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1.
Genes Immun ; 18(2): 59-66, 2017 03.
Article in English | MEDLINE | ID: mdl-28077880

ABSTRACT

Genetic studies have demonstrated association between single-nucleotide polymorphisms within the IL2RA (interleukin-2 receptor α-subunit) gene and risk of developing multiple sclerosis (MS); however, these variants do not have obvious functional consequences. DNA methylation is a source of genetic variation that could impact on autoimmune disease risk. We investigated DNA methylation of the IL2RA promoter in genomic DNA obtained from peripheral blood mononuclear cells and neural tissue using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A differential methylation profile of IL2RA was identified, suggesting that IL2RA expression was regulated by DNA methylation. We extended our analysis of DNA methylation to peripheral blood mononuclear cell (PBMC) of MS cases and controls using MALDI-TOF and Illumina HumanMethylation450 arrays. Analyses of CpG sites within the proximal promoter of IL2RA in PBMC showed no differences between MS cases and controls despite an increase in IL2RA expression. In contrast, we inferred significant DNA methylation differences specific to particular leukocyte subtypes in MS cases compared with controls by deconvolution of the array data. The decrease in methylation in patients correlated with an increase in IL2RA expression in T cells from MS cases in comparison with controls. Our data suggest that differential methylation of the IL2RA promoter in T cells could be an important pathogenic mechanism in MS.


Subject(s)
DNA Methylation , Interleukin-2 Receptor alpha Subunit/genetics , Multiple Sclerosis/genetics , Promoter Regions, Genetic , T-Lymphocytes/metabolism , CpG Islands , Gene Expression , Humans , Leukocytes, Mononuclear/metabolism , Mass Spectrometry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
2.
Mult Scler ; 22(4): 461-9, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26199349

ABSTRACT

AIM: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). METHODS: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. RESULTS: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. CONCLUSIONS: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.


Subject(s)
Multiple Sclerosis/epidemiology , Adolescent , Adult , Antibodies, Viral/blood , Australia/epidemiology , Case-Control Studies , Epstein-Barr Virus Nuclear Antigens/immunology , Female , Gene-Environment Interaction , HLA-DR Serological Subtypes/genetics , HLA-DR Serological Subtypes/immunology , Humans , Immunoglobulin G/blood , Incidence , Infectious Mononucleosis/epidemiology , Logistic Models , Male , Middle Aged , Multiple Sclerosis/diagnosis , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Multivariate Analysis , Odds Ratio , Polymorphism, Single Nucleotide , Prevalence , Risk Assessment , Risk Factors , Seasons , Smoking/adverse effects , Smoking/epidemiology , Sunlight , Time Factors , Young Adult
3.
Clin Exp Immunol ; 172(3): 466-74, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23600835

ABSTRACT

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18-59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'.


Subject(s)
Asthma/etiology , Demyelinating Diseases/etiology , Hygiene Hypothesis , Hygiene , Adolescent , Adult , Asthma/immunology , Asthma/microbiology , Autoimmunity , Case-Control Studies , Demyelinating Diseases/immunology , Demyelinating Diseases/microbiology , Fatigue Syndrome, Chronic/etiology , Fatigue Syndrome, Chronic/immunology , Female , Humans , Hypersensitivity/etiology , Hypersensitivity/immunology , Hypersensitivity/microbiology , Male , Middle Aged , Risk Factors , Siblings , Young Adult
4.
Am J Epidemiol ; 177(9): 954-61, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23585328

ABSTRACT

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.


Subject(s)
Agriculture/statistics & numerical data , Demyelinating Diseases/etiology , Occupational Exposure/adverse effects , Adolescent , Adult , Animals , Australia , Case-Control Studies , Demyelinating Diseases/complications , Demyelinating Diseases/diagnosis , Female , Humans , Interviews as Topic , Livestock , Logistic Models , Male , Middle Aged , Multicenter Studies as Topic , Multiple Sclerosis/etiology , Occupational Exposure/statistics & numerical data , Occupations/classification , Occupations/statistics & numerical data , Risk Factors , Sex Distribution , Surveys and Questionnaires , Time Factors , Young Adult
5.
Mol Psychiatry ; 18(2): 245-54, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22212595

