The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach

Yarwood, Annie; McAllister, Kate; Al-Mudhaffer, Shibeb; Fu, Bo; Flynn, Edward; Symmons, Deborah; Young, Adam; Barton, Anne

doi:10.1136/annrheumdis-2013-204972

Cited by 12 publications

(6 citation statements)

References 11 publications

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“…117 This strategy has linked genetic determinants of vitamin D status with overall human mortality 125 and has also been used to study RA outcomes, albeit with less consistent results. 126 One particular GC SNP (rs2282679) known to be associ ated with low serum 25(OH)D levels has been linked with an increased risk of osteoporotic fractures in patients with RA. 127 …”

Section: Ra Genetic Associations and Vitamin Dmentioning

confidence: 99%

Vitamin D in rheumatoid arthritis—towards clinical application

2015

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In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression.

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Section: Ra Genetic Associations and Vitamin Dmentioning

confidence: 99%

Vitamin D in rheumatoid arthritis—towards clinical application

2015

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“…Only two SNPs at DHCR7 (rs4944997 and its perfect proxy rs4944076) presented a consistent effect size that achieved Bonferroni corrected level of significance after meta-analyzing NOAR and ERAS (P = 0.003 for rs4944997; P = 0.009 for rs4944076). Therefore, the authors concluded that the effect of vitamin D SNPs and consequently vitamin D levels is unlikely to play a major role in the etiology of RA radiographic damage [14].…”

Section: Vitamin Dmentioning

confidence: 99%

Modifiable environmental exposure and risk of rheumatoid arthritis—current evidence from genetic studies

Jiang

Alfredsson

2020

Arthritis Res Ther

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Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology. It has been shown that genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors. Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality. Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data. The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design. In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis. We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions. The application of MR design in the field of rheumatology remains limited. Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found. Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results. Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers). As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered. Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates. To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.

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“…Genetic polymorphisms have been described for all these genes, linked to altered serum levels of vitamin D metabolites (CYP2R1, CYP27B1, CYP24A1 and others) and actions (like those in VDR) 12 . Recent evidence also discloses an association between vitamin D-related polymorphisms and RA susceptibility 13 but not severity 14 . Whether in RA these polymorphisms influence the association between vitamin D levels and clinical features and account for the heterogeneous results previously reported remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Receptor Polymorphism and DHCR7 Contribute to the Abnormal Interplay Between Vitamin D and Lipid Profile in Rheumatoid Arthritis

Rodríguez‐Carrio¹,

Alperi-López²,

Naves-Díaz³

et al. 2019

Sci Rep

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Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNFα-blockade. Vitamin D was decreased in RA (p < 0.001), correlated to HDL-cholesterol (r = 0.217, p < 0.001) and total-/HDL-cholesterol ratio (r = −0.227, p = 0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p = 0.028), higher tender (p = 0.005) and swollen (p = 0.002) joint counts, higher DAS28 (p = 0.018) and HAQ (p = 0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p = 0.008) and vitamin D (p < 0.001) and increased total-cholesterol (p = 0.025) being found in winter/spring. Increasing vitamin D upon TNFα-blockade paralleled RA clinical improvement (r = −0.610, p = 0.027) and DHCR7 elevation (r = 0.766, p = 0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.

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The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach

Cited by 12 publications

References 11 publications

Vitamin D in rheumatoid arthritis—towards clinical application

Vitamin D in rheumatoid arthritis—towards clinical application

Modifiable environmental exposure and risk of rheumatoid arthritis—current evidence from genetic studies

Vitamin D Receptor Polymorphism and DHCR7 Contribute to the Abnormal Interplay Between Vitamin D and Lipid Profile in Rheumatoid Arthritis

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