The F158V polymorphism in FcγRIIIA shows disparate associations with rheumatoid arthritis in two genetically distinct populations

Objectives: To investigate the association of the FcγRIIIA gene with rheumatoid orthritis (RA) in two genetically distinct groups: a white group from the United Kingdom and a northern Indian group. Methods: The distributions of the two alleles of the FcγRIIIA F158V polymorphism were determined in 398 white patients from the United Kingdom and 63 Indian patients with RA and compared with those from 289 United Kingdom and 93 Indian healthy controls, respectively. Results: Among the Indian patients, the frequency of the rare 158V allele and the proportion of 158VV homozygotes were reduced (relative risk (RR)=0.3, 95% confidence interval (95% CI) 0.1 to 1.1, p<0.06), reaching statistical significance for carrying the 158VV phenotype relative to 158FV or FF (RR=0.2, 95% CI 0.05-0.9, p<0.02). Conversely, no significant deviation in allelic frequencies was noted between the patients and controls from the United Kingdom. Conclusions: The 158VV phenotype showed a weak protective effect against developing RA in the Indian group. However, this sample was small (resulting in a low power for statistical analysis) and no independent confirmation was found in the larger white United Kingdom group. Thus the FcγRIIIA locus is unlikely to be of major importance in causing RA.

Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis

Objectives: The aim of the current study was to determine the contribution of interleukin (IL) 1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide. Methods: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. Results: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. Conclusions: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.

Associations between extreme precipitation and childhood hand, foot and mouth disease in urban and rural areas in Hefei, China

Background Understanding the relationship between extreme weather events and childhood hand, foot and mouth disease (HFMD) is important in the context of climate change. This study aimed to quantify the relationship between extreme precipitation and childhood HFMD in Hefei, China, and further, to explore whether the association varied across urban and rural areas. Methods Daily data on HFMD counts among children aged 0–14 years from 2010 January 1st to 2012 December 31st were retrieved from Hefei Center for Disease Control and Prevention. Daily data on mean temperature, relative humidity and precipitation during the same period were supplied by Hefei Bureau of Meteorology. We used a Poisson linear regression model combined with a distributed lag non-linear model to assess the association between extreme precipitation (≥ 90th precipitation) and childhood HFMD, controlling for mean temperature, humidity, day of week, and long-term trend. Results There was a statistically significant association between extreme precipitation and childhood HFMD. The effect of extreme precipitation on childhood HFMD was the greatest at six days lag, with a 5.12% (95% confident interval: 2.7–7.57%) increase of childhood HFMD for an extreme precipitation event versus no precipitation. Notably, urban children and children aged 0–4 years were particularly vulnerable to the effects of extreme precipitation. Conclusions Our findings indicate that extreme precipitation may increase the incidence of childhood HFMD in Hefei, highlighting the importance of protecting children from forthcoming extreme precipitation, particularly for those who are young and from urban areas.

The prevalence, predictors and associations of hypertension in Sri Lanka: A cross-sectional population based national survey

We studied the community prevalence, patterns and predictors of hypertension in a large sub-population of South Asian adults with a view of identifying differential risk factors. Data were collected between years 2005-2006 and 5000 adults were invited for the study. The sample size was 4485, and about 39.5% were males. Mean systolic and diastolic blood pressures were 127.1 ± 19.8 mmHg and 75.4 ± 11.3 mmHg, respectively. Age-adjusted prevalence in all adults, males and females was 23.7%, 23.4% and 23.8%, respectively. Urban adults had a significantly higher prevalence of hypertension than rural adults. In the binary logistic-regression analysis, male gender (OR: 1.2), increasing age, Sri Lankan Moor ethnicity (OR: 1.6), physical inactivity (OR: 1.7), presence of diabetes (OR: 2.2) and central obesity (OR: 2.3) all were significantly associated with hypertension. In conclusion, nearly one-third of the Sri Lankan adult population is hypertensive. Hence, public health initiatives should encourage healthier lifestyles with emphasis on preventing obesity and increasing physical activity.

Genetic associations and functional characterization of M1 aminopeptidases and immune-mediated diseases

Endosplasmic reticulum aminopeptidase 1 (ERAP1), endoplasmic reticulum aminopeptidase 2 (ERAP2) and puromycin-sensitive aminopeptidase (NPEPPS) are key zinc metallopeptidases that belong to the oxytocinase subfamily of M1 aminopeptidase family. NPEPPS catalyzes the processing of proteosome-derived peptide repertoire followed by trimming of antigenic peptides by ERAP1 and ERAP2 for presentation on major histocompatibility complex (MHC) Class I molecules. A series of genome-wide association studies have demonstrated associations of these aminopeptidases with a range of immune-mediated diseases such as ankylosing spondylitis, psoriasis, Behçet's disease, inflammatory bowel disease and type I diabetes, and significantly, genetic interaction between some aminopeptidases and HLA Class I loci with which these diseases are strongly associated. In this review, we highlight the current state of understanding of the genetic associations of this class of genes, their functional role in disease, and potential as therapeutic targets.

