scholarly journals An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1607
Author(s):  
Nadia Barizzone ◽  
Rachele Cagliani ◽  
Chiara Basagni ◽  
Ferdinando Clarelli ◽  
Laura Mendozzi ◽  
...  

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

2019 ◽  
Vol 10 ◽  
Author(s):  
Nicole Ziliotto ◽  
Giovanna Marchetti ◽  
Chiara Scapoli ◽  
Matteo Bovolenta ◽  
Silvia Meneghetti ◽  
...  

2016 ◽  
Vol 2 ◽  
pp. 205521731664872 ◽  
Author(s):  
Julia Y Mescheriakova ◽  
Linda Broer ◽  
Simin Wahedi ◽  
André G Uitterlinden ◽  
Cornelia M van Duijn ◽  
...  

Background Approximately 20% of multiple sclerosis patients have a family history of multiple sclerosis. Studies of multiple sclerosis aggregation in families are inconclusive. Objective To investigate the genetic burden based on currently discovered genetic variants for multiple sclerosis risk in patients from Dutch multiple sclerosis multiplex families versus sporadic multiple sclerosis cases, and to study its influence on clinical phenotype and disease prediction. Methods Our study population consisted of 283 sporadic multiple sclerosis cases, 169 probands from multiplex families and 2028 controls. A weighted genetic risk score based on 102 non-human leukocyte antigen loci and HLA-DRB1*1501 was calculated. Results The weighted genetic risk score based on all loci was significantly higher in familial than in sporadic cases. The HLA-DRB1*1501 contributed significantly to the difference in genetic burden between the groups. A high weighted genetic risk score was significantly associated with a low age of disease onset in all multiple sclerosis patients, but not in the familial cases separately. The genetic risk score was significantly but modestly better in discriminating familial versus sporadic multiple sclerosis from controls. Conclusion Familial multiple sclerosis patients are more loaded with the common genetic variants than sporadic cases. The difference is mainly driven by HLA-DRB1*1501. The predictive capacity of genetic loci is poor and unlikely to be useful in clinical settings.


Author(s):  
Maria Gazouli ◽  
Leonardo Sechi ◽  
Daniela Paccagnini ◽  
Stefano Sotgiu ◽  
Giannina Arru ◽  
...  

Background:Multiple sclerosis (MS) is believed to be an autoimmune disease occurring in genetically predisposed individuals after an appropriate environmental exposure such as viral infections. Recent studies suggest a significant association between MS and the functional 5’-(GT)n polymorphism in the promoter region of the NRAMP1 gene. In the present study we aimed to evaluate the contribution of the allelic variation in the NRAMP1 promoter to MS susceptibility and to study the role of viral infection in relation to specific NRAMP1 genotypes, in a Sardinian cohort.Methods:Sixty MS patients and 66 healthy individuals were genotyped, and screened for the presence of Epstein-bar virus (EBV) and JC virus (JCV) sequences.Results:Consistent with previous autoimmune disease studies, allele 3 at the functional 5’(GT)n promoter region repeat polymorphism, was significantly overrepresented among MS patients when compared to controls (p=0.02). The EBV and JCV sequences were detected in 8/60 (13.33%) and in 4/60 (6.66%) of MS patients respectively and in 5/66 (7.57%) and in 0/66 of controls.Conclusion:The allelic variation in the NRAMP1 promoter may contribute to MS susceptibility in the Sardinian population. The viral sequences were not confined to a specific NRAMP1 genotype.


2009 ◽  
Vol 11 (3) ◽  
pp. 122-126 ◽  
Author(s):  
Sarah A. Morrow ◽  
Marcelo Kremenchutzky

