Background Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Methods Using case–control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus–specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. Results A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. Conclusions A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.)

A genome wide association scan of ~6.6 million genotyped or imputed variants in 882 Sardinian Multiple Sclerosis (MS) cases and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (overall P =1.60 × 10-10). CBLB encodes a negative regulator of adaptive immune responses and mice lacking the orthologue are prone to experimental autoimmune encephalomyelitis, the animal model of MS.

The aim of our study was to explore restless legs syndrome (RLS) frequency in multiple sclerosis (MS)-patients and establish whether RLS could be a symptom of MS. Over a period of 1 year, we consecutively enrolled 202 MS-patients and 212 healthy controls, matched for sex and age, in a case-control study. All of them filled in a structured questionnaire according to IRLSSG criteria. Those patients who fit the diagnostic criteria were subsequently examined by a neurologist to verify the effective presence of RLS. A total of 91 MS-patients (45%) responded positively to the questionnaires. The diagnosis of RLS was carried out in 29 subjects (14.4%). Among the healthy controls, a definite diagnosis of RLS was achieved only in 6 subjects (2.8%). The risk of MS patients to present RLS was significantly higher (OR.5.76 P:0.00002) than the general population. None of them was affected by other medical conditions related to RLS developing. The 62 remaining patients presented numbness and weakness of the legs not suggestive of RLS. Our findings confirm a significant correlation between MS and RLS. In our opinion, MS must be definitively included among RLS causes.

Our data confirm Sardinia as a high-risk area for MS and support the relevance of genetic factors in MS, as evidenced in St Peter Island. However, we found an unexpectedly high MS prevalence in one village, in particular in males, suggesting an environmental influence on MS occurrence.

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