Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts

Thor Aspelund; Martin R. Grübler; Albert V. Smith; Elias F. Gudmundsson; Martin Keppel; Mary Frances Cotch; Tamara B. Harris; Rolf Jorde; Guri Grimnes; Ragnar Joakimsen; Henrik Schirmer; Tom Wilsgaard; Ellisiv B. Mathiesen; Inger Njølstad; Maja Lisa Løchen; Winfried März; Marcus E. Kleber; Andreas Tomaschitz; Diana Grove-Laugesen; Lars Rejnmark; Karin M.A. Swart; Ingeborg A. Brouwer; Paul Lips; Natasja M. van Schoor; Christopher T. Sempos; Ramón A. Durazo-Arvizu; Zuzana Škrabáková; Kirsten G. Dowling; Kevin D. Cashman; Mairead Kiely; Stefan Pilz; Vilmundur Gudnason; Gudny Eiriksdottir

doi:10.3390/nu11010074

Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts

Thor Aspelund, Martin R. Grübler, Albert V. Smith, Elias F. Gudmundsson, Martin Keppel, Mary Frances Cotch, Tamara B. Harris, Rolf Jorde, Guri Grimnes, Ragnar Joakimsen, Henrik Schirmer, Tom Wilsgaard, Ellisiv B. Mathiesen, Inger Njølstad, Maja Lisa Løchen, Winfried März, Marcus E. Kleber, Andreas Tomaschitz, Diana Grove-Laugesen, Lars RejnmarkKarin M.A. Swart, Ingeborg A. Brouwer, Paul Lips, Natasja M. van Schoor, Christopher T. Sempos, Ramón A. Durazo-Arvizu, Zuzana Škrabáková, Kirsten G. Dowling, Kevin D. Cashman, Mairead Kiely, Stefan Pilz, Vilmundur Gudnason, Gudny Eiriksdottir^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

Original language	English
Article number	74
Pages (from-to)	1-12
Number of pages	12
Journal	Nutrients
Volume	11
Issue number	1
Early online date	2 Jan 2019
DOIs	https://doi.org/10.3390/nu11010074
Publication status	Published - Jan 2019

Funding

21 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands; [email protected] (K.M.A.S.); [email protected] (N.M.v.S.) 22 Department of Health Sciences, Faculty of Sciences and Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands; [email protected] 23 Department of Internal Medicine, Endocrine Section, VU University Medical Center, Funding: Age, Gene/Environment Susceptibility Reykjavik Study: This study has been funded by NIH contract N01-AG012100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), an Intramural Research Program Award (ZIAEY000401) from the National Eye Institute, an award from the National Institute on Deafness and Other Communication Disorders (NIDCD) Division of Scientific Programs (IAA Y2-DC_1004-02), The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. Ludwigshafen RIsk and Cardiovascular Health Study: None. Tromsø Study: None.

Funders	Funder number
Division of Scientific Programs	00-063
National Institutes of Health	N01-AG012100
National Institute on Aging
National Eye Institute	ZIAEY000401
National Institute on Deafness and Other Communication Disorders	IAA Y2-DC_1004-02
Hjartavernd

Keywords

Cohorts
Individual participant data
Mendelian randomization
Mortality
Standardized 25(OH)D
Vitamin D

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/nu11010074

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356674

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Aspelund, T., Grübler, M. R., Smith, A. V., Gudmundsson, E. F., Keppel, M., Cotch, M. F., Harris, T. B., Jorde, R., Grimnes, G., Joakimsen, R., Schirmer, H., Wilsgaard, T., Mathiesen, E. B., Njølstad, I., Løchen, M. L., März, W., Kleber, M. E., Tomaschitz, A., Grove-Laugesen, D., ... Eiriksdottir, G. (2019). Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts. Nutrients, 11(1), 1-12. Article 74. https://doi.org/10.3390/nu11010074

