TOWARDS AN ENDOPHENOTYPE IN MULTIPLE SCLEROSIS. Issue 11 (9th October 2013) - Dobson, Ruth
Abstract : Objective: An endophenotype is a concept that allows us to describe complex diseases with genetic and environmental contributions. This enables the identification of an "at risk" population. We aim to describe an endophenotypic gradient between healthy controls (HC), siblings of people with MS (PwMS) and PwMS. Background: Siblings of PwMS have an increased risk of developing MS. This increased risk is thought to be a result of genetic and environmental contributions. Epidemiological studies have identified factors contributing to MS including smoking, vitamin–D, infection with and IgG titres against Epstein–Barr virus and HLA–DRB1*1501. A genome wide association study (GWAS) in 2011 gave information regarding the contribution of HLA–type and non–HLA SNPs to MS risk. We set out to integrate these into an endophenotypic risk score for MS. Methods: PwMS (n=78), their unaffected siblings (n=121) and healthy controls (HC; n=103) were recruited. Serum anti–EBNA–1 IgG, vitamin D and cotinine were measured. Subjects were genotyped for HLA–DRB1*1501 and all HLA and non–HLA SNPs associated with MS using the Illumina immunochip. Previous infectious mononucleosis, smoking and month of birth were recorded. The relative risks associated with these factors were established from meta–analyses and integrated into an overall risk score for each individual. Full genetic data was available for 73 people with MS, 107 siblings and 99 HC. Risk scores with genetic contribution from HLA–DRB1*1501 only, and from all MS–associated genetic variants were calculated. Results: When the genetic contribution from HLA–DRB1*1501 alone was used, the mean risk score was significantly higher for PwMS (2.82; SD 1.18) than for siblings (1.98; SD 1.38) or HC (1.53; SD 1.34) (p<0.0005 between MS and siblings and MS and HC; p=0.042 between siblings and HC). A ROC curve comparing PwMS to HC generated an AUC of 0.772 (95% CI 0.702–0.842). PwMS had an OR of 6.29 (95% CI 2.64–14.98, p<0.0001) compared to HC of having a score >1.25 SD higher than the mean HC score. When full genetic data was included, the mean risk score was highest for people with MS (9.71; SD 1.38) intermediate for siblings (8.83; SD 1.47) and lowest for HC (8.00; SD 1.49) (p<0.0005 for all comparisons). A ROC curve comparing PwMS to HC generated an AUC of 0.801 (0.735–0.866). PwMS had an OR of 7.05 (3.31–15.06, p<0.00001) compared to HC of being in the highest risk score group. PwMS had an OR of 1296.00 (95% CI 78.02–21, 527.34; p<0.00001) and siblings 33.06 (95% CI 7.37–148.41; p<0.00001) of being in the highest risk score vs the lowest risk score group. As people with MS had significantly higher vitamin D than HC, presumably secondary to behavioural modification post–diagnosis, a model excluding vitamin D was created. This generated an AUC of 0.818 (95% CI 0.754–0.881). Conclusions: This study demonstrates the validity of the risk score generated, which integrates genetic and environmental risk factors. Siblings have a risk score intermediate to PwMS and HC, confirming their "at risk" position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with environmental factors potentially providing the trigger for clinically apparent disease.