Impact of serum 25 hydroxyvitamin D deficiency on lipid biomarkers in established coronary artery disease
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Turk J Biochem 2021; aop
Research Article
Shaheena Yassir, Madan Gopal Ramarajan, Seema Patil, Shaheen B. Shaikh,
Yassir M. Abdulla and Poornima A. Manjrekar*
Impact of serum 25 hydroxyvitamin D
deficiency on lipid biomarkers in
established coronary artery disease
https://doi.org/10.1515/tjb-2021-0148 logistic regression analysis showed no statistically signifi-
Received March 22, 2021; accepted August 9, 2021; cant impact of 25(OH)D with lipid biomarkers.
published online September 16, 2021 Conclusions: We found low 25(OH)D mean value among
CAD and a significant negative correlation of 25(OH)D with
Abstract
TC/HDL. This study suggests VDD may affect primary lipid
target resulting in unfavorable outcomes in CAD.
Objectives: Vitamin D deficiency (VDD) is associated with
coronary artery disease (CAD) directly by augmenting Keywords: coronary artery disease; dyslipidemia; Vitamin
atherosclerosis and indirectly through cardiovascular risk D deficiency
factors. The present study was aimed to find an association
of 25 hydroxyvitamin D (25(OH)D) with lipid profile among
established CAD. Introduction
Methods: A cross-sectional study was conducted among
73 patients of angiographically confirmed CAD aged be- Vitamin D is a pro-hormone concerned with skeletal
tween 35 and 55 years of both gender. Serum 25(OH)D and effects. The discovery of vitamin D receptors (VDR) and the
lipid profile were estimated by ELISA kit and Roche auto- 1α-hydroxylase enzyme, which is essential to activate
analyzer respectively. Atherogenic index of plasma (AIP) 25-hydroxyvitamin D [25(OH)D], to 1,25-dihydroxyvitamin
and sdLDL (small dense low-density lipoprotein) were D {1,25(OH)2D} in a variety of cells has sparked interest in
calculated using the accepted formula. its extra skeletal role [1]. Vitamin D deficiency (VDD) had
Results: The mean 25(OH)D level was 17.95 ± 13.51. Only been accounted for worldwide both in sunshine deficient
15% had sufficient 25(OH)D level. There was a significant and sufficient sunshine countries including India. Growing
negative correlation of 25(OH)D with TC/HDL (T.cholesterol/ evidence revealed that VDD is closely associated with
High-density lipoprotein) ratio (p=0.022). Multivariate cardiovascular disease (CVD) directly by augmenting
atherosclerosis [2] and indirectly through its association
with traditional called cardiovascular risk factors, which
are obesity, dyslipidemia, hypertension, diabetes mellitus
*Corresponding author: Poornima A Manjrekar, Department of
Biochemistry, Kasturba Medical College, Mangalore, Manipal
(DM), metabolic syndrome, and inflammation due to the
Academy of Higher Education, Manipal, Karnataka, India, complex biological interaction between vitamin D and its
E-mail: poornima.manjrekar@manipal.edu. https://orcid.org/0000- receptors [3–6]. Apart from this, VDD has got a direct effect
0003-1383-9641 on the cardiovascular system through its interaction with
Shaheena Yassir and Shaheen B. Shaikh, Department of receptors present on cardiomyocytes, vascular myocytes
Biochemistry, Yenepoya Medical College, Yenepoya (Deemed to be
and vascular endothelial cells [7]. In patients with no
University), Derelakatte, Mangalore, Karnataka, India. https://
orcid.org/0000-0001-9300-1851 (S. Yassir). indication of coronary artery disease (CAD), an indepen-
https://orcid.org/0000-0002-6584-3223 (S.B. Shaikh) dent association of [25(OH)D], with the extent of intimal
Madan Gopal Ramarajan, Institute of Bioinformatics, Bangalore, media thickness of thoracic aorta relation was found [8]. In
Karnataka, India; and Manipal Academy of Higher Education, Manipal, established CAD, vitamin D deficient subjects had signifi-
Karnataka, India
cantly high triglyceride (TG) in comparison with subjects
Seema Patil, Department of Statistics, Yenepoya (Deemed to be
University), Mudipu, Mangalore, Karnataka, India
having sufficient vitamin D [9]. Lipoprotein lipase enzyme,
Yassir M. Abdulla, Department of Radiodiagnosis, Srinivas Institute of which is involved in the metabolism of TG, may be regu-
Medical Sciences and Research Centre, Mangalore, Karnataka, India lated by the [25(OH)D] resulting in TG reduction [10] since
Open Access. © 2021 Shaheena Yassir et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0
International License.2 Yassir et al.: Serum 25 hydroxyvitamin D deficiency and lipid biomarkers
CAD is a manifestation of several risk factors, we planned two-tailed and the p-value of less than 0.05 was deemed as statistically
to study in established CAD without taking into account the significant.