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abstract = "The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.",

keywords = "Cohorts, Individual participant data, Mendelian randomization, Mortality, Standardized 25(OH)D, Vitamin D",

author = "Thor Aspelund and Gr{\"u}bler, {Martin R.} and Smith, {Albert V.} and Gudmundsson, {Elias F.} and Martin Keppel and Cotch, {Mary Frances} and Harris, {Tamara B.} and Rolf Jorde and Guri Grimnes and Ragnar Joakimsen and Henrik Schirmer and Tom Wilsgaard and Mathiesen, {Ellisiv B.} and Inger Nj{\o}lstad and L{\o}chen, {Maja Lisa} and Winfried M{\"a}rz and Kleber, {Marcus E.} and Andreas Tomaschitz and Diana Grove-Laugesen and Lars Rejnmark and Swart, {Karin M.A.} and Brouwer, {Ingeborg A.} and Paul Lips and {van Schoor}, {Natasja M.} and Sempos, {Christopher T.} and Durazo-Arvizu, {Ram{\'o}n A.} and Zuzana {\v S}krab{\'a}kov{\'a} and Dowling, {Kirsten G.} and Cashman, {Kevin D.} and Mairead Kiely and Stefan Pilz and Vilmundur Gudnason and Gudny Eiriksdottir",

year = "2019",

month = jan,

doi = "10.3390/nu11010074",

language = "English",

volume = "11",

pages = "1--12",

journal = "Nutrients",

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number = "1",

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Aspelund, T, Grübler, MR, Smith, AV, Gudmundsson, EF, Keppel, M, Cotch, MF, Harris, TB, Jorde, R, Grimnes, G, Joakimsen, R, Schirmer, H, Wilsgaard, T, Mathiesen, EB, Njølstad, I, Løchen, ML, März, W, Kleber, ME, Tomaschitz, A, Grove-Laugesen, D, Rejnmark, L, Swart, KMA, Brouwer, IA, Lips, P, van Schoor, NM, Sempos, CT, Durazo-Arvizu, RA, Škrabáková, Z, Dowling, KG, Cashman, KD, Kiely, M, Pilz, S, Gudnason, V & Eiriksdottir, G 2019, 'Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts', Nutrients, vol. 11, no. 1, 74, pp. 1-12. https://doi.org/10.3390/nu11010074

TY - JOUR

T1 - Effect of genetically low 25-hydroxyvitamin D on mortality risk

T2 - Mendelian randomization analysis in 3 large european cohorts

AU - Aspelund, Thor

AU - Grübler, Martin R.

AU - Smith, Albert V.

AU - Gudmundsson, Elias F.

AU - Keppel, Martin

AU - Cotch, Mary Frances

AU - Harris, Tamara B.

AU - Jorde, Rolf

AU - Grimnes, Guri

AU - Joakimsen, Ragnar

AU - Schirmer, Henrik

AU - Wilsgaard, Tom

AU - Mathiesen, Ellisiv B.

AU - Njølstad, Inger

AU - Løchen, Maja Lisa

AU - März, Winfried

AU - Kleber, Marcus E.

AU - Tomaschitz, Andreas

AU - Grove-Laugesen, Diana

AU - Rejnmark, Lars

AU - Swart, Karin M.A.

AU - Brouwer, Ingeborg A.

AU - Lips, Paul

AU - van Schoor, Natasja M.

AU - Sempos, Christopher T.

AU - Durazo-Arvizu, Ramón A.

AU - Škrabáková, Zuzana

AU - Dowling, Kirsten G.

AU - Cashman, Kevin D.

AU - Kiely, Mairead

AU - Pilz, Stefan

AU - Gudnason, Vilmundur

AU - Eiriksdottir, Gudny

PY - 2019/1

Y1 - 2019/1

N2 - The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

AB - The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

KW - Cohorts

KW - Individual participant data

KW - Mendelian randomization

KW - Mortality

KW - Standardized 25(OH)D

KW - Vitamin D

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Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts

Abstract

Funding

Keywords

UN SDGs

Access to Document

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