Common polygenic variation contributes to risk of migraine in the Norfolk Island population

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole-blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case-control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case-control status in this population (P=0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, 4 were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.

Whole-genome screening in ankylosing spondylitis: Evidence of non-MHC genetic-susceptibility loci

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: Results of a randomised placebo-controlled trial (ABILITY-1)

Purpose: To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Methods: Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index. Results: Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases. Conclusions: In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

Identification of major loci controlling clinical manifestations of ankylosing spondylitis

Objective. To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS). Methods. A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study. Results. Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23-0.75), BASFI 0.76 (P = 10-7, 95% CI 0.49-1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04-0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). "Significant" linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed "suggestive" linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9). Conclusion. In contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.

Susceptibility to ankylosing spondylitis in twins: The role of genes, HLA, and the environment

Objective To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Methods Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence- specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Results Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co- twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Conclusion Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

A genome-wide screen for susceptibility loci in ankylosing spondylitis

Objective. To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). Methods. One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. Results. When only the MRC set was considered, 11 markers in 7 regions achieved a P value of ≤0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10-5) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10-9). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. Conclusion. The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.

Role of NOD2 variants in spondylarthritis

Objective. To investigate the role of the gene NOD2 in susceptibility to, and clinical manifestations of, ankylosing spondylitis (AS). Methods. A case-control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro268 Ser, Arg702 Trp, GlY908 Arg, and Len1007fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls. Associations between NOD2 polymorphisms and several clinical features of AS, including disease severity assessed by questionnaire and age at spondylarthritis onset, were also investigated. Exclusion linkage mapping of chromosome 16 was performed in a separate group of 185 multicase families with AS. Results. An association was identified between Gly908 Arg and UC spondylarthritis (P = 0.016, odds ratio [OR] 4.6, 95% confidence interval [95% CI] 1.316), and a nonsignificant trend with a similar magnitude was observed in association with CD spondylarthritis (P = 0.08, OR 3.9, 95% CI 0.8-18). The Pro268Ser variant was inversely associated with UC spondylarthritis (P = 0.003, OR 0.55, 95% CI 0.37-0.82), but not with CD spondylarthritis. No association was demonstrated between NOD2 variants and primary AS, or between other variants of NOD2 and either UC or CD spondylarthritis. Carriage of the Pro268 Ser polymorphism was associated with greater disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = 0.002). Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset. In primary AS, the presence of a gene with a magnitude of association >2.0 was excluded (exclusion logarithm of odds score less than -2.0), and no association was observed with the microsatellite D16S3136. Conclusion. NOD2 variants do not significantly affect the risk of developing primary AS, but may influence susceptibility to, and clinical manifestations of, colitic spondylarthritis.

The X-chromosome and susceptibility to ankylosing spondylitis

Objective. Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (λ(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X- chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility. Methods. A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis. Results. No linkage of the X-chromosome with susceptibility to AS was found. Model- free multipoint linkage analysis strongly excluded any significant genetic contribution (λ ≥1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] <-2.0). Smaller genetic effects (A ≥1.3) were also found to be unlikely (LOD <-1.0). Conclusion. The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.

Spinal inflammation in the absence of sacroiliac joint inflammation on magnetic resonance imaging in patients with active nonradiographic axial spondyloarthritis

Objective: To evaluate the presence of spinal inflammation with and without sacroiliac (SI) joint inflammation on magnetic resonance imaging (MRI) in patients with active nonradiographic axial spondyloarthritis (SpA), and to compare the disease characteristics of these subgroups. Methods: ABILITY-1 is a multicenter, randomized, controlled trial of adalimumab versus placebo in patients with nonradiographic axial SpA classified using the Assessment of SpondyloArthritis international Society axial SpA criteria. Baseline MRIs were centrally scored independently by 2 readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) method for the SI joints and the SPARCC 6-discovertebral unit method for the spine. Positive evidence of inflammation on MRI was defined as a SPARCC score of >2 for either the SI joints or the spine. Results: Among patients with baseline SPARCC scores, 40% had an SI joint score of >2 and 52% had a spine score of >2. Forty-nine percent of patients with baseline SI joint scores of <2, and 58% of those with baseline SI joint scores of >2, had a spine score of >2. Comparison of baseline disease characteristics by baseline SI joint and spine scores showed that a greater proportion of patients in the subgroup with a baseline SPARCC score of >2 for both SI joints and spine were male, and patients with spine and SI joint scores of <2 were younger and had shorter symptom duration. SPARCC spine scores correlated with baseline symptom duration, and SI joint scores correlated negatively with the baseline Bath Ankylosing Spondylitis Disease Activity Index, but neither correlated with the baseline Ankylosing Spondylitis Disease Activity Score, total back pain, the patient's global assessment of disease activity, the Bath Ankylosing Spondylitis Functional Index, morning stiffness, nocturnal pain, or C-reactive protein level. Conclusion: Assessment by experienced readers showed that spinal inflammation on MRI might be observed in half of patients with nonradiographic axial SpA without SI joint inflammation.