individual risk factors. Whether the vitamin D continues to
affect lipid parameters once CAD is clinically established is
not certain. Atherogenic Index of Plasma (AIP) and small Result
dense low-density lipoprotein (sdLDL) are also a marker of
metabolic syndrome. Hence this study was planned to In the present study, 73 patients of CAD participated, with
establish the relationship of serum [25(OH)D] level with 73.8% males and 26.2% females. Vitamin D deficiency was
lipid biomarkers which include serum TG, Total Choles- highly prevalent among total study participants. Table 1
terol (TC), Low-density lipoprotein (LDL), High-density displays the general characteristics of the whole study
Lipoprotein (HDL), AIP, sdLDL among established CAD population. CAD was found to be more prevalent among
patients. males. There were 64.4, 20.5 and 15.06% of [25(OH)D]
deficient, insufficient and sufficient cases, respectively
(Figure 1). Mean lipid values were found to be near normal
Materials and methods in our study participants (Figure 2). Our analysis found a
negative correlation of [25(OH)D] with TC, TG, LDL, and
A cross-sectional study was performed on 73 established CAD partic- TC/HDL ratio, but only the TC/HDL ratio was statistically
ipants of age between 35 and 55 years at the cardiac department of a significant (Table 2). Multivariate regression model anal-
tertiary care hospital with their prior informed consent. G*Power ysis showed no statistically significant impact of 25(OH)D
version 3.1.9 was used to calculate sample size with 0.30 effect size, with TC (β coefficient = −0.112, p=0.804), HDL (β coeffi-
80% power, and 0.05 level of significance. Patients who had a history
cient = −0.03, p=0.710), TC/HDL (β coefficient = 0.003,
of vitamin D supplementation and previous angiography were not
included in the study.
p=0.774), AIP (β coefficient = 0.001, p=0.884), non HDL
The study participants were included in the study after informed (β coefficient = −0.082, p=0.853) and sdLDL (β coeffi-
consent and their rights were protected, as per the Helsinki Declara- cient = 0.003, p=0.984) which is shown in Table 3. There
tion. The research has been complied with the policies of the institu- was no statistically significant association of vitamin D
tion and, as per the fundamentals of the Helsinki Declaration, and has with angiographic severity assessed by number of coronary
been sanctioned by the institutional ethics committee.
vessels stenosed (Table 4).
General physical examination and systemic examination were
done for all participants. Body mass index (BMI) was determined using
the following formula: weight (kg)/height (m)2. According to the World
Health Organisation (WHO), a BMI of 18–24.9 kg/m2 was considered Discussion
average weight, 25–29.9 kg/m2 was considered overweight,
and ≥30 kg/m2 was considered obese. Blood was collected in a sterile
We discovered a high prevalence of vitamin D deficiency
plain vacutainer under aseptic precautions, and serum was separated
by centrifuging for 5 min at 3,000 rotations per minute. The separated among established cases of CAD aged 35–55 years of both
serum was then labeled according to sample number and stored genders in the current research, which aimed to study the
separately for [25(OH)D]. Estimation of lipid biomarkers - TC, HDL, association of vitamin D with lipid indices in established
LDL, TG was done using Roche auto analyzer under the principle of the cases of CAD aged 35–55 years of both genders (Table 1).
enzymatic assay. AIP value was calculated as log[TG/HDL-C. sdLDL
VDD, on the other hand, is a recognized fact among CAD
was calculated as = (0.084 × TG)+(0.281 × TC) − (0.251 × HDL) − 17.236.