ABSTRACT

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of ß-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Catecholamines/metabolism , Monoamine Oxidase/metabolism , Amyloid beta-Protein Precursor/deficiency , Animals , Blood Pressure/drug effects , Blood Pressure/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Chromatography, High Pressure Liquid , Dopamine/toxicity , Embryo, Mammalian , Fibroblasts/drug effects , Fibroblasts/metabolism , Heart Rate/drug effects , Heart Rate/genetics , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidation-Reduction/drug effects
6.
J Clin Neurosci ; 19(12): 1689-94, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23084347

ABSTRACT

The initiating events in multiple sclerosis (MS) plaque formation are poorly understood. Retrospective analysis of serial imaging data can improve the understanding of tissue changes characterising acute MS lesion evolution. This study aimed to assess lesion evolution using diffusion tensor imaging data from serially acquired scans from 22 patients with MS. Mean diffusivity (MD) and fractional anisotropy (FA) were measured from 13 suitable plaques from five patients and carefully matched regions of contralateral normal-appearing white matter. Measurement times were on average: 5 months and 1 month prior to, during, and 1 month and 2 months post gadolinium-enhancement. A significant increase in MD (7.25%) but no change in FA was observed in white matter areas that exhibited enhancement 5 months later. The pre-lesional MD increase was significantly correlated with the MD increase 2 months subsequent to enhancement (R=0.73, p=0.04) but not to the MD increase during enhancement (R=0.11). These results suggest that MD is sensitive to tissue changes that precede blood-brain barrier (BBB) breakdown by at least 5 months and that MD assessments may predict injury following BBB restoration.


Subject(s)
Brain/pathology , Diffusion Tensor Imaging , Inflammation/pathology , Multiple Sclerosis, Relapsing-Remitting/pathology , Adult , Anisotropy , Double-Blind Method , Female , Humans , Image Interpretation, Computer-Assisted , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Vitamin D/administration & dosage , Vitamins/administration & dosage
7.
Neurology ; 78(12): 867-74, 2012 Mar 20.
Article in English | MEDLINE | ID: mdl-22402857

ABSTRACT

OBJECTIVE: To examine the association between past pregnancy, offspring number, and first clinical demyelination risk. METHODS: Cases (n = 282) were aged 18-59 years with a first clinical diagnosis of CNS demyelination (first clinical demyelinating event [FCD]) and resident within 1 of 4 Australian centers (from latitudes 27° south to 43° south) from 2003 to 2006. Controls (n = 542) were matched to cases on age, sex, and study region, without first clinical diagnosis of CNS demyelination. RESULTS: Higher offspring number was associated with FCD risk among women (p < 0.001) but not men (p = 0.71); difference in effect; p = 0.001. Among women, higher parity was associated with reduced risk of FCD (adjusted odds ratio 0.51 [95% confidence interval 0.36, 0.72] per birth) with a similar magnitude of effect observed among classic first demyelinating events (adjusted odds ratio 0.47 [95% confidence interval 0.29, 0.74]). The apparent beneficial effect of higher parity was also evident among parous women only (p < 0.001). Among cases, a clear female excess was evident for those with low but not high (4 or more) offspring number. Factors such as human leukocyte antigen DR15 genotype did not appear to modify the association between higher parity and a reduced FCD risk among women. CONCLUSIONS: These findings are consistent with a cumulative beneficial effect of pregnancy. Temporal changes toward an older maternal age of parturition and reduced offspring number may partly underlie the increasing female excess among MS cases over time.


Subject(s)
Demyelinating Diseases/epidemiology , Demyelinating Diseases/etiology , Parity/physiology , Pregnancy Complications/epidemiology , Pregnancy/physiology , Abortion, Spontaneous/epidemiology , Adolescent , Adult , Australia/epidemiology , Autoimmune Diseases/epidemiology , Confidence Intervals , DNA/genetics , Data Interpretation, Statistical , Female , Genotype , HLA-DR Antigens/genetics , Humans , Male , Menarche , Middle Aged , Odds Ratio , Risk Assessment , Risk Factors , Sex Factors , Surveys and Questionnaires , Young Adult
8.
Neurology ; 77(17): 1611-8, 2011 Oct 25.
Article in English | MEDLINE | ID: mdl-22025459

ABSTRACT

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04). CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.


