Identification of novel associations and localization of signals in idiopathic inflammatory myopathies using genome-wide imputation

Objective: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. Results: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. Conclusion: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types

Trajectories of maternal symptoms of anxiety and depression. A 13-year longitudinal study of a population-based sample

<p>Abstract</p> <p>Background</p> <p>There is a lack of population-based studies of developmental trajectories following mothers throughout the whole child-rearing phase and there are few longitudinal studies focusing on both symptoms of depression and anxiety. The aim of the current study is to identify latent trajectory groups based on counts of symptoms of anxiety and depression among mothers throughout the child-rearing phase and the relations of the latent groups to maternal socio-demographic variables.</p> <p>Methods</p> <p>Data is from a prospective, longitudinal study of nearly 1000 families in Norway followed from when the index children were 18 months until they were 14.5 years old (the TOPP study). The study used latent profile analysis (LPA) to identify latent groups of mothers with distinct trajectories across time of symptom counts. Latent group differences on socio-demographic variables were tested with one-way ANOVAs, chi-square tests and exact tests.</p> <p>Results</p> <p>Six trajectories based on maternal scores from six waves of data collection of symptoms of anxiety and depression were identified; a 'No symptoms' group with mothers without symptoms; a 'Low' group with mothers reporting low symptom levels; a 'Moderate-low' group with mothers reporting moderately low symptom levels; a 'Moderate' group with mothers with moderate symptoms; a 'High-chronic' group with mothers with overall high symptom levels; and a 'Low-rising' group with mothers starting with a low symptom level that increased over time. The mothers in the High-chronic symptom group differed from the other mothers on several socio-demographic variables. They were significantly younger than the mothers in the Low group comprising the oldest mothers. The mothers in the High-chronic group had significantly lower education, were less likely to have paid work and were less likely to be living with a partner than the mothers in the other groups.</p> <p>Conclusions</p> <p>The study shows socio-demographic differences between mothers classified into six trajectory groups based on symptoms of anxiety and depression covering 13 years of the child-rearing period. Specific socio-demographic risk factors characterised mothers in the High-chronic symptom group. Identifying subgroups with enduring problems might inform more targeted preventive efforts.</p

Translating HbA1c measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA1c measurements are applicable to pregnant women with diabetes. Methods CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA1c measure. In total, 688 average glucose–HbA1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA1c. Results There was a strong association between HbA1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. Conclusions/interpretation The HbA1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care

Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A

<p>Abstract</p> <p>Background</p> <p>Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population.</p> <p>Objective</p> <p>In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus.</p> <p>Methods</p> <p>Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter.</p> <p>Results</p> <p>Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8⁺T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4⁺/CD8⁺) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (<it>P </it>< 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%).</p> <p>Conclusions</p> <p>Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity.</p

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10^{-5}. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10^{-53}  and HLA-DRB1*03:01, p=3.25×10^{-9}, anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10^{-26}) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10^{-11}). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10^{-13}) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10^{-6}). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10^{-64} and position 9 of HLA-B (p=7.03×10^{-11}). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research

Severe hypoglycaemia during pregnancy in women with type 1 diabetes: Possible role of renin-angiotensin system activity?

Aims: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin-angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). Methods: Severe hypoglycaemic events the year preceding pregnancy were recorded retrospectively in 107 consecutive pregnant women with T1DM. Events during pregnancy were recorded prospectively. Measurements of ACE, renin and angiotensinogen were determined at 8, 14, 21, 27 and 33 weeks and postpartum. Results: The rate of severe hypoglycaemia was 1.1 and 5.3 events/patient-year the year preceding pregnancy and in first trimester, respectively (p < 0.0001). Levels of ACE, renin or angiotensinogen did not differ between women with and without severe hypoglycaemia during pregnancy. Multivariate regression analysis identified a positive association between rate of severe hypoglycaemia the year preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7-11.9), p = 0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. Conclusions: in early pregnancy increased RAS activity does not explain the 5-fold increase in severe hypoglycaemia in women with T1DM. A positive association between occurrence of severe hypoglycaemia and ACE activity outside pregnancy was demonstrated. (C) 2009 Elsevier Ireland Ltd. All rights reserved

Cardiovascular health and the modifiable burden of incident myocardial infarction: The Tromsø Study

Background: The American Heart Association has proposed an impact goal for the year 2020 to improve cardiovascular health by 20%. The objectives of the study were to assess the association between the proposed cardiovascular health metric score and incident myocardial infarction (MI) and to estimate the generalized impact fraction (GIF). Methods: The health metric score was derived from ideal levels of six cardiovascular risk factors from the population-based Tromsø Study of 22,121 residents of Tromsø, Norway aged 30 to 79 years, examined in 1994–95, 2001, and 2007–08. Incident events of MI were recorded from the date of enrollment in 1994–95 to the end of 2010. Adjudication of hospitalized and out-of hospital events was performed by an independent endpoints committee based on data from hospital and out-of hospital journals, autopsy records and death certificates. Cox proportional hazard regression was used to estimate hazard ratios (HR). GIF was calculated from age stratified analysis using a case-load weighted-sum method. Bootstrapping was used to estimate 95% simulation intervals. Results: A total of 1652 MIs accrued over an average of 14.7 person-years of follow-up. Few men (0.96%) and women (3.6%) had ideal levels in all 6 metrics. 64.7% (men) and 55.7% (women) had ideal levels in 2 or 3 metrics. The age-adjusted HR per point increase in health score was 0.65 (95% confidence interval: 0.61, 0.70) in men and 0.59 (0.54, 0.64) in women. A shift of 30% of subjects from low score levels ≤3 to scores ≥4 was estimated to prevent 13.7% (11.2, 16.2) of incident MI in men and 15.9% (12.1, 19.4) in women. Conclusions: The association between the health metric score and MI indicate that close to 15% of incident MIs could be prevented by attainable and realistic improvements in the health metrics