Non-HDL was calculated as (TC – HDL). The commercially available patients. Vitamin D can influence endothelial cell function
enzyme-linked immunosorbent assay kit was used to estimate serum by lowering adhesion molecule expression [11]. VDD was
[25(OH)D] on ELx 800 (BioTek ® Instruments, Inc). As per the Current linked to the severity of coronary artery stenosis as
International Osteoporosis Foundation Guidelines, Vitamin D levels measured by the Gensini score. Even after adjustments for
of ≤20 ng/mL, 21–29 ng/mL and ≥30 ng/mL were considered as defi- risk factors of cardiovascular disease, vitamin D appeared to
cient, insufficient and sufficient, respectively [10]. Angiographic
be a significant predictor for angiographic severity of CAD
severity was assessed by the number of stenosis of coronary artery
vessels. [12]. We choose a younger middle age, economically pro-
Statistical analysis was done using Statistical Package for the ductive population, as the prevalence of CAD is currently
Social Sciences 23.0 (SPSS Inc., Chicago, IL. Normality test was per- increasing among the younger population. We specifically
formed, and all the variables were normally distributed. The mean and selected angiographically established CAD because endo-
standard deviation were used to express normally distributed
thelial dysfunction triggers plaque formation, which is
continuous variables. Pearson’s correlation was used to determine the
relationship between [25(OH)D] and lipid biomarkers. The impact of driven by impaired lipid transport mechanisms, stimulating
[25(OH)D] with lipid biomarkers in the study population was investi- an inflammatory response. As a result, lipids play a key role
gated using Multivariate regression model analysis. All p values were in the production of atherosclerosis [13].Yassir et al.: Serum 25 hydroxyvitamin D deficiency and lipid biomarkers 3
Table : Demographic and clinical characteristics of study Table : Correlation of vitamin D with lipid profile among study
population. participants.
Variables Study participants Lipid profile Pearson correlation, r p-Value
Age, years . ± . T.Cholesterol −. .
Male: Female, n : Triglyceride −. .
BMI . ± . HDL . .
Vitamin D, ng/mL . ± . LDL −. .
TC, mg/dL . ± . TC/HDL ratio −.* .*
HDL, mg/dL . ± . AIP . .
TC/HDL . ± . SdLDL −. .
TG, mg/dL . ± . Non HDL −. .
LDL, mg/dL . ± .
HDL, High-density lipoprotein; TG, Triglyceride; LDL, Low density
VLDL, mg/dL . ± .
lipoprotein; AIP, Artherogenic Index of plasma; sdLDL, small dense
AIP . ± .
low density lipoprotein. *p value4 Yassir et al.: Serum 25 hydroxyvitamin D deficiency and lipid biomarkers
improves glucose tolerance and glucose-induced insulin serum [25(OH)D] levels and lipid parameters by reviewing 22
secretion [6], with VDD causing the opposite effect. The observational cross-sectional studies and 10 randomized
study participants were not overtly obese as per BMI, yet a placebo-controlled trials. Overall, cross-sectional studies
significant proportion had vitamin D deficiency. Central found a favorable relationship between HDL-C and serum
obesity, which is more prevalent to CAD risk, can be better [25(OH)D] levels. Furthermore, though all studies have
determined by waist circumference and waist-hip than BMI shown a negative relationship between serum [25(OH)D]
[14] and we have assessed obesity only by BMI. Indians are levels and TG, vitamin D supplementation didn’t demon-
more prone to CAD, despite normal BMI, due to inherently strate any impact on serum TG levels. These findings were
high IR. The presence of genetically predicted higher levels contradictory, with some studies showing a positive corre-
of insulin resistance phenotypes was linked to a higher risk lation, while some studies reported an inverse relationship
of CAD [15]. between serum [25(OH)D] and TG levels. Hyperlipidemia
We found near normal mean lipid values in our study was not a prerequisite for inclusion in any of the studies [22].