Subject(s)
25-Hydroxyvitamin D 2/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Vitamins/therapeutic use , 25-Hydroxyvitamin D 2/blood , Adult , Brain/drug effects , Brain/pathology , Calcifediol/blood , Calcium/blood , Disability Evaluation , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/pathology , Radioimmunoassay , Time Factors , Treatment Outcome
9.
Neurology ; 76(6): 540-8, 2011 Feb 08.
Article in English | MEDLINE | ID: mdl-21300969

ABSTRACT

OBJECTIVES: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia. METHODS: This was a multicenter incident case-control study. Cases (n = 216) were aged 18-59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status. RESULTS: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53-0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m(2) (range 508-6,397 kJ/m(2)). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17-0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86-1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions. CONCLUSIONS: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.


Subject(s)
Demyelinating Diseases/blood , Demyelinating Diseases/epidemiology , Sunlight , Vitamin D/blood , Adolescent , Adult , Case-Control Studies , Demyelinating Diseases/etiology , Female , Humans , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/epidemiology , Multiple Sclerosis/etiology , Risk Factors , South Australia/epidemiology , Tasmania/epidemiology , Victoria/epidemiology , Vitamin D/administration & dosage , Vitamin D Deficiency/blood , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Young Adult
10.
Mult Scler ; 17(3): 344-52, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21149397

ABSTRACT

BACKGROUND: HLA-DRB1*1501 (DR15) and other HLA class II alleles increase the risk of developing multiple sclerosis (MS). However, the contribution of genetic heterogeneity to the clinical course of MS remains controversial. We examined the influence of DR15 and other common DRB1 alleles (DRB1*01 (DR1), DRB1*03 (DR3) and DRB1*04 (DR4) on MS severity in a large, Australian, population-based cohort. METHODS: We studied the association between common HLA-DRB1 alleles and genotypes and age of onset as well as three clinical disease severity descriptors: Multiple Sclerosis Severity Score, progression index), and the interval between the first and second attack in 978 patients with relapsing remitting MS and secondary progressive MS. We assessed cognition using the Symbol Digit Modalities Test in 811 patients and brain atrophy using the linear magnetic resonance imaging marker, the intercaudate ratio, in 745 patients. RESULTS: Carrying DR15 significantly decreased the age of MS onset by 3.2 years in homozygotes and 1.3 years in heterozygotes. Carrying the HLA-DR15, -DR1, -DR3 or -DR4 alone or in combination did not affect clinical disease severity, cognition or cerebral atrophy. CONCLUSIONS: This study confirms that heterogeneity of HLA-DRB1 does not influence disease outcome in relapsing MS patients, with the exception of a younger age of onset in HLA-DR15 carriers.


Subject(s)
Brain/pathology , Cognition , Genetic Variation , HLA-DR Antigens/genetics , Multiple Sclerosis, Chronic Progressive/genetics , Multiple Sclerosis, Relapsing-Remitting/genetics , Adult , Age of Onset , Atrophy , Australia , Female , Gene Frequency , Genotype , HLA-DRB1 Chains , Heterozygote , Homozygote , Humans , Logistic Models , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/pathology , Multiple Sclerosis, Chronic Progressive/psychology , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Relapsing-Remitting/psychology , Neuropsychological Tests , Phenotype , Predictive Value of Tests , Risk Assessment , Risk Factors , Severity of Illness Index
11.
J Neurol Neurosurg Psychiatry ; 81(9): 1033-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20542931

