Lin, R and Taylor, BV and Simpson Jr, S and Charlesworth, J and Ponsonby, A-L and Pittas, F and Dwyer, T and van der Mei, IAF, Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis, Journal of Neurology, Neurosurgery and Psychiatry, 85, (4) pp. 399-404. ISSN 0022-3050 (2014) [Refereed Article]
Copyright 2013 the Authors
Background: The interplay between genes and environmental factors on multiple sclerosis (MS) clinical course has been little studied.
Methods: We conducted a prospective cohort study of 141 participants with relapsing-remitting MS (RRMS) and genotype data followed from 2002 to 2005 and examined genes in the vitamin D metabolism and vitamin D receptor (VDR)/retinoid X receptor (RXR) transcription factor formation pathway. Gene-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis. Genetic predictors of 25-hydroxyvitamin D (25(OH)D) were evaluated by multilevel mixed-effects linear regression. Significance threshold was adjusted by Bonferroni correction for the number of genes evaluated.
Results: The relationship between 25(OH)D and hazard of relapse was significantly different for different alleles of two intronic single nucleotide polymorphisms (SNPs) (rs908742 in PRKCZ and rs3783785 in PRKCH) in the protein kinase C (PKC) family genes (pinteraction=0.001, padj=0.021, respectively). Two other intronic SNPs (rs1993116 in CYP2R1 and rs7404928 in PRKCB) were significantly associated with lower levels of 25(OH)D (pinteraction=0.001, padj=0.021, respectively). A cumulative effect of multiple 'risk' genotypes on 25(OH)D levels and hazard of relapse was observed for the significant SNPs (ptrend=7.12×10-6 for 25(OH)D levels, ptrend=8.86×10-6 for hazard of relapse).
Conclusions: Our data support the hypothesis that gene-vitamin D interactions may influence MS clinical course and that the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse.
|Item Type:||Refereed Article|
|Keywords:||gene-vitamin D interaction, relapse, multiple sclerosis, genetic, circulating vitamin D, epidemiology|
|Research Division:||Medical and Health Sciences|
|Research Group:||Public Health and Health Services|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Nervous System and Disorders|
|Author:||Lin, R (Ms Lin)|
|Author:||Taylor, BV (Professor Bruce Taylor)|
|Author:||Simpson Jr, S (Dr Steve Simpson JR)|
|Author:||Charlesworth, J (Dr Jac Charlesworth)|
|Author:||Pittas, F (Dr Fotini Pittas)|
|Author:||van der Mei, IAF (Associate Professor Ingrid van der Mei)|
|Year Published:||2014 (online first 2013)|
|Funding Support:||Australian Research Council (FT100100553)|
|Web of Science® Times Cited:||18|
|Deposited By:||Menzies Institute for Medical Research|
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