participants (Figure 2). This could be due to the treatment According to Ponda et al., a group of 108,711 subjects who
they received; we have not taken into account any treatment received repeated serum [25(OH)D] supplementation and
they received during the study duration. However, we lipid testing 4–26 weeks apart reported a rise in [25(OH)D]
discovered a significant inverse correlation of [25(OH)D] and levels, but a highly significant reduction in TC, LDL, and TG,
TC/HDL ratio but not with any of the other variables as well as an increase in HDL [23]. Over 12 months, Motiwala
(Table 2). Studies have observed that low [25(OH)D] is and Wang [24] randomized overweight participants to
associated with dyslipidemia as well. In a study conducted vitamin D supplementation vs. placebo, finding a substan-
by Dziedzic E et al., among cardiac patients, results showed tial reduction in TG but not in LDL levels. Vitamin
significant negative correlation between the serum [25(OH) D-mediated TG reduction could be mediated through two
D] and TG, LDL-C and TC. They also found low mean vitamin mechanisms: (a) Vitamin D enhances calcium absorption in
D levels among cardiac patients [16]. Since we didn’t find the intestine. The calcium prevents TG synthesis and release
any significant correlation of vitamin D with lipid parame- in the liver, lowering serum TG levels. (b) Vitamin D has an
ters except for TC/HDL, we did multivariate regression inhibitory effect on serum PTH levels. A decrease in PTH
analysis with vitamin D, as the independent predictor and may result in the increased peripheral elimination ofTGs
(T. Cholesterol, HDL, TC/HDL, AlP, sdLDL, non HDL) as [25]. Insulin resistance is another possible factor to explain
multivariate responses (Table 3). There was no statistically the interrelationship of [25(OH)D] and TG: VDD increases
significant impact of [25(OH)D] on lipid biomarkers. insulin resistance [7] which is linked to an increase in VLDL
AIP is a significant predictor of cardiovascular risk [17]. and TG [26]. Calcium reduces the level of total and LDL
sdLDL is strongly associated with metabolic syndrome [18]. cholesterol by decreasing the absorption of fat via the
Wang y et al. found to have a negative association of [25(OH) insoluble calcium fatty acid complex formation [27]. The
D] with TG [pYassir et al.: Serum 25 hydroxyvitamin D deficiency and lipid biomarkers 5
also suggest vitamin D screening among all high-risk car- 5. Scragg R, Sowers M, Bell C. Third national health and nutrition
diac populations. examination Survey. Serum 25-hydroxyvitamin D, diabetes, and
ethnicity in the third national health and nutrition examination
Survey. Diabetes Care 2004;27:2813–8.
6. Thomas GN, Hartaigh B, Bosch JA, Pilz S, Loerbroks A, Kleber ME.
Limitation Vitamin D levels predict all-cause and cardiovascular disease
mortality in subjects with the metabolic syndrome: the
Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.
As the present study was an observational cross-sectional
Diabetes Care 2012;35:1158–64.
study, a causal relationship couldn’t be confirmed. To 7. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B,
validate the link between serum [25(OH)D] level and lipid et al. Independent association of low serum 25-hydroxyvitamin D
biomarker, interventional prospective studies are really and 1,25- dihydroxyvitamin D levels with all-cause and
needed. One of the major limitations of our study was lack cardiovascular mortality. Arch Intern Med 2008;168:1340–9.
8. Kalkan GY, Gür M, Koyunsever NY, Seker T, Gozukara MY, Ucar H,
of control group, using a control group without CAD would
et al. Serum 25-hydroxyvitamin D level and aortic intima-media
have given a better picture. We have not taken into account thickness in patients without clinical manifestation of
any kind of treatment taken by the participants which may atherosclerotic cardiovascular disease. J Clin Lab Anal 2015;29:
affect lipid profile. 305–11.
9. Saedisomeolia A, Taheri E, Djalali M, MalekshahiMoghadam A,
Qorbani M. Association between serum level of vitamin D and
Acknowledgments: Authors acknowledge Manipal Acad- lipid profiles in type 2 diabetic patients in Iran. J Diabetes Metab
emy of Higher Education (award number - CK MU 274777) Disord 2014;13:7.
for financial assistance. 10. Wang JH, Keisala T, Solakivi T, Minasyan A, Kalueff AV, Tuohimaa
This study was presented at Association of Medical P. Serum cholesterol and expression of ApoAI, LXR [beta] and
SREBP2 in vitamin D receptor knock-out mice. J Steroid Biochem
Biochemist of India fourth State Conference – Telangana
2009;113:222–6.
Chapter 11. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K,
Research funding: This study was financially supported et al. Vitamin D deficiency and risk of cardiovascular disease.
by Manipal Academy of Higher Education (award Circulation 2008;117:503–11.
number - CK MU 274777). The funding agency had no 12. Akin F, Ayca B, Kose N, Duran M, Sari M, Uysal OK, et al. Serum
vitamin D levels are independently associated with severity of
involvement in the study’s design, data collection,
coronary artery disease. J Invest Med 2012;60:869–73.
analyzation, and interpretation, report writing, or 13. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the
judgement for submission and publication of article. vulnerable plaque. J Am Coll Cardiol 2006;47:C13–8.