ABSTRACT

OBJECTIVE: A stratified, randomised, waitlist controlled study over 12 months assessed the effectiveness of a 6 week bladder rehabilitation programme in persons with multiple sclerosis (pwMS) in an Australian community cohort. METHODS: Patients with definite MS and bladder issues (n=74) recruited from a tertiary hospital database were randomised to a treatment group (n=40) for an individualised bladder rehabilitation programme or to a control waitlist group (n=34). The Urogenital Distress Inventory (UDI6), Neurological Disability Scale (NDS) and the American Urological Association Symptom Index (AUA) assessed bladder impairment and 'activity limitation'; a single Quality of life (QoL) item in the AUA and the Incontinence Impact Questionnaire (IIQ7) measured restriction in 'participation'. Primary outcome measures were assessed at baseline and at 12 months. RESULTS: Analysis of per protocol data from 58 patients (treatment n=24, control n=34) showed reduced disability in the treatment group, with significant differences (p<0.001) and large effect sizes (>0.5) in post-treatment UDI6, NDS, AUA total, AUA QoL and IIQ7 scores for the two groups. The treatment group compared with the control group showed improvement: 78% versus 27% for UDI6 and 59% versus 17% improved for IIQ7. More patients in the control group deteriorated over the study period on the UDI6 (30% vs 0%; p<0.001) and IIQ7 (39 vs 0%; p=0.001). CONCLUSION: A multifaceted, individualised bladder rehabilitation programme reduces disability and improves QoL in pwMS compared with no intervention after 12 months of follow-up. Information on specific interventions in different bladder types in MS and the impact on QoL need further evaluation. Australian Clinical trials Registry ACTRNO12605000676617.


Subject(s)
Multiple Sclerosis/therapy , Patient Education as Topic/methods , Urinary Bladder Diseases/rehabilitation , Adult , Aged , Female , Humans , Male , Middle Aged , Multiple Sclerosis/complications , Severity of Illness Index , Urinary Bladder Diseases/complications
12.
Neurology ; 73(13): 1018-25, 2009 Sep 29.
Article in English | MEDLINE | ID: mdl-19786693

ABSTRACT

BACKGROUND: The influence of APOE allelic heterogeneity on multiple sclerosis (MS) disease severity has been reported in multiple datasets with conflicting results. Several studies have reported an unfavorable association of APOE epsilon4 with more severe clinical disease course while, in contrast, APOE epsilon2 has been associated with a more benign disease course. In this study, we examine the influence of heterogeneity of the APOE gene on disease severity in a large, Australian, population-based MS cohort. METHODS: Associations between APOE allele status, 2 promoter region single nucleotide polymorphisms (-219 G/T and +113 C/G), and 4 measures of disease severity were tested in 1,006 patients with relapsing-remitting MS and secondary progressive MS: 1) Multiple Sclerosis Severity Score; 2) Progression Index (Expanded Disability Status Scale/disease duration); 3) age at first symptom; and 4) interval between the first and second attack. The Symbol Digit Modalities Test was used as a single cognitive marker in 889 patients. Brain atrophy was measured in 792 patients using the intercaudate ratio. APOE epsilon4 and epsilon3 carriers were stratified by -219 G/T or +113 C/G to investigate haplotypic heterogeneity in the APOE gene region. RESULTS: In this MS study, neither APOE allele status nor promoter region heterogeneity at positions -219 G/T or +113 C/G influenced the clinical disease severity, cognition, or cerebral atrophy. CONCLUSIONS: Allelic and haplotypic heterogeneity of the APOE gene region does not influence multiple sclerosis disease course in this well-defined Australian multiple sclerosis cohort.


Subject(s)
Apolipoproteins E/genetics , Brain/pathology , Cognition/physiology , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/pathology , Adult , Apolipoprotein E2/genetics , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Atrophy , Australia , Cohort Studies , Disability Evaluation , Female , Haplotypes , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Phenotype , Promoter Regions, Genetic/genetics , Severity of Illness Index
13.
Tissue Antigens ; 74(1): 17-21, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19392788

ABSTRACT

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10(-45)), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10(-7)). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.


Subject(s)
Genetic Predisposition to Disease , HLA-DR Antigens/genetics , Multiple Sclerosis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Australia/epidemiology , Female , Gene Frequency , HLA-DRB1 Chains , Humans , Male , Middle Aged , Multiple Sclerosis/epidemiology , Young Adult
14.
Genes Immun ; 9(7): 624-30, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18650830

ABSTRACT

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.


