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• W4367311393 abstract "In recent years, the association between low levels of vitamin D (measured as plasma level of 25-hydroxyvitamin D) and psoriasis has been debated. Besides playing a key role in calcium homeostasis and bone metabolism, vitamin D has several immunomodulatory actions, and suboptimal vitamin D status may be a risk factor for autoimmune diseases (Holick, 2007Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10869) Google Scholar). Several case-control studies have found low levels of plasma vitamin D in patients with psoriasis compared with the levels in healthy controls; however, these findings have been in studies with small sample sizes (Lee and Song, 2018Lee Y.H. Song G.G. Association between circulating 25-hydroxyvitamin D levels and psoriasis, and correlation with disease severity: a meta-analysis.Clin Exp Dermatol. 2018; 43: 529-535Crossref PubMed Scopus (0) Google Scholar), and the findings could therefore be due to random effects. To elucidate the association between vitamin D and psoriasis, we assessed the levels of plasma 25-hydroxyvitamin D in 35,973 individuals from the Danish general population using data from the Copenhagen City Heart Study and the Copenhagen General Population Study (Madsen et al., 2017Madsen C.M. Varbo A. Nordestgaard B.G. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.Eur Heart J. 2017; 38: 2478-2486Crossref PubMed Scopus (337) Google Scholar). All participants gave written informed consent. Both studies were conducted according to the Declaration of Helsinki and were approved by the Danish Ethics Committees (KF-100.2039/91 and H-KF-01-144/01). Approximately 114,000 individuals from the two Copenhagen cohort studies were also genotyped for seven genetic variants biologically linked to and associated with plasma 25-hydroxyvitamin D (Çolak et al., 2021Çolak Y. Nordestgaard B.G. Afzal S. Low vitamin D and risk of bacterial pneumonias: Mendelian randomisation studies in two population-based cohorts.Thorax. 2021; 76: 468-478Crossref PubMed Scopus (0) Google Scholar). To avoid population stratification bias, we only included individuals of Danish or Scandinavian descent (Haycock et al., 2016Haycock P.C. Burgess S. Wade K.H. Bowden J. Relton C. Davey Smith G.D. Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies.Am J Clin Nutr. 2016; 103: 965-978Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). We collected data on psoriasis by linking participants to the Danish National Patient Registry, which contains diagnoses for all in-patients and outpatients in Danish hospitals since 1977 (Schmidt et al., 2015Schmidt M. Schmidt S.A.J. Sandegaard J.L. Ehrenstein V. Pedersen L. Sørensen H.T. The Danish National Patient Registry: a review of content, data quality, and research potential.Clin Epidemiol. 2015; 7: 449-490Crossref PubMed Scopus (2486) Google Scholar), registered according to the International Classification of Diseases. Patients with psoriasis were identified by the International Classification of Diseases, Eight Revision codes 696.09, 696.10, and 696.19 and International Classification of Diseases, Tenth Revision code L40, compatible with moderate-to-severe psoriasis (Ahlehoff et al., 2011Ahlehoff O. Gislason G.H. Charlot M. Jørgensen C.H. Lindhardsen J. Olesen J.B. et al.Psoriasis is associated with clinically significant cardiovascular risk: A Danish nationwide cohort study.J Intern Med. 2011; 270: 147-157Crossref PubMed Scopus (337) Google Scholar) because these patients are referred to a dermatologist in a hospital setting and thus captured by the Danish National Patient Registry. Plasma samples for measurement of 25-hydroxyvitamin D were taken on the day of study enrollment. The concentrations of 25-hydroxyvitamin D were measured using a direct competitive chemiluminescent immunoassay (DiaSorin, Stillwater, MN), blinded to information on genetic variants and psoriasis. At study enrollment, a physical examination was performed, including measurements of blood pressure, body height and weight, and blood samples for biochemical analyses. No skin evaluation was performed. Of the 35,973 individuals included in the observational analyses, 152 had a diagnosis of moderate-to-severe psoriasis on the day of enrollment. Because only 20% of patients with psoriasis have moderate-to-severe disease, this number is in line with what would be expected in a population with a psoriasis prevalence of 2−3% (Michalek et al., 2017Michalek I.M. Loring B. John S.M. A systematic review of worldwide epidemiology of psoriasis.J Eur Acad Dermatol Venereol. 