Author contributions: None. 14. Wildman RP, Gu D, Reynolds K, Duan X, Wu X, He J. Are waist
Competing interests: There is no conflict of interest as circumference and body mass index independently associated
declared by the authors. with cardiovascular disease risk in Chinese adults? Am J Clin Nutr
2005;82:1195–202.
Declaration of patient consent: All participants provided
15. Chen W, Wang S, Lv W, Pan Y. Causal associations of insulin
written informed patient consent and were assured of their resistance with coronary artery disease and ischemic stroke: a
privacy and confidentiality. Mendelian randomization analysis. BMJ Open Diabetes Res Care
2020;8:e001217.
16. Dziedzic EA, Przychodzen S, Dabrowski M. The effects of Vitamin D
on severity of coronary artery atherosclerosis and lipid profile of
References cardiac patients. Arch Med Sci 2016;12:1199–206.
17. Won KB, Han D, Lee JH, Choi SY, Chun EJ, Park SH, et al.
1. Adams JS, Hewison M. Extrarenal expression of the Atherogenic index of plasma and coronary artery calcification
25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys 2012; progression beyond traditional risk factors according to baseline
523:95–102. coronary artery calcium score. Sci Rep 2020;10:21324.
2. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D 18. Fan J, Liu Y, Yin S, Chen N, Bai X, Ke Q, et al. Small dense LDL
improves endothelial function in patients with Type 2 diabetes cholesterol is associated with metabolic syndrome traits
mellitus and low vitamin D levels. Diabet Med 2008;25:320–5. independently of obesity and inflammation. Nutr Metab 2019;
3. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, 16:7.
and blood pressure in the third national health and nutrition 19. Wang Y, Si S, Liu J, Wang Z, Jia H, Feng K, et al. The associations
examination Survey. Am J Hypertens 2007;20:713–9. of serum lipids with vitamin D status. PLoS One 2016;11:
4. Lee P, Greenfield JR, Seibel MJ, Eisman JA, Center JR. Adequacy of e0165157.
Vitamin D replacement in severe deficiency is dependent on body 20. Alkhatatbeh MJ, Amara NA, Abdul-Razzak KK. Association of
mass index. Am J Med 2009;122:1056–60. 25-hydroxyvitamin D with HDL-cholesterol and other6 Yassir et al.: Serum 25 hydroxyvitamin D deficiency and lipid biomarkers
cardiovascular risk biomarkers in subjects with non-cardiac oxidative stress in hyperlipidemic patients with type 2 diabetes
chest pain. Lipids Health Dis 2019;18:1–10. mellitus. ARYA Atherosclerosis 2014;10:82.
21. Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum 26. Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma
vitamin D and the metabolic syndrome among US adults. triglycerides in insulin resistance and diabetes. Arch Med Res
Diabetes Care 2005;28:1228–30. 2005;36:232–40.
22. Jorde R, Grimnes G. Vitamin D and metabolic health with special 27. Christensen R, Lorenzen JK, Svith CR, Bartels E, Melanson E, Saris
reference to the effect of vitamin D on serum lipids. Prog Lipid Res W, et al. Effect of calcium from dairy and dietary supplements on
2011;50:303–12. faecal fat excretion: a metaanalysis of randomized controlled
23. Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW. Vitamin trials. Obes Rev 2009;10:475–86.
D may not improve lipid levels: a serial clinical laboratory data 28. Dhibar DP, Sharma YP, Bhadada SK, Sachdeva N, Sahu KK.
study. Circulation 2012;126:270–7. Association of vitamin D deficiency with coronary artery disease. J
24. Motiwala SR, Wang TJ. Vitamin D and cardiovascular risk. Curr Clin Diagn Res 2016;10:OC24–8.
Hypertens Rep 2012;14:209–18. 29. May HT, Bair TL, Galenko O, Horne BD, Lappé DL, Carlquist JF, et al.
25. Eftekhari MH, Akbarzadeh M, Dabbaghmanesh MH, No association between baseline vitamin D levels and angiographic
Hassanzadeh J. The effect of calcitriol on lipid profile and severity of coronary artery disease. Circulation 2010;122:A16033.You can also read
