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Abstract Background Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. Methods We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. Results Case–control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. Conclusions This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.

Abstract Background A significant proportion of individuals with suspicious onset of multiple sclerosis (MS) does not fulfill the diagnostic criteria. Although some receive other diagnoses, many remain undiagnosed and lack healthcare follow‐up. This study aimed to characterize persons with undetermined diagnosis (PwUD) through a questionnaire. Methods Incident cases with suspected MS were consecutively admitted to a tertiary neurological healthcare center in a prospective cohort study. Those who remained undiagnosed after 40 months (mean, range 31–52) were considered PwUD. They completed a modified questionnaire, previously used in a population‐based case‐control study of incident MS cases. Their responses were compared with two control cohorts, persons with MS (PwMS) and healthy controls, randomly selected from national registries, matched by age, gender, and area of residence. Results Out of 271 patients with suspected MS onset, 72 (20.3%) were PwUD with a female majority (79%). The response rate was 83% and 39% reported persisting MS‐like symptoms. Compared to controls (n = 548) and PwMS (n = 277), fewer PwUD were currently smoking (p = .4 and p = .03), consumed less alcohol (p = .04 and p = .01), and had children (p = .02 and p = .002). PwUD reported occurrence of other autoimmune disease in 29%, higher compared to PwMS and controls (p

Abstract Background Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. Methods Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; N overall = 368,929; N men = 180,094; N women = 188,908), crude SHBG (N overall = 370,125; N men = 180,726; N women = 189,473), and RA (N case = 22,350; N control = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. Results Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ( $$r_{{\text{g}}}$$ r g = 0.11, P = 1.0 × 10−4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01–1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997–1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. Conclusion Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.

Abstract Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Abstract Objectives To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA). Methods This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996–2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level. Results Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74–1.16), 12 (OR 0.96, 95%CI 0.75–1.23), or 60 (OR 0.89, 95%CI 0.72–1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54–1.31), 12 (OR 0.81, 95%CI 0.56–1.16), or 60 (OR 1.37, 95%CI 0.94–2.01) months. Conclusion In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.

Abstract Background Studies on the association between coffee, a modifiable lifestyle factor, and rheumatoid arthritis (RA), a chronic autoimmune disease primarily affecting the joints, have been conflicting. The aim of the present study was to study the association between coffee consumption and risk of RA in the context of different lifestyle factors. Methods We included 2184 cases (72% women, mean age 55 years) newly diagnosed with RA during 2005–2018 in Sweden and 4201 controls matched on age, sex, and residential area. Data on coffee consumption was collected through a food frequency questionnaire and categorized into < 2 (reference), 2–< 4, 4–< 6, and ≥ 6 cups/day. We calculated odds ratios (OR) with 95% confidence intervals (CI) for coffee consumption and risk of RA, in a crude model (taking matching factors into account), and then adjusted first for smoking and further for BMI, educational level, alcohol consumption, and physical activity. We also stratified analyses on sex, smoking, rheumatoid factor, and anti-CCP2 status. Results In the crude model, high coffee consumption was associated with increased risk of RA (OR = 1.50, 95% CI 1.20–1.88 for ≥ 6 cups/day compared to < 2 cups). After adjusting for smoking, the OR decreased and was no longer statistically significant (OR = 1.16, 95% CI 0.92–1.46) and decreased further in the full model (OR = 1.14 95% CI 0.89–1.45). This pattern held true in all strata. Conclusion The findings from this large, population-based case-control study did not support a significant association between coffee consumption and risk of RA as a whole nor within different subgroups.

