Genetic loci linked to type 1 diabetes and multiple sclerosis families in Sardinia.

BACKGROUND: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. METHODS: To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. RESULTS: In T1D, aside from the HLA locus, we found four regions showing a lod-score > or =1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score > or =1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). CONCLUSION: This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.

Effect of dose and frequency of interferon beta-1a administration on clinical and magnetic resonance imaging parameters in relapsing-remitting multiple sclerosis.

There is still debate over the optimal dosage, frequency and route of administration of interferon (IFN) beta in multiple sclerosis (MS). A prospective, non-randomized, comparative study was performed to evaluate differences in magnetic resonance imaging and clinical outcomes of two IFN beta-1a preparations (30mcg intramuscular [im] once-weekly [qw], AVO; and 22 mcg subcutaneous [sc] three-times-weekly [tiw]; R22). Relapsing-remitting MS patients on one of the two IFN preparations (AVO, n=47; R22, n=48) were assessed at baseline and after 6 months of further treatment. There were no significant differences between the two groups at baseline. Both groups showed significantly reduced relapse rates (F=19.5; p<0.001) from baseline (0.6) to 6-month assessment (0.2; p<0.001). Univariate analysis showed a significant difference in favour of R22 on T2 lesion volume (F=14.4; p<0.001) and T1 black hole lesion load (F=8.5; p=0.004), the latter showing a significant increase in the AVO group (p<0.001). The incidence of patients with new T1 black holes was also higher for AVO than R22 (23.5% vs 8.3%; p=0.025). These results from patients receiving AVO or R22 in normal clinical practice are in line with randomized clinical studies that show the benefits of high-dose, high-frequency administration of IFN beta-1a in MS therapy.

A genome-wide screen for linkage disequilibrium in Sardinian multiple sclerosis.

Using indirect whole genome association screening, we have searched for multiple sclerosis susceptibility genes in the genetically isolated high risk Sardinian population. Two screens were performed; the first was based on 229 cases and 264 unrelated controls, and the second on 235 trio families. Each screen employed a dense set of microsatellite markers and DNA pooling. Data from both screens were available from 2764 markers. Nine markers showed nominally significant results in both screens independently. Five of these markers-D2S408 (2q36), D6S271 (6p21), D6S344 (6p25), D7S1818 (7p12) and D16S420 (16p12)-remained nominally significant in both studies after conservative refining analysis.

PTPRC (CD45) C77G mutation does not contribute to multiple sclerosis susceptibility in Sardinian patients.

A linkage and association of the CD45 (protein-tyrosine phosphatase, receptor-type C) C77G polymorphism and multiple sclerosis (MS) has been found in some studies but not in others. We analysed the C77G polymorphism in MS patients from the genetically homogeneous population of Sardinia. Using the transmission disequilibrium test, the mutation has been sought in 241 patients and 217 healthy sibs (HS) from singleton MS families and it was found in 5 (2.07 %) affected and 3 (1.38%) HS from 7 heterozygous parents (1.45 %). Transmission of the G77 allele was 71.4 % (TDT = 1.3, P = 0.26) in patients and 50% (TDT = 0, P = 1) in HS. Stratifying families according to carriage of MS-predisposing (DR+) or not-predisposing (DR-) HLA-DR-DQ genotype in patients, percentage of G77 transmission to DR+ patients was 33 (TDT = 0.33, P = 0.56, Pc = 1.12), while it was 100 (TDT = 4, P = 0.045, Pc = 0.09) in the DR-patients. We concluded that, despite the presence of CD45 G77 polymorphism in a few patients who did not carry the HLADR- DQ MS-predisposing molecules, CD45 did not contribute to development of the disease in Sardinian MS.

Safety and tolerability in relapsing-remitting multiple sclerosis patients treated with high-dose subcutaneous interferon-beta by Rebiject autoinjection over a 1-year period: the CoSa study.