A systematic review of axillary web syndrome (AWS)

Introduction Axillary web syndrome (AWS) can result in early post-operative and long-term difficulties following lymphadenectomy for cancer and should be recognised by clinicians. This systematic review was conducted to synthesise information on AWS clinical presentation and diagnosis, frequency, natural progression, grading, pathoaetiology, risk factors, symptoms, interventions and outcomes. Methods Electronic searches were conducted using Cochrane, Pubmed, MEDLINE, CINAHL, EMBASE, AMED, PEDro and Google Scholar until June 2013. The methodological quality of included studies was determined using the Downs and Black checklist. Narrative synthesis of results was undertaken. Results Thirty-seven studies with methodological quality scores ranging from 11 to 26 on a 28-point scale were included. AWS diagnosis relies on inspection and palpation; grading has not been validated. AWS frequency was reported in up to 85.4 % of patients. Biopsies identified venous and lymphatic pathoaetiology with five studies suggesting lymphatic involvement. Twenty-one studies reported AWS occurrence within eight post-operative weeks, but late occurrence of greater than 3 months is possible. Pain was commonly reported with shoulder abduction more restricted than flexion. AWS symptoms usually resolve within 3 months but may persist. Risk factors may include extensiveness of surgery, younger age, lower body mass index, ethnicity and healing complications. Low-quality studies suggest that conservative approaches including analgesics, non-steroidal anti-inflammatory drugs and/or physiotherapy may be safe and effective for early symptom reduction. Conclusions AWS appears common. Current evidence for the treatment of AWS is insufficient to provide clear guidance for clinical practice. Implications for Cancer Survivors Cancer survivors should be informed about AWS. Further investigation is needed into pathoaetiology, long-term outcomes and to determine effective treatment using standardised outcomes.

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda ≤ 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

Neuropsychological studies of late onset and subthreshold diagnoses of adult Attention-Deficit/Hyperactivity Disorder

Background Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. Methods We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. Results Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. Conclusions Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder.

The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood

Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2306862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.

Spectrum of ankylosing spondylitis in Portugal. Development of BASDAI, BASFI, BASMI and mSASSS reference centile charts

The availability of population-specific normative data regarding disease severity measures is essential for patient assessment. The goals of the current study were to characterize the pattern of ankylosing spondylitis (AS) in Portuguese patients and to develop reference centile charts for BASDAI, BASFI, BASMI and mSASSS, the most widely used assessment tools in AS. AS cases were recruited from hospital outpatient clinics, with AS defined according to the modified New York criteria. Demographic and clinical data were recorded. All radiographs were evaluated by two independent experienced readers. Centile charts for BASDAI, BASFI, BASMI and mSASSS were constructed for both genders, using generalized linear models and regression models with duration of disease as independent variable. A total of 369 patients (62.3% male, mean ± (SD) age 45.4 ± 13.2 years, mean ± (SD) disease duration 11.4 ± 10.5 years, 70.7% B27-positive) were included. Family history of AS in a first-degree relative was reported in 17.6% of the cases. Regarding clinical disease pattern, at the time of assessment 42.3% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopatic disease. Anterior uveitis (33.6%) was the most common extra-articular manifestation. The centile charts suggest that females reported greater disease activity and more functional impairment than males but had lower BASMI and mSASSS scores. Data collected through this study provided a demographic and clinical profile of patients with AS in Portugal. The development of centile charts constitutes a useful tool to assess the change of disease pattern over time and in response to therapeutic interventions.

Comparison of visual status of Iranian military and commercial drivers

Background There is no legal requirement for Iranian military truck drivers to undergo regular visual checkups as compared to commercial truck drivers. Objectives This study aimed to evaluate the impact of drivers’ visual checkups by comparing the visual function of Iranian military and commercial truck drivers. Patients and Methods In this comparative cross-sectional study, two hundred military and 200 commercial truck drivers were recruited and their Visual Acuity (VA), Visual Field (VF), color vision and Contrast Sensitivity (CS) were assessed and compared using the Snellen chart, confrontation screening method, D15 test and Pelli-Robson letter chart, respectively. A questionnaire regarding driving exposure and history of motor-vehicle crashes (MVCs) was also filled by drivers. Results were analyzed using an independent samples t-test, one-way ANOVA (assessing difference in number of MVCs across different age groups), chi-square test and Pearson correlation at statistical significance level of P < 0.05. Results Mean age was 41.6 ± 9.2 for the military truck drivers and 43.4 ± 10.9 for commercial truck drivers (P > 0.05). No significant difference between military and commercial drivers was found in terms of driving experience, number of MVCs, binocular VA, frequency of color vision defects and CS scores. In contrast, the last ocular examination was significantly earlier in military drivers than commercial drivers (P < 0.001). In addition, 4% of military drivers did not meet the national standards to drive as opposed to 2% of commercial drivers. There was a significant but weak correlation between binocular VA and age (r = 0.175, P < 0.001). However, CS showed a significantly moderate correlation with age (r = -0.488, P < 0.001). Conclusions The absence of legal requirement for regular eye examination in military drivers caused the incompetent drivers to be missed in contrast to commercial drivers. The need for scientific revision of VA standard for Iranian drivers is also discussed. The CS measurement in visual checkups of older drivers deserves to be investigated more thoroughly.