2017; 31: 205-212Crossref PubMed Scopus (564) Google Scholar). The median seasonally adjusted plasma 25-hydroxyvitamin D level was 50 nmol/l (interquartile range = 32−67) in individuals with moderate-to-severe psoriasis and 49 nmol/l (interquartile range = 35−65) in individuals without moderate-to-severe psoriasis (P = 0.92). Individuals with insufficient (25−50 nmol/l) or deficient (<25 nmol/l) levels of seasonally adjusted plasma 25-hydroxyvitamin D did not have an increased risk of moderate-to-severe psoriasis compared with individuals with an optimal level (>50 nmol/l) in a multivariable model adjusted for age, sex, body mass index, kidney function (estimated glomerular filtration rate), inflammatory bowel disease, and study (Copenhagen General Population Study/Copenhagen City Heart Study) (Figure 1, upper panel). On a continuous scale using restricted cubic splines, the risk of moderate-to-severe psoriasis did not increase with decreasing seasonally adjusted plasma 25-hydroxyvitamin D (Figure 1, lower panel). To avoid confounding and reverse causation, we used genetic variants as proxies for plasma 25-hydroxyvitamin D (Lawlor et al., 2008Lawlor D.A. Harbord R.M. Sterne J.A.C. Timpson N. Davey Smith G.D. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.Stat Med. 2008; 27: 1133-1163Crossref PubMed Scopus (1754) Google Scholar) and did not find an increased risk of psoriasis in individuals genetically predisposed to lower levels of plasma 25-hydroxyvitamin D (Figure 2).Figure 2Risk of psoriasis according to plasma vitamin D decreasing genetic variants. The time until the first psoriasis diagnosis was assessed using Cox regression models with age as the underlying time scale (age adjusted). Because genes are present from birth, we included all psoriasis events; thus, the entry in the Cox model was at the start of the Danish National Patient Registry (January 1, 1997) or at birth for individuals born after 1977. Follow-up ended at psoriasis diagnosis, at death, at emigration, or on December 13, 2018, and the median follow-up was 42 years. Analyses were adjusted for age (underlying timescale), sex, and study (Copenhagen City Heart Study/Copenhagen General Population Study). No., number; CI, confidence interval; HR, hazard ratio.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In conclusion, using both cross-sectional and genetic data from more than 100,000 individuals from the Danish general population, we did not find an association between plasma 25-hydroxyvitamin D and the risk of moderate-to-severe psoriasis. Limitations of this study include the use of International Classification of Diseases codes, which resulted in no cases of mild disease and a possible time delay from onset of symptom to diagnosis as well as limited power. Our findings are in line with those of a previous cross-sectional population-based study from the United States (Wilson, 2013Wilson P.B. Serum 25-hydroxyvitamin D status in individuals with psoriasis in the general population.Endocrine. 2013; 44: 537-539Crossref PubMed Scopus (19) Google Scholar) but are in contrast to those of previous case-control studies (Lee and Song, 2018Lee Y.H. Song G.G. Association between circulating 25-hydroxyvitamin D levels and psoriasis, and correlation with disease severity: a meta-analysis.Clin Exp Dermatol. 2018; 43: 529-535Crossref PubMed Scopus (0) Google Scholar). The evidently conflicting results between case-control and cross-sectional studies could be a result of sampling or publication bias. Recently, Zhang et al., 2022Zhang Y. Jing D. Zhou G. Xiao Y. Shen M. Chen X. et al.Evidence of a causal relationship between vitamin D status and risk of psoriasis from the UK Biobank study.Front Nutr. 2022; 9807344Google Scholar found an increased risk of incident psoriasis with decreasing levels of plasma vitamin D in a prospective analysis of the UK Biobank. Even though Zhang et al., 2022Zhang Y. Jing D. Zhou G. Xiao Y. Shen M. Chen X. et al.Evidence of a causal relationship between vitamin D status and risk of psoriasis from the UK Biobank study.Front Nutr. 2022; 9807344Google Scholar adjusted for body mass index in their observational analyses, the association seems to be driven by obesity (body mass index > 30 mmHg) according to their stratified analyses. The mean body mass index in participants from the UK Biobank was higher than that of individuals in our study (27.4 kg/m2 vs. 25.5 kg/m2), and because obesity is strongly associated with vitamin D deficiency (Pereira-Santos et al., 2015Pereira-Santos M. Costa P.R.F. Assis A.M.O. Santos C.A.S.T. Santos D.B. Obesity and vitamin D deficiency: a systematic review and meta-analysis.Obes Rev. 2015; 16: 341-349Crossref PubMed Scopus (525) Google Scholar), this may in part explain the discrepancies between our study and findings in the UK Biobank. Furthermore, although data from the UK Biobank indicate a causal role for vitamin D in the development of psoriasis, we cannot confirm this in our cohort. Zhang et al., 2022Zhang Y. Jing D. Zhou G. Xiao Y. Shen M. Chen X. et al.Evidence of a causal relationship between vitamin D status and risk of psoriasis from the UK Biobank study.Front Nutr. 2022; 9807344Google Scholar use genetic variants discovered in GWAS, whereas in our study, we use genetic variants involved in the synthesis, conversion, or/and metabolism of plasma 25-hydroxyvitamin D (Çolak et al., 2021Çolak Y. Nordestgaard B.G. Afzal S. Low vitamin D and risk of bacterial pneumonias: Mendelian randomisation studies in two population-based cohorts.Thorax. 