Subject(s)
CD58 Antigens/genetics , Genetic Predisposition to Disease , Interleukin-2 Receptor alpha Subunit/genetics , Lectins, C-Type/genetics , Monosaccharide Transport Proteins/genetics , Multiple Sclerosis/genetics , Ribosomal Proteins/genetics , Adolescent , Adult , Aged , Australia , Case-Control Studies , Child , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide
15.
J Neurol Neurosurg Psychiatry ; 79(11): 1230-5, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18535027

ABSTRACT

OBJECTIVE: A stratified, randomised, waitlist controlled study over 12 months assessed the effectiveness of rehabilitation in persons with multiple sclerosis (MS) in an Australian community cohort. METHODS: Patients with definite MS (n = 101) recruited from a tertiary hospital database, randomised to a treatment group (n = 49) for individualised rehabilitation programme or a control waitlist group (n = 52). Functional Independence Measure (FIM) was used to assess "activity" while the Multiple Sclerosis Impact Scale (MSIS-29) and General Health Questionnaire (GHQ-28) assessed "participation" and quality of life (QoL). Assessments were at baseline and 12 months. RESULTS: Analysis of data from 98 patients (treatment n = 48, control n = 50) showed reduced disability in the treatment group, with statistically significant differences in post-treatment FIM motor scores for the two groups (p<0.001). There was a clinical and statistically significant improvement in FIM (motor) total scores (p<0.001), and the FIM motor domains of: transfer (p<0.001), locomotion (p<0.001), self-care (p<0.001) and the FIM cognitive subscale (p<0.016). In the treated group, 70.8% improved compared with 13% of controls. Significantly more patients in the control group deteriorated over the study period (58.7% vs 16.7%; p<0.001). There were no differences between the control and treatment group scores on the MSIS-physical (p = 0.18), MSIS-psychological (p = 0.45) or GHQ subscales. CONCLUSION: An individualised rehabilitation programme reduces disability in persons with MS compared with no intervention. The impact of rehabilitation on QoL needs further evaluation. More information on the effectiveness of the various components of the multidisciplinary rehabilitation programmes are now needed. Australian clinical trials registry: Trials registration number: ACTRNO12605000676617.


Subject(s)
Brain/pathology , Multiple Sclerosis , Psychomotor Disorders/diagnosis , Psychomotor Disorders/rehabilitation , Quality of Life/psychology , Adult , Disability Evaluation , Disease Progression , Female , Humans , Male , Middle Aged , Multiple Sclerosis/pathology , Multiple Sclerosis/physiopathology , Multiple Sclerosis/psychology , Physical Therapy Modalities , Psychomotor Disorders/physiopathology , Severity of Illness Index , Surveys and Questionnaires
16.
J Clin Neurosci ; 15(2): 130-7, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18068987

ABSTRACT

Linear measures of cerebral ventricular enlargement may act as surrogate measures of cerebral atrophy in multiple sclerosis (MS). Linear atrophy markers were measured from routine MRI scans during a population survey of 171 Tasmanian MS patients and 91 healthy controls. Thirty-five Victorian MS clinic patients were recruited as a validation cohort with 14 of these re-assessed 4 years later. In the population survey, we measured three linear brain atrophy markers: inter-caudate distance (ICD), third ventricle width (TVW) and frontal horn width (FHW). TVW (OR 2.0, p=0.001) and ICD (OR 16.1, p<0.001) differentiated between MS cases and controls. In the validation study, we correlated the intercaudate ratio (ICR=ICD/brain width) and third ventricular ratio (TVR=TVW/brain width) with brain parenchymal volume. Cross-sectionally, ICR (R=-0.453, p<0.01) and TVR (R=-0.653, p<0.01) were correlated with brain parenchymal volume. Longitudinally, brain parenchymal volume loss was inversely correlated with increased ICD (R=-0.77, p<0.01) and TVW (R=-0.71, p<0.01). This study shows that ICD measurements obtained from clinical MRI scans are valid brain atrophy measures for use in monitoring MS progression.


Subject(s)
Cerebral Cortex/pathology , Multiple Sclerosis/complications , Multiple Sclerosis/pathology , Adult , Atrophy/etiology , Atrophy/pathology , Female , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Middle Aged , Predictive Value of Tests , Severity of Illness Index
17.
Genes Immun ; 9(1): 1-6, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17928869

ABSTRACT

IL7 regulates T cell survival, differentiation and proliferation. The alpha chain of its receptor, CD127, is polymorphic, and its haplotypes are associated with recovery from transplantation and with the autoimmune disease multiple sclerosis (MS), especially primary progressive MS (PPMS). We demonstrate that two CD127 haplotypes are highly associated with the proportion of the mRNA encoding the soluble isoform of CD127 (P

Subject(s)
Haplotypes , Multiple Sclerosis/genetics , Neutrophils/metabolism , Receptors, Interleukin-7/genetics , Th1 Cells/metabolism , Alleles , Case-Control Studies , Cohort Studies , Female , Gene Expression , Heterozygote , Humans , Male , RNA, Messenger/metabolism , Statistics as Topic
18.
Tissue Antigens ; 71(1): 42-50, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17971048

ABSTRACT

This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.


