Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

Abstract

Background Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. Objective To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. Methods Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708). Results The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P << 10 −22). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. Conclusion The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

“…Several studies addressed the role of HLA allelic isoforms on the MS phenotype, the most replicated being the association between HLA-DRB1*15:01 and earlier disease onset, 6,8,10,26,27 followed by the predominance of female patients 7,28 and the positivity of oligoclonal bands. 28,29 The HLA alleles and SNPs included for analysis in the present study were originated from the most recent study of the International Multiple Sclerosis Genetics Consortium 5 in which HLA alleles were statistically imputed from a large, high-density SNP data set.…”

The immunogenetics of neurological disease

“…57 Another study confirmed interactions involving pairs of HLA class II alleles: DQA1*01:01-DRB1*15:01 and DQB1*03:01-DQB1*03:02, with a protective effect in MS. 61 In the same study, HLA class I-mediated protection has also been observed for HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01. 61 More recently, HLA-B*44-mediated protection was also reported in MS. 62 Similarly, an imputation study revealed protection by the high-resolution HLA-B*44:02 genotype in MS. 63 Finally, HLA-B*44:02 was observed in LD with HLA-C*05, which independently demonstrated protection for MS in the absence of DRB1 risk alleles; 64 thus, it is challenging to discriminate whether these observations reflect a single effect through strong LD.…”

Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis

“…At the present time, we can state that the wGRS has a low predictive power and clinical utility 3,8,9,13 and we believe that a composite score is needed including different parameters and different layers of data for a clinical application.…”