2021; 76: 468-478Crossref PubMed Scopus (0) Google Scholar). Using genetic variants chosen only by the association in GWAS increases the risk of bias from pleiotropy (Burgess and Gill, 2022Burgess S. Gill D. Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical.Eur Heart J. 2022; 43 ([published correction appears in Eur Heart J 2022;43:2659]): 1740-1742Crossref PubMed Scopus (0) Google Scholar), which means that the genetic variants influence the risk of psoriasis through another pathway other than vitamin D. This argument is further supported by the insignificant results from pleiotropy-robust methods reported by Zhang et al., 2022Zhang Y. Jing D. Zhou G. Xiao Y. Shen M. Chen X. et al.Evidence of a causal relationship between vitamin D status and risk of psoriasis from the UK Biobank study.Front Nutr. 2022; 9807344Google Scholar. Recently, a Mendelian Randomization study with 13,229 psoriasis cases and 21,543 controls did not find evidence of a causal relationship between plasma vitamin D and psoriasis (Bohmann et al., 2023Bohmann P. Stein M. Konzok J. Tsoi L.C. Elder J.T. Leitzmann M.F. et al.Relationship between genetically proxied vitamin D and psoriasis risk: a Mendelian randomization study [epub ahead of print].Clin Exp Dermatol. 2023; (accessed March 13, 2023)https://doi.org/10.1093/ced/llad095Crossref Google Scholar). In further support of this and our findings, randomized controlled trials have not been able to show an effect of oral vitamin D supplementation on the risk or/and severity of psoriasis (Theodoridis et al., 2021Theodoridis X. Grammatikopoulou M.G. Stamouli E.M. Talimtzi P. Pagkalidou E. Zafiriou E. et al.Effectiveness of oral vitamin D supplementation in lessening disease severity among patients with psoriasis: a systematic review and meta-analysis of randomized controlled trials.Nutrition. 2021; 82111024Crossref PubMed Scopus (13) Google Scholar), and thus, plasma vitamin D seems to have a low, if any, effect on the risk of psoriasis. All participants gave written informed consent. Both studies were conducted according to the Declaration of Helsinki and were approved by the Danish Ethics Committees (KF-100.2039/91 and H-KF-01-144/01). Data from the Copenhagen General Population Study are subject to protection from the national Danish Data Protection Agency, and we are not allowed to share the data ourselves. However, interested researchers can contact members of the steering committee to request data access. Additional data are available upon request, and requests may be made to the corresponding author. Charlotte Näslund-Koch: http://orcid.org/0000-0003-2414-3076 Signe Vedel-Krogh: http://orcid.org/0000-0002-0435-1110 Stig Egil Bojesen: http://orcid.org/0000-0002-4061-4133 Lone Skov: http://orcid.org/0000-0002-4784-9680 CNK has served as an investigator for Galderma, Abbvie, LEO Pharma, and CSL Behring. LS has received research funding from Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the LEO Foundation, and the Kgl Hofbundtmager Aage Bang Foundation as well as honoraria as a consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, LEO Pharma, Janssen, UCB, Almirall, Bristol-Myers Squibb, and Sanofi. She has served as an investigator for AbbVie, Pfizer, Sanofi, Janssen, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novartis, Regeneron, Galderma, and LEO Pharma. The remaining authors state no conflict of interest. We would like to thank the participants and the staff of the Copenhagen City Heart Study and the Copenhagen General Population Study. This study was funded by Krista and Viggo Petersen's Foundation and the Danish National Psoriasis Foundation. Conceptualization: CNK, SVK, SEB, LS; Formal Analysis: CNK, SVK; Funding Acquisition: CNK, SVK, SEB, LS; Methodology: CNK, SVK, SEB, LS; Project Administration: CNK, SEB, LS; Supervision: SVK, SEB, LS; Visualization: CNK; Writing – Original Draft Preparation: CNK, Writing – Review and Editing: SVK, SEB, LS" @default.
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• W4367311393 date "2023-10-01" @default.
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• W4367311393 title "Plasma Vitamin D Is Not Associated with Moderate-to-Severe Psoriasis: Results from Danish General Population Studies" @default.
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