Multiple sclerosis (MS) is a common disabling neurologic disease with an overall prevalence in Canada of 240 in 100,000. Multiple sclerosis clinics are located at tertiary-care centers that may be difficult for a patient to access during an acute relapse. Many relapses are evaluated by primary-care physicians in private clinics or emergency departments, but these physicians' familiarity with MS is not known. Therefore, a survey was undertaken to determine the knowledge and experience of primary-care physicians regarding the diagnosis and treatment of MS relapses. A total of 1282 licensed primary-care physicians in the catchment area of the London (Ontario, Canada) Multiple Sclerosis Clinic were identified and mailed a two-page anonymous survey. A total of 237 (18.5%) responses were obtained, but only 216 (16.8%) of these respondents were still in active practice. Of these 216 physicians, only 9% reported having no MS patients in their practice, while 70% had one to five patients, 16.7% had six to ten, and 1.9% had more than ten (3.7% did not respond to this question). Corticosteroids were recognized as an MS treatment by 49.5% of the respondents, but only 43.1% identified them as a treatment for acute relapses. In addition, 31% did not know how to diagnose a relapse, and only 37% identified new signs or symptoms of neurologic dysfunction as indicating a potential relapse. Despite the high prevalence of MS in Canada, primary-care physicians require more education and support from specialists in MS care regarding the diagnosis and treatment of MS relapses.


2021 ◽  
Vol 7 (4) ◽  
pp. 205521732110615
Author(s):  
Peter Rieckmann ◽  
Robert Zivadinov ◽  
Alexey Boyko ◽  
Krzysztof Selmaj ◽  
Jessica K. Alexander ◽  
...  

Objective Describe the long-term outcomes of early-start (ES) and delayed-start (DS) glatiramer acetate 40 mg/mL treatment three times weekly (GA40) for up to seven years in the Glatiramer Acetate Low-frequency Administration (GALA) study in patients with relapsing multiple sclerosis (RMS). Methods Patients were evaluated every three to six months. The primary efficacy endpoint was annualized relapse rate (ARR); additional endpoints were exploratory or post hoc. For efficacy, data from the entire exposure period were used for the ES and DS cohorts. For safety, exposure only under GA40 was considered. Results Of the patients who continued into the open-label extension (OLE), 580/834 (70%) ES and 261/419 (62%) DS completed the OLE. For the entire placebo-controlled and OLE study period, ARR was 0.26 for ES and 0.31 for DS patients (risk ratio = 0.83; 95% confidence interval [CI]: 0.70–0.99). ES prolonged median time to first relapse versus DS (4.9 versus 4.3 years; hazard ratio = 0.82; 95% CI: 0.6–0.96). OLE-only results showed DS patients experienced similar efficacy for relapse and disability outcomes as ES patients. Adverse events were consistent with the well-established GA safety profile. Conclusions GA40 treatment conferred clinical benefit up to seven years, resulting in sustained efficacy and was generally well tolerated in RMS patients.


2015 ◽  
Vol 22 (8) ◽  
pp. 1080-1085 ◽  
Author(s):  
Sakari Simula ◽  
Tomi Laitinen ◽  
Tiina M Laitinen ◽  
Tuula Tarkiainen ◽  
Päivi Hartikainen ◽  
...  

Background: Fingolimod modulates sphingosine-1-phosphate receptors that are also found in cardiovascular tissue. Objective: To investigate the effects of fingolimod on cardiac autonomic regulation prospectively. Methods: Twenty-seven relapsing–remitting multiple sclerosis patients underwent 24-hour electrocardiogram recording before, at the first day of fingolimod treatment (1d) and after three months of continuous dosing (3mo). The time interval between two consecutive R-peaks (RR-interval) was measured. Cardiac autonomic regulation was assessed by the various parameters of heart rate variability. Parasympathetic stimulation prolongs the RR-interval and increases heart rate variability while the effects of sympathetic stimulation are mainly the opposite. The low frequency/high frequency ratio reflects sympathovagal balance. Results: From baseline to 1d, a prolongation of the RR-interval ( P<0.001), an increase in the values of various heart rate variability parameters ( P<0.05 to P<0.001) and a decrease in the low frequency/high frequency ratio ( P<0.05) were demonstrated. At 3mo, although the RR-interval remained longer ( P<0.01), the values of various heart rate variability parameters were lower ( P<0.01 to P<0.001) as compared to baseline. At 3mo, the low frequency/high frequency ratio ( P<0.05) was higher in men than in women although no such difference was found at baseline or at 1d. Conclusions: After an initial increase in parasympathetic regulation, continuous fingolimod dosing shifts cardiac autonomic regulation towards sympathetic predominance, especially in men. Careful follow-up of fingolimod-treated relapsing–remitting multiple sclerosis patients is warranted as sympathetic predominance associates generally with impaired outcome. ClinicalTrials.cov: NCT01704183


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