancer. Anticancer Res 26(4A):2515–2524PubMedGoogle Scholar
  3. 3.
    Mathieu C, Adorini L (2002) The coming of age of 1, 25 dihydroxyvitamin D3 analogs as immunomodulatory agents. Trends Mol Med 8:174–178PubMedCrossRefGoogle Scholar
  4. 4.
    Zitterman A, Schleithoff SS, Koerfer R (2005) Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr 94:483–492CrossRefGoogle Scholar
  5. 5.
    Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, Modlin RL, Adams JS (2007) Extra-renal 25-hydroxyvitamin D(3)-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 103:316–321PubMedCrossRefGoogle Scholar
  6. 6.
    Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716PubMedCrossRefGoogle Scholar
  7. 7.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  8. 8.
    Zadshir A, Tareen N, Pan D, Norris K, Martins D (2005) The prevalence of hypovitaminosis D among US adults: data from NHANES III. Ethn Dis 15S5:97–101Google Scholar
  9. 9.
    Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R (1990) Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol 19:559–563PubMedCrossRefGoogle Scholar
  10. 10.
    Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, Reeve J, Warburton EA (2006) Reduced vitamin D in acute stroke. Stroke 37:243–245PubMedCrossRefGoogle Scholar
  11. 11.
    Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D’Agostino RB, Wolf M, Vasan RS (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117:503–511PubMedCrossRefGoogle Scholar
  12. 12.
    Giovannucci E, Liu Y, Hollis BW, Rimm EB (2008) 25-Hydroxyvitamin D and risk of myocardial infarction in men. Arch Intern Med 168:1174–1180PubMedCrossRefGoogle Scholar
  13. 13.
    Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W (2008) Independent association of low serum 25-hydroxyvitamin D and 1, 25 dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 168:1340–1349PubMedCrossRefGoogle Scholar
  14. 14.
    Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, Felsenfeld A, Levine B, Mehrotra R, Norris K (2007) Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 167:1159–1165PubMedCrossRefGoogle Scholar
  15. 15.
    Ford ES, Ajani UA, McGuire LC, Liu S (2005) Concentrations of serum vitamin D and the metabolic syndrome among US adults. Diabetes Care 28:1228–1230PubMedCrossRefGoogle Scholar
  16. 16.
    Baynes KC, Boucher BJ, Feskens EJ, Kromhout D (1997) Vitamin D, glucose intolerance, and insulinemia in elderly men. Diabetologia 40:344–347PubMedCrossRefGoogle Scholar
  17. 17.
    Rigby WF, Stacy T, Fanger MW (1984) Inhibition of T lymphocyte mitogenesis by 1, 25 dihydroxyvitamin D3 (calcitriol). J Clin Invest 74:1451–1455PubMedCrossRefGoogle Scholar
  18. 18.
    Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC (1983) 1, 25 Dihydroxyvitamin D3 receptors in human leukocytes. Science 221:1181–1193PubMedCrossRefGoogle Scholar
  19. 19.
    Briffa NK, Keogh AM, Sambrook PN, Eisman JA (2003) Reduction of immunosupressant therapy requirement in heart transplantation by calcitriol. Transplantation 75:2133–2134PubMedCrossRefGoogle Scholar
  20. 20.
    Lange U, Jung O, Teichmann J, Neeck G (2001) Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis. Osteoporos Int 12:1031–1035PubMedCrossRefGoogle Scholar
  21. 21.
    Mahon BD, Gordon SA, Cruz J (2003) Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol 134:128–132PubMedCrossRefGoogle Scholar
  22. 22.
    Rajasree S, Rajpal K, Kartha CC, Sarma PS, Kutty VR, Iyer CS, Girija G (2001) Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. Eur J Epidemiol 17:567–571PubMedCrossRefGoogle Scholar
  23. 23.
    Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL (1997) Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 96:1755–1760PubMedGoogle Scholar
  24. 24.
    Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, Arcaro G (2006) Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin Endocrinol 65:593–597CrossRefGoogle Scholar
  25. 25.
    McKusick VA (1978) Medical genetics studies of the amish. Johns Hopkins University Press, Baltimore, MDGoogle Scholar
  26. 26.
    Beiler K (2002) Church directory of the Lancaster County Amish. Peqaea Publishers, Gordonsville, PAGoogle Scholar
  27. 27.
    Hsueh WC, Mitchell BD, Schneider JL et al (2000) QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31–34 in the Old Order Amish. Circulation 101:2810–2816PubMedGoogle Scholar
  28. 28.