Subject(s)
Chromosome Mapping , Genetic Predisposition to Disease , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Major Histocompatibility Complex/genetics , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, DNA , Case-Control Studies , Female , Humans , Tasmania
19.
Mult Scler ; 13(7): 827-39, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17881396

ABSTRACT

Rising multiple sclerosis incidence over the last 50 years and geographic patterns of occurrence suggest an environmental role in the causation of this multifactorial disease. Design options for epidemiological studies of environmental causes of multiple sclerosis are limited by the low incidence of the disease, possible diagnostic delay and budgetary constraints. We describe scientific and methodological issues considered in the development of the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study), which seeks, in particular, to better understand the causes of the well-known MS positive latitudinal gradient. A multicentre, case-control design down the eastern seaboard of Australia allows the recruitment of sufficient cases for adequate study power and provides data on environmental exposures that vary by latitude. Cases are persons with an incident first demyelinating event (rather than prevalent multiple sclerosis), sourced from a population base using a two tier notification system. Controls, matched on sex, age (within two years) and region of residence, are recruited from the general population. Biases common in case-control studies, eg, prevalence-incidence bias, admission-rate bias, non-respondent bias, observer bias and recall bias, as well as confounding have been carefully considered in the study design and conduct of the Ausimmune Study.


Subject(s)
Bias , Case-Control Studies , Multicenter Studies as Topic , Multiple Sclerosis/epidemiology , Multiple Sclerosis/immunology , Australia/epidemiology , Humans , Incidence
20.
Acta Neurol Scand ; 116(5): 293-9, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17850407

ABSTRACT

AIMS - A number of physical and psychological factors have been shown to affect health-related quality of life (HRQoL) in patients with multiple sclerosis (MS). Among these, the role of illness perceptions has not been established as an independent factor. This study, the first of its kind in an Australian population, aimed to use a large sample to determine the relative importance of individual factors to each domain of HRQoL, in particular the role of illness perception. MATERIALS AND METHODS - 580 patients with confirmed MS were assessed cross sectionally in a designated research clinic to determine the relative impact of physical factors (illness severity, duration, age, fatigue and pain) and psychological factors (mood, cognition and illness representations) on each domain of the SF-36. RESULTS - Categorical regression analysis showed that a combination of physical and psychological factors predicted 38-71% of variance in HRQoL. Illness perception was shown to have an independent effect on HRQoL in MS. The Extended Disability Status Scale was a significant determinant in all domains except for mental health. Depression was less prevalent than anxiety, but had a greater effect on function. CONCLUSION - Illness perception is an independent factor contributing to HRQoL in people with MS. Individual domains of HRQoL are associated with different patterns of physical and psychological factors. In the domains of role and social function, activities most highly valued by patients with MS, depression, anxiety, fatigue and illness perceptions are key determinants, all of which have the potential to be improved through specific interventions.


Subject(s)
Mental Disorders/epidemiology , Mental Disorders/psychology , Multiple Sclerosis/epidemiology , Multiple Sclerosis/psychology , Quality of Life/psychology , Activities of Daily Living/psychology , Adult , Anxiety Disorders/epidemiology , Anxiety Disorders/psychology , Australia/epidemiology , Cohort Studies , Comorbidity , Cross-Sectional Studies , Depressive Disorder/epidemiology , Depressive Disorder/psychology , Disability Evaluation , Fatigue Syndrome, Chronic/epidemiology , Fatigue Syndrome, Chronic/psychology , Female , Health Status Indicators , Humans , Male , Mental Disorders/diagnosis , Middle Aged , Multiple Sclerosis/physiopathology , Pain/epidemiology , Pain/psychology
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