Postnatal depressive symptoms amongst women in Central Vietnam: A cross-sectional study investigating prevalence and associations with social, cultural and infant factors

Background This study investigated the prevalence and socio-cultural correlates of postnatal mood disturbance amongst women 18–45 years old in Central Vietnam. Son preference and traditional confinement practices were explored as well as factors such as poverty, parity, family and intimate partner relationships and infant health. Methods A cross-sectional study was conducted in twelve randomly selected Commune Health Centres from urban and rural districts of Thua Thien Hue Province, Vietnam. Mother-infant dyads one to six months postpartum were invited to participate. Questionnaires from 431 mothers (urban n = 216; rural n = 215) assessed demographic and family characteristics, traditional confinement practices, son preference, infant health and social capital. The Edinburgh Postnatal Depression Scale (EPDS) and WHO5 Wellbeing Index indicated depressive symptoms and emotional wellbeing. Data were analysed using general linear models. Results Using an EPDS cut-off of 12/13, 18.1 % (n = 78, 95 % CI 14.6 - 22.1) of women had depressive symptoms (20.4 % urban; 15.8 % rural). Contrary to predictions, infant gender and traditional confinement were unrelated to depressive symptoms. Poverty, food insecurity, being frightened of family members, and intimate partner violence increased both depressive symptoms and lowered wellbeing. The first model accounted for 30.2 % of the variance in EPDS score and found being frightened of one’s husband, husband’s unemployment, breastfeeding difficulties, infant diarrhoea, and cognitive social capital were associated with higher EPDS scores. The second model had accounted for 22 % of the variance in WHO5 score. Living in Hue city, low education, poor maternal competence and a negative family response to the baby lowered maternal wellbeing. Conclusions Traditional confinement practices and son preference were not linked to depressive symptoms among mothers, but were correlates of family relationships and wellbeing. Poverty, food insecurity, violence, infant ill health, and discordant intimate and family relationships were linked with depressive symptoms in Central Vietnam.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Signs of driver sleepiness and risky sleepy driving behaviours: the associations with demographic, work and sleep-related factors

Driving while sleepy is regarded as a substantial crash risk factor. Reducing the risk of sleep-related crashes predominately rests with the driver’s awareness of experiencing signs that are common when sleepy; such as yawning, frequent eye blinks, and difficulty keeping eyes open. However the relationship between the signs of sleepiness and risky sleepy driving behaviours is largely unknown. The current study sought to examine the relationships between drivers’ experiences of the signs of sleepiness, risky sleepy driving behaviours, and the associations with demographic, work and sleep-related factors. In total 1,608 participants completed a questionnaire administered via a telephone interview that assessed their experiences and behaviours of driving while sleepy. The results revealed a number of demographic, work and sleep-related factors were associated with experiencing signs of sleepiness when driving. Signs of sleepiness were also found to mediate the relationship between continuing to drive while sleepy and having a sleep-related close call event. A subgroup analysis based on age (under 30 and 30 years or older) found younger drivers were more likely to continue to drive when sleepy despite experiencing more signs of sleepiness. The results suggest participants had considerable experience with the signs of sleepiness and driving while sleepy. Actions to be taken from this research include informing the content of driver education campaigns regarding the importance of the signs of sleepiness. Working together to educate all drivers about the dangerousness of driving when experiencing signs of sleepiness is an important road safety outcome.

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 tdthomlt; 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.

Non-B27 MHC associations of ankylosing spondylitis

Ankylosing spondylitis (AS) has been associated with human leukocyte antigen (HLA)-B27 for over 30 years; however, the mechanism of action has remained elusive. Although many studies have reported associations between AS and other genes in the major histocompatibility complex (MHC) in AS, no conclusive results have emerged. To investigate the contribution of non-B27 MHC genes to AS, a large cohort of AS families and controls were B27 typed and genotyped across the region. Interrogation of the data identified a region of 270kb, lying from 31952649 to 32221738 base pairs from the p-telomere of chromosome 6 and containing 23 genes, which is likely to include genes involved with susceptibility to AS.

HLA-DR/DQ haplotype in rheumatoid arthritis: Novel allelic associations in UK Caucasians

Objective. To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). Methods. HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. Results. Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRβ molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. Conclusion. These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.

Medical negligence, causation and 'exceptional cases' under the civil liability legislation

Under the civil liability legislation enacted in most Australian jurisdictions, factual causation will be established if, on the balance of probabilities, the claimant can prove that the defendant's negligence was 'a necessary condition of the occurrence of the [claimant's] harm'. Causation will then be satisfied by showing that the harm would not have occurred 'but for' the defendant's breach of their duty of care. However, in an exceptional or appropriate case, sub-section 2 of the legislation provides that if the 'but for' test is not met, factual causation may instead be determined in accordance with other 'established principles'. In such a case, 'the court is to consider (amongst other relevant things) whether or not and why responsibility for the harm should be imposed' on the negligent party.

Dieting and non-dieting: Socio-cognitive determinants and associations with nutrition and health status indicators

Dieting and non-dieting are two contrasting approaches to the management of overweight/obesity, but less is known about why people follow non-dieting approaches and how these approaches are associated with health and nutrition status indicators. This thesis enables a greater understanding of why dieting and non-dieting approaches are adopted and provides insight into whether one approach is more favourably associated with nutrition and health status indicators. The findings of this thesis will be useful for clinicians who wish to encourage dieting or non-dieting approaches in their clients and for researchers wishing to understand how best to address overweight and obesity.

Cycling for transport and recreation: Associations with the socio-economic, natural and built environment

This study examined associations between objective environmental attributes and, separately, transport (TC) and recreational cycling (RC). Environmental attributes were more strongly associated with TC than RC. Distances to areas with the best bicycle infrastructure and urban amenities may be key environmental factors influencing TC but not RC. Government investments in bicycle infrastructure within inner Brisbane appear to have resulted in more TC than in outer areas and to appeal to residents of both the most and least disadvantaged neighbourhoods. Extending this infrastructure to residents living in disadvantaged and advantaged neighbourhoods outside the CBD could expand TC participation.