Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach

Tea Skaaby; Lise Lotte Nystrup Husemoen; Torben Martinussen; Jacob P Thyssen; Michael Melgaard; Betina Heinsbæk Thuesen; Charlotta Pisinger; Torben Jørgensen; Jeanne D Johansen; Torkil Menné; Berit Carlsen; Pal B Szecsi; Steen Stender; Runa Vavia Fenger; Mogens Fenger; Allan Linneberg

doi:10.1371/journal.pone.0057647

Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach

Tea Skaaby, Lise Lotte Nystrup Husemoen, Torben Martinussen, Jacob P Thyssen, Michael Melgaard, Betina Heinsbæk Thuesen, Charlotta Pisinger, Torben Jørgensen, Jeanne D Johansen, Torkil Menné, Berit Carlsen, Pal B Szecsi, Steen Stender, Runa Vavia Fenger, Mogens Fenger, Allan Linneberg

47 Citationer (Scopus)

Abstract

Background: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Methods: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Results: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Conclusion: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

Originalsprog	Engelsk
Tidsskrift	P L o S One
Vol/bind	8
Udgave nummer	2
Sider (fra-til)	e57647
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0057647
Status	Udgivet - 27 feb. 2013

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Skaaby, T., Husemoen, L. L. N., Martinussen, T., Thyssen, J. P., Melgaard, M., Thuesen, B. H., Pisinger, C., Jørgensen, T., Johansen, J. D., Menné, T., Carlsen, B., Szecsi, P. B., Stender, S., Fenger, R. V., Fenger, M., & Linneberg, A. (2013). Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach. P L o S One, 8(2), e57647. https://doi.org/10.1371/journal.pone.0057647

Skaaby, T, Husemoen, LLN, Martinussen, T, Thyssen, JP, Melgaard, M, Thuesen, BH, Pisinger, C, Jørgensen, T, Johansen, JD, Menné, T, Carlsen, B, Szecsi, PB, Stender, S, Fenger, RV, Fenger, M & Linneberg, A 2013, 'Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach', P L o S One, bind 8, nr. 2, s. e57647. https://doi.org/10.1371/journal.pone.0057647

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title = "Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach",

abstract = "Background: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Methods: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Results: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Conclusion: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.",

author = "Tea Skaaby and Husemoen, {Lise Lotte Nystrup} and Torben Martinussen and Thyssen, {Jacob P} and Michael Melgaard and Thuesen, {Betina Heinsb{\ae}k} and Charlotta Pisinger and Torben J{\o}rgensen and Johansen, {Jeanne D} and Torkil Menn{\'e} and Berit Carlsen and Szecsi, {Pal B} and Steen Stender and Fenger, {Runa Vavia} and Mogens Fenger and Allan Linneberg",

year = "2013",

month = feb,

day = "27",

doi = "10.1371/journal.pone.0057647",

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journal = "P L o S One",

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TY - JOUR

T1 - Vitamin d status, filaggrin genotype, and cardiovascular risk factors

T2 - a mendelian randomization approach

AU - Skaaby, Tea

AU - Husemoen, Lise Lotte Nystrup

AU - Martinussen, Torben

AU - Thyssen, Jacob P

AU - Melgaard, Michael

AU - Thuesen, Betina Heinsbæk

AU - Pisinger, Charlotta

AU - Jørgensen, Torben

AU - Johansen, Jeanne D

AU - Menné, Torkil

AU - Carlsen, Berit

AU - Szecsi, Pal B

AU - Stender, Steen

AU - Fenger, Runa Vavia

AU - Fenger, Mogens

AU - Linneberg, Allan

PY - 2013/2/27

Y1 - 2013/2/27

N2 - Background: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Methods: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Results: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Conclusion: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

AB - Background: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Methods: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Results: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Conclusion: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

U2 - 10.1371/journal.pone.0057647

DO - 10.1371/journal.pone.0057647

M3 - Journal article

C2 - 23460889

SN - 1932-6203

VL - 8

SP - e57647

JO - P L o S One

JF - P L o S One

IS - 2

ER -

Vitamin d status, filaggrin genotype, and cardiovascular risk factors: a mendelian randomization approach

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