Robert Heard

The effectiveness of a community-based program for reducing the incidence of falls in the elderly: a randomized trial.

Objectives: To test whether Stepping On, a multifaceted community-based program using a small-group learning environment, is effective in reducing falls in at-risk people living at home. n nDesign: A randomized trial with subjects followed for 14 months. n nSetting: The interventions were conducted in community venues, with a follow-up home visit. n nParticipants: Three hundred ten community residents aged 70 and older who had had a fall in the previous 12 months or were concerned about falling. n nIntervention: The Stepping On program aims to improve fall self-efficacy, encourage behavioral change, and reduce falls. Key aspects of the program are improving lower-limb balance and strength, improving home and community environmental and behavioral safety, encouraging regular visual screening, making adaptations to low vision, and encouraging medication review. Two-hour sessions were conducted weekly for 7 weeks, with a follow-up occupational therapy home visit. n nMeasurements: The primary outcome measure was falls, ascertained using a monthly calendar mailed by each participant. n nResults: The intervention group experienced a 31% reduction in falls (relative risk (RR)=0.69, 95% confidence interval (CI)=0.50–0.96; P=.025). This was a clinically meaningful result demonstrating that the Stepping On program was effective for community-residing elderly people. Secondary analysis of subgroups showed that it was particularly effective for men (n=80; RR=0.32, 95% CI=0.17–0.59). n nConclusion: The results of this study renew attention to the idea that cognitive-behavioral learning in a small-group environment can reduce falls. Stepping On offers a successful fall-prevention option.Objectives: To test whether Stepping On, a multifaceted community‐based program using a small‐group learning environment, is effective in reducing falls in at‐risk people living at home.

A high-density screen for linkage in multiple sclerosis.

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

The expanding genetic overlap between multiple sclerosis and type I diabetes

Familial clustering of autoimmune disease is well recognized and raises the possibility that some susceptibility genes may predispose to autoimmunity in general. In light of this observation, it might be expected that some of the variants of established relevance in one autoimmune disease may also be relevant in other related conditions. On the basis of this hypothesis, we tested seven single nucleotide polymorphisms (SNPs) that are known to be associated with type I diabetes in a large multiple sclerosis data set consisting of 2369 trio families, 5737 cases and 10u2009296 unrelated controls. Two of these seven SNPs showed evidence of association with multiple sclerosis; that is rs12708716 from the CLEC16A gene (P=1.6 × 10−16) and rs763361 from the CD226 gene (P=5.4 × 10−8). These findings thereby identify two additional multiple sclerosis susceptibility genes and lend support to the notion of autoimmune susceptibility genes.

Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor

In a recent genome-wide association study (GWAS) based on 12u2009374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 × 10−6, odds ratio=1.32 (1.17–1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.

Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-|[alpha]| gene and their associations with multiple sclerosis

We have investigated the interleukin-7 receptor (IL-7R) α-chain gene as a positional and functional candidate gene for susceptibility to multiple sclerosis (MS), in view of its chromosomal location on 5p14–p12, a region that has shown suggestive linkage in MS genome screens, and its role in T- and B-cell proliferation and reactivity. Amplification and DNA sequencing of the IL-7Rα gene in pooled and individual samples identified 13 single nucleotide polymorphisms (SNPs), 11 of which are novel, including three in the promoter region, three in exons encoding amino-acid changes (ACC(Thr)66ATC(Ile), ATC(Ile)244ACC(Thr), ATC(Ile)336GTC(Val)), four in introns and one in the 3′ untranslated region. Four IL-7R haplotypes were identified for nine SNPs, showing linkage disequilibrium across the gene, and allowing haplotype frequency determination from just three of the nine SNPs. Genotyping of the −504 polymorphism in 101 MS and 90 controls showed a suggestive (P=0.1) association of the T allele with MS; however, this was not supported by transmission disequilibrium testing in 186 MS trio families (P=0.8). There were trends towards an increase of the GTG+ haplotype (odds ratio=1.45), and under-representation of the TTA+ haplotype (OR=0.65) in DRB1*1501-positive MS cases, suggesting that larger sample sizes and comparison in more defined MS patient groups may support an association with the IL-7R gene. These polymorphisms would also be useful for studying genetic associations with other immunologic diseases.

The CCR5 Deletion Mutation Fails to Protect Against Multiple Sclerosis

Recent advances in the understanding and identification of chemokines and their receptors have provided evidence for their consideration as candidate loci with respect to genetic susceptibility/resistance to MS. Increased levels of the chemokine, macrophage inflammatory protein (MIP)-1 alpha, have been demonstrated in the cerebrospinal fluid of both patients with MS and mice with EAE, and anti-MIP-1 alpha antibodies have been shown to prevent EAE. Recently, a common deletion mutation in the gene for the major receptor for MIP-1 alpha, chemokine receptor 5 (CCR5) has been described. Homozygotes for the mutation fail to express this receptor. Moreover, homozygotes are highly protected against HIV infection this has potential implications for the cell entry of infectious agents in other multifactorial disease where a viral component may be involved. In view of these aspects, a group of 120 unrelated Australian relapsing remitting MS and 168 unrelated control subjects were screened for the CCR5 delta 32 mutation. There was no significant difference in the allele frequency of CCR5 delta 32 gene between the MS patients (0.1125) and the control population (0.0921). The presence of two CCR5 delta 32 homozygotes in the MS patients indicates that the absence of CCR5 is not protective against MS. These data suggest that CCR5 is not an essential component in MS expression, though this may be due to redundancy in the chemokine system where different chemokine receptors may substitute for CCR5 when it is absent.

Refining genetic associations in multiple sclerosis

Genome-wide association studies involve several hundred thousand markers and, even when quality control is scrupulous, are invariably confounded by residual uncorrected errors that can falsely inflate the apparent difference between cases and controls (so-called genomic inflation). As a consequence such studies inevitably generate false positives alongside genuine associations. By use of Bayesian logic and empirical data, the Wellcome Trust Case Control Consortium suggested that association studies in complex disease should involve at least 2000 cases and 2000 controls, at which level they predicted that p values of less than 5×10 −7 would more commonly signify true positives than false positives.

Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10−4, χ2). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), −504xa0C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.