Vitamin D genetic risk score is strongly associated with vitamin D levels and relapse rate in pediatric MS patients
Author(s): ,
J Graves
Affiliations:
UCSF, San Francisco
,
L Barcellos
Affiliations:
UC Berkeley, Berkeley, CA
,
A Belman
Affiliations:
National Pediatric MS Center, Stonybrook, Stony Brook
,
M George
Affiliations:
UC Berkeley, Berkeley, CA
,
X Shao
Affiliations:
UC Berkeley, Berkeley, CA
,
H Quach
Affiliations:
UC Berkeley, Berkeley, CA
,
L Krupp
Affiliations:
New York University Langone Medical Center, New York, NY, United States
E Waubant
Affiliations:
UCSF, San Francisco
ECTRIMS Online Library. Graves J. 09/16/16; 146672; P832
Jennifer Graves
Jennifer Graves
Contributions
Abstract

Abstract: P832

Type: Poster

Abstract Category: Clinical aspects of MS - Paediatric MS

Background: Low 25-OH vitamin D levels have been associated with increased risk to have MS and with greater disability and lesion burdens, but establishing a causal relationship has been challenged by multiple confounding factors.

Objective: We sought to determine if an instrumental variable of a genetic risk score for functional single nucleotide polymorphisms in vitamin D pathways is associated with vitamin D levels and relapse activity in pediatric MS subjects.

Methods: Consecutive subjects seen at two Pediatric MS Centers of Excellence between 2006 and 2011 were offered enrollment if they met published criteria for pediatric MS or clinically isolated syndrome with high risk of MS. DNA samples from enrolled subjects who were also followed for relapses were typed for 29 functional polymorphisms in vitamin D pathway genes identified through the literature to be associated with 25-OH vitamin D levels in human subjects. Linear regression models were used to compare genotype to 25-OH D level and Cox regression for association of a genetic risk score for low 25-OH D with relapse hazard.

Results: Six of the 29 polymorphisms were strongly associated with vitamin D levels in pediatric MS subjects (n=181) after Bonferroni correction (p=0.0017) for multiple comparisons. An unweighted risk score of these 6 SNPs was normally distributed and explained 12% of the variance of vitamin D level in these subjects. A five-unit change in the risk score for lower vitamin D (range 0 to 12), was associated with 5.4 ng/ml lower 25-OH D level (95% CI -7.58, -3.14, p=0.0000018). This risk score was associated with a 25% increase in the hazard to relapse (HR 1.25, 95% CI 1.03, 1.49, p=0.017).

Conclusion: A genetic score of six functional polymorphisms captures risk of hypovitaminosis D and identifies those who may be at greater risk of relapse related to this risk factor. These findings support a causal association of vitamin D with relapse rate.

Disclosure: Dr. Graves has no relevant disclosures and is supported by grants from the Race to Erase MS, NMSS, Biogen and Genentech.

Dr. Barcellos: No disclosures

Dr. Noble: No disclosures

Dr. George: No disclosures

Xiarong Shao: No disclosures

Hong Quach: No disclosures

Dr. Belman: No disclosures

Dr. Krupp: No disclosures

Dr. Waubant: No relevant disclosures. She is supported by grants from the NIH, the National MS Society, The Race to Erase MS Foundation. She volunteers on an advisory board for a Novartis trial. She is the site PI for trials with Roche, Biogen and Novartis.

Abstract: P832

Type: Poster

Abstract Category: Clinical aspects of MS - Paediatric MS

Background: Low 25-OH vitamin D levels have been associated with increased risk to have MS and with greater disability and lesion burdens, but establishing a causal relationship has been challenged by multiple confounding factors.

Objective: We sought to determine if an instrumental variable of a genetic risk score for functional single nucleotide polymorphisms in vitamin D pathways is associated with vitamin D levels and relapse activity in pediatric MS subjects.

Methods: Consecutive subjects seen at two Pediatric MS Centers of Excellence between 2006 and 2011 were offered enrollment if they met published criteria for pediatric MS or clinically isolated syndrome with high risk of MS. DNA samples from enrolled subjects who were also followed for relapses were typed for 29 functional polymorphisms in vitamin D pathway genes identified through the literature to be associated with 25-OH vitamin D levels in human subjects. Linear regression models were used to compare genotype to 25-OH D level and Cox regression for association of a genetic risk score for low 25-OH D with relapse hazard.

Results: Six of the 29 polymorphisms were strongly associated with vitamin D levels in pediatric MS subjects (n=181) after Bonferroni correction (p=0.0017) for multiple comparisons. An unweighted risk score of these 6 SNPs was normally distributed and explained 12% of the variance of vitamin D level in these subjects. A five-unit change in the risk score for lower vitamin D (range 0 to 12), was associated with 5.4 ng/ml lower 25-OH D level (95% CI -7.58, -3.14, p=0.0000018). This risk score was associated with a 25% increase in the hazard to relapse (HR 1.25, 95% CI 1.03, 1.49, p=0.017).

Conclusion: A genetic score of six functional polymorphisms captures risk of hypovitaminosis D and identifies those who may be at greater risk of relapse related to this risk factor. These findings support a causal association of vitamin D with relapse rate.

Disclosure: Dr. Graves has no relevant disclosures and is supported by grants from the Race to Erase MS, NMSS, Biogen and Genentech.

Dr. Barcellos: No disclosures

Dr. Noble: No disclosures

Dr. George: No disclosures

Xiarong Shao: No disclosures

Hong Quach: No disclosures

Dr. Belman: No disclosures

Dr. Krupp: No disclosures

Dr. Waubant: No relevant disclosures. She is supported by grants from the NIH, the National MS Society, The Race to Erase MS Foundation. She volunteers on an advisory board for a Novartis trial. She is the site PI for trials with Roche, Biogen and Novartis.

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