    Post W, Bielak LF, Ryan KA, Cheng YC, Shen H, Rumberger JA, Sheedy PFII, Shuldiner AR, Peyser PA, Mitchell BD (2007) Determinants of coronary artery and aortic calcification in the Old Order Amish. Circulation 115:717–724PubMedCrossRefGoogle Scholar
  29. 29.
    Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502PubMedGoogle Scholar
  30. 30.
    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832PubMedCrossRefGoogle Scholar
  31. 31.
    Rampersaud E, Bielak LF, Parsa A, Shen H, Post W, Ryan KA, Donnelly P, Rumberger JA, Sheedy PFII, Peyser PA, Shuldiner AR, Mitchell BD (2008) The association of coronary artery calcification and carotid artery intima-media thickness with distinct, traditional coronary artery disease risk factors in asymptomatic adults. Am J Epidemiol 168:1016–1023PubMedCrossRefGoogle Scholar
  32. 32.
    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 30:771–777PubMedCrossRefGoogle Scholar
  33. 33.
    Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211PubMedCrossRefGoogle Scholar
  34. 34.
    Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, Curhan GC (2007) Plasma 25-hydroxyvitamin D levels and the risk of incident hypertension. Hypertension 49:1063–1069PubMedCrossRefGoogle Scholar
  35. 35.
    Arunabh S, Pollack S, Yeh J, Aloia JF (2003) Body fat content and 25-hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab 88:157–161PubMedCrossRefGoogle Scholar
  36. 36.
    Hypponen E, Power C (2006) Vitamin D status and glucose homeostasis in the 1958 British birth cohort: the role of obesity. Diabetes Care 29:2244–2246PubMedCrossRefGoogle Scholar
  37. 37.
    Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, Stehle P (2003) Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 41:105–112PubMedCrossRefGoogle Scholar
  38. 38.
    Kunitomo M, Kinoshita K, Bando Y (1981) Experimental atherosclerosis in rats fed a vitamin D, cholesterol-rich diet. J Pharmacobiodyn 4:718–723PubMedGoogle Scholar
  39. 39.
    Ito M, Cho BH, Kummerow FA (1990) Effects of a dietary magnesium deficiency and excess vitamin D3 on swine coronary arteries. J Am Coll Nut 9:155–163Google Scholar
  40. 40.
    Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P, Heckbert SR, Johnson KC, Manson JE, Sidney S, Trevisan M, Women’s Health Initiative Investigators (2007) Calcium/vitamin D supplementation and cardiovascular events. Circulation 115:827–828CrossRefGoogle Scholar
  41. 41.
    Michos ED, Blumenthal RS (2007) Vitamin D supplementation and cardiovascular disease risk. Circulation 115:827–828PubMedCrossRefGoogle Scholar
  42. 42.
    Autier P, Gandini S (2007) Vitamin D Supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 167:1730–1737PubMedCrossRefGoogle Scholar
  43. 43.
    Arad Y, Spadaro LA, Roth M, Scordo J, Goodman K, Sherman S, Lerner G, Newstein D, Guerci AD (1998) Serum concentration of calcium, 1, 25 vitamin D and parathyroid hormone are not correlated with coronary calcifications. An electron beam computed tomography study. Coron Artery Dis 9:513–518PubMedCrossRefGoogle Scholar
  44. 44.
    Knekt P, Laaksonen M, Mattila C, Härkänen T, Marniemi J, Heliövaara M, Rissanen H, Montonen J, Reunanen A (2008) Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology 19:666–671PubMedCrossRefGoogle Scholar
  45. 45.
    Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC (2005) Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin–angiotensin systems. Am J Physiol Endocrinol Metab 288:E125–E132PubMedCrossRefGoogle Scholar
  46. 46.
    Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002) 1, 25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229–238PubMedGoogle Scholar
  47. 47.
    Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ (2002) Circulating MMP9, vitamin D, and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Q J Med 95:787–796Google Scholar
  48. 48.
    Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R (2003) Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab 88:4623–4632PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Erin D. Michos
    • 1
  • Elizabeth A. Streeten
    • 2
  • Kathleen A. Ryan
    • 2
  • Evadnie Rampersaud
    • 2
  • Patricia A. Peyser
    • 3
  • Lawrence F. Bielak
    • 3
  • Alan R. Shuldiner
    • 2
  • Braxton D. Mitchell
    • 2
  • Wendy Post
    • 1
  1. 1.Division of CardiologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Division of Endocrinology, Diabetes, and NutritionUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborUSA

Personalised recommendations