OBJECTIVES: Approved multiple sclerosis (MS) treatments include subcutaneous and intramuscular interferon beta (IFN-beta) Patient satisfaction during long-term IFN-beta treatment is crucial. This study investigated the satisfaction of patients with relapsing-remitting MS treated with IFN-beta-1a (Rebif) by the autoinjection system, Rebiject. MATERIALS AND METHODS: This prospective observational study recruited subjects with relapsing-remitting MS (n = 76) from 19 neurological centers in Italy who were eligible for subcutaneous IFN-beta-1a treatment either as a first immunomodulatory therapy or as a switch from other treatments. Patients received IFN-beta-1a 44 mug 3 times weekly via the Rebiject system. A questionnaire on the use of Rebiject and the most common adverse effects related to IFN-beta-1a administration was completed monthly under the supervision of trained nurses. RESULTS: Satisfaction with treatment was reported by 80.2% of patients who received at least 1 dose. Advantages reported for the Rebiject system included its convenience (53% of all patients), ease of use (25%), reduced trauma and pain (11% and 6%, respectively), and reduced local skin reactions (5%). No significant changes from baseline were observed regarding the frequency or severity of local reactions. CONCLUSIONS: During the 1-year observation of this small cohort, most patients considered the Rebiject system to be convenient, with a third of the patients feeling that the system was easier to use than conventional procedures. Rebiject was also associated with less pain and trauma in some patients. Use of Rebiject may facilitate IFN-beta-1a administration and may lead to an increase in compliance and adherence, thus increasing the effectiveness of treatment.

Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis.

OBJECTIVE: Our objective was to assess brain damage in first-degree relatives of patients with sporadic and familial multiple sclerosis (MS). METHODS: Asymptomatic first-degree relatives of sporadic (sMS, n = 152) and familial MS (fMS, n = 88) and healthy volunteers (NC, n = 56) underwent brain MRI and magnetization transfer (MT) imaging on a mobile MR scan. On MR examinations, we visually assessed white matter (WM) lesions and quantified WM lesion volumes, brain volumes, and MT ratio (MTr) in lesions and normal-appearing WM (NAWM). RESULTS: A lesional MR pattern similar to that of MS patients was found in 4% sMS and 10% fMS. In these WM lesions, MTr was lower (p < 0.0001) than in the WM of NC. In contrast, there was no difference in NAWM-MTr and brain volume values between the three groups. INTERPRETATION: Focal brain abnormalities indistinguishable from those of MS occur in asymptomatic first-degree relatives of MS patients. These are twice more frequent in fMS than in sMS but do not lead to the widespread tissue damage commonly found in MS patients. Although there is a genetic susceptibility to develop brain abnormalities suggestive of focal demyelination in first-degree relatives of MS patients, other factors are probably critical for the development of a diffuse, clinically relevant, pathology.

Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study.

BACKGROUND: Individuals from Sardinia, Italy, are at high risk of developing multiple sclerosis and type 1 diabetes mellitus. We attempted to assess the prevalence in this region of type 1 diabetes mellitus in individuals with multiple sclerosis, and to ascertain disease risk factors. METHODS: We did a cohort study to assess prevalence of type 1 diabetes in 1090 people with multiple sclerosis, and in their parents (n=2180) and siblings (n=3300), all born and living in Sardinia. All participants were patients at the multiple sclerosis clinic in Cagliari, and were judged representative of the total Sardinian outpatients and inpatients. We asked patients whether their parents or siblings had multiple sclerosis or diabetes, confirming replies by examining clinical records. We identified risk factors for diabetes with univariate and multivariate logistic regression analyses. FINDINGS: Diabetes prevalence in people with multiple sclerosis was, respectively, about three-fold and five-fold that in their healthy siblings (p=0.001) and in the general population (p<0.0001). Presence of other relatives with multiple sclerosis conferred increased risk of type 1 diabetes to healthy siblings of individuals with multiple sclerosis (odds ratio=3.41, p=0.0019). Diabetes risk was six-fold higher in patients with relatives having multiple sclerosis than in healthy siblings of multiple sclerosis patients without other relatives with the disease (p=0.0001). INTERPRETATION: In Sardinian families with genetic inheritance of multiple sclerosis type 1 diabetes is prevalent, both in multiple sclerosis patients and in healthy siblings. This finding indicates that common genes contribute to susceptibility to both diseases in this population.