Neurogenetics research group:
Annette Bang Oturai, Helle Bach Søndergaard, Julie Hejgaard, Eva Petersen, Finn Sellebjerg, Per Soelberg Sørensen
One major step towards revealing the genetic component in MS was taken in 2013 identifying 48 new MS genetic variations. We participated in the study as part of the International Multiple Sclerosis Genetics Consortium (IMSGC) investigating thousands of MS patients and controls in the “Immuno-chip project” (study of common autoimmune disease genes). We are now looking forward to the next step investigating the first so called “MS-chip” (replication and fine-mapping of all known MS genes). A study including more than 1000 Danish MS patients/1000 controls, all together the study include more than 18.000 MS patients and 18.000 controls in more than 288.000 single nucleotide polymorphisms (SNPs).
We have made several studies investigating gene-environmental interactions, all based on information from a newly collected questionnaire from 2000 Danish MS patients and 5000 Danish blood donors including more than 100 questions on lifestyle and environmental factors (smoking, alcohol, mononucleosis, BMI, sun habits, geographical upbringing etc.).
Vitamin D is known to have a strong immunomodulatory potential and accumulating evidence is supporting a beneficial effect of vitamin D in the pathogenesis and disease course of MS. Genome-wide association studies (GWAS) have shown significant associations between serum levels of 25(OH)D and single nucleotide polymorphisms (SNPs) in several key genes in the vitamin D metabolism. In 1500 MS patients we have examined the association between 25(OH)D and six GWAS SNPs, season, age, sex, eye colour, body mass index, vitamin D supplements, smoking, fish intake, sun habits and severity of MS. We found effects of environmental factors on 25(OH)D levels and to our knowledge for the first time, effects of SNPs in genes important for 25-hydroxylases in the liver (CYP2R1,gene) and vitamin D metabolism (GC, gene) (Hejgaard et al., ).
It is known that both HLA genes and smoking increases the risk of MS. However, the effect and interaction of smoking and HLA type on treatment response have not yet been investigated. We have investigated if smoking status and HLA type are associated with disease activity and disease severity in interferon-beta (IFN-beta) treated relapsing-remitting MS patients and could demonstrate for the first time a higher disease activity and severity in MS patients who smoked before and during treatment with IFN-beta, and the effect seems to be modulated by HLA-DRB1*15:01. The previously reported interaction between HLA genes, smoking and MS susceptibility may thus extend to an effect on the disease course (Petersen et al., submitted abstract to ECTRIMS 2014)
BMI, mononucleosis and alcohol
To determine the most important genetic and environmental-lifestyle factors for age at disease onset in Danish MS patients we investigated about 1500 patients and tested the predictive value for age of MS onset for: body mass index, smoking habits smoking, alcohol consumption sex; previous mononucleosis; education; HLA-DRB1*15:01 and HLA-A*02:01. We found that high BMI at age 20, previous mononucleosis and high alcohol consumption between age 15-19 are the most important known factors for lowering age at onset in Danish MS patients (Oturai et al., oral presentation at the ECTRIMS congress 2013).
Genetic influence on oligoclonal band status
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in MS. In a Scandinavian collaboration, genetic differences in MS relating to OCB status were studied. Data from earlier GWAS were compared in 1367 OCB positive and 161 OCB negative MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. Results showed that SNPs from the HLA complex and six other loci were associated to OCB status. The study confirmed both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS patients with implications for patient management (Mero, PLoS ONE, 2012).
Genetic influence on treatment and clinical outcome
Investigations of the genetic influence on how patients respond to various disease modifying treatments are important to guide the most effective treatment for each patient.
Previously, six single nucleotide polymorphisms were suggested to be associated with the response to treatment with IFN-β. We investigated these variants in 575 patients with relapsing-remitting MS followed prospectively after the initiation of their first treatment with IFN-β. These gene variants in IRF5, IRF8 and GPC5 did not show association with risk of relapse or disease progression in this patient cohort. However, the analyses showed that the pre-treatment relapses and clinical disease activity during the first two years of treatment may be associated with disease progression in MS patients treated with IFN-β (Sellebjerg et al.,).
The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis (MS). A deletion in the CCR5 gene, which results in lower gene expression of this receptor, could possibly lower disease activity in MS patients. We investigated the impact of CCR532 in patients treated with Natalizumab (Tysabri) and found a less severe disease in patients carrying the deletion, but no effect on disease activity in the investigated cohort (Møller et al., 2013).