Novel Heterozygous Variants in the HLA-DRB1 Gene in a Saudi Family with Early-Onset Familial Multiple Sclerosis: Therapeutic Failure and Success

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system. Familial MS is arbitrarily defined as a type of MS that runs in families with one or more first- to third-degree relatives in addition to the index case affected by MS. The aim of this article is to report a unique case of familial MS from Saudi Arabia with two novel variants in the HLA-DRB1 gene that may contribute to the pathogenesis. We observed an unfavorable response to interferon therapy and successful treatment using fingolimod therapy. This observation needs further study, including whether this lack of response is really specific to interferon treatment or possibly a chance occurrence. This family work-up illustrates the importance of genetic testing in identifying variants associated with familial MS, especially if more than two members of the same family are affected. Although this genetic tool is used mainly for research purposes, it had clinical implications for our patient, including the appropriate selection of disease-modifying therapy and prognostic counseling. Further large-scale studies are needed to expand the genetic spectrum of familial MS with clinical and pharmacologic correlation.

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents the current state of knowledge on the impact of HLA-DRB1 gene, functioning both as a component of the patient’s genome and as an environmental risk factor. The impact of known HLA-DRB1 risk variants on the specific structure of the polymorphic HLA-DR molecule, and epitope binding affinity, is presented. The issues of the potential influence of HLA-DRB1 on the occurrence of non-articular disease manifestations and response to treatment are also discussed. A deeper understanding of the role of the HLA-DRB1 gene is essential to explore the complex nature of RA, which is a result of multiple contributing factors, including genetic, epigenetic and environmental factors. It also creates new opportunities to develop modern and personalized forms of therapy.