Objective The study objective was to identify subgroups of patients with rheumatoid arthritis (RA) based on their health status 3 years after diagnosis and to assess potential associations to clinical presentation at diagnosis. Methods This observational study included patients with RA with 3‐year follow‐up data from the Swedish Epidemiological Investigation of RA study, collected from 2011 to 2018. Hierarchical agglomerative cluster analysis, based on symptoms of pain, fatigue, sleep quality, mood disturbances, and overall health‐related quality of life (HRQoL), was used to identify subgroups 3 years after diagnosis. Modified Poisson regression was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for the associations between the subgroups and patient characteristics at diagnosis. Results A total of 1055 individuals constituted the study population, of whom 1011 had complete data on the clustering variables and were therefore eligible for analysis (73% women, median age 58 years). The following three clusters were identified: cluster 1 (466 patients with good health status), cluster 2 (398 patients in an intermediate group), and cluster 3 (147 patients with high levels of pain and fatigue together with markedly impaired HRQoL). Cluster 3 was associated to higher baseline pain (RR: 3.71 [95% CI: 2.14‐6.41]), global health (RR: 6.60 [95% CI: 3.53‐12.33]), and the Stanford Health Assessment Questionnaire (RR: 4.40 [95% CI: 2.46‐7.87]), compared with cluster 1 (highest compared with lowest quartiles). An inverse association was seen for baseline swollen joint count (RR: 0.51 [95% CI: 0.34‐0.85]). Conclusion A subgroup of patients with RA experience high levels of pain, fatigue, and psychosocial distress 3 years after diagnosis. This subgroup already displayed pronounced pain and functional disabilities at diagnosis.

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

Abstract Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case–control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend

Abstract Background Tea is a popular beverage around the world and has properties that can affect the immune system. The association between tea consumption and the risk of rheumatoid arthritis (RA), a chronic autoimmune disease primarily affecting the joints, is not well studied and results are conflicting. Methods We collected data on tea consumption for 2237 incident RA cases diagnosed 2005–2018 and 4661 controls matched on age, sex, and residential area. Tea consumption was classified into no (0 cups/day), irregular (

Abstract Background There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules. Result We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10− 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS. Conclusions We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases.

Summary: Background: Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use. Methods: In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies with baseline data collection on alcohol consumption, drinking patterns, and history between 1986 and 2005 (the IPD-Work Consortium). Self-reported alcohol consumption was categorised according to UK guidelines – non-drinking (never or former drinkers); moderate consumption (1–14 units); heavy consumption (>14 units per week). We further subdivided moderate and heavy drinkers by binge drinking pattern (alcohol-induced loss of consciousness). In addition, we assessed problem drinking using linked data on hospitalisations due to alcohol abuse or poisoning. Follow-up for chronic diseases for all participants included incident type 2 diabetes, coronary heart disease, stroke, cancer, and respiratory disease (asthma and chronic obstructive pulmonary disease) as ascertained via linkage to national morbidity and mortality registries, repeated medical examinations, and/or self-report. We estimated years lived without any of these diseases between 40 and 75 years of age according to sex and characteristics of alcohol use. We repeated the main analyses using data from 427,621 participants in the UK Biobank cohort study. Findings: During 1·73 million person-years at risk, 22,676 participants in IPD-Work cohorts developed at least one chronic condition. From age 40 to 75 years, never-drinkers [men: 29·3 (95%CI 27·9–30·8) years, women 29·8 (29·2–30·4) years)] and moderate drinkers with no binge drinking habit [men 28·7 (28·4–29·0) years, women 29·6 (29·4–29·7) years] had the longest disease-free life span. A much shorter disease-free life span was apparent in participants who experienced alcohol poisoning [men 23·4 (20·9–26·0) years, women 24·0 (21·4–26·5) years] and those with self-reported heavy overall consumption and binge drinking [men: 26·0 (25·3–26·8), women 27·5 (26·4–28·5) years]. The pattern of results for alcohol poisoning and self-reported alcohol consumption was similar in UK Biobank. In IPD-Work and UK Biobank, differences in disease-free years between self-reported moderate drinkers and heavy drinkers were 1·5 years or less. Interpretation: Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. Differences in disease-free life between categories of self-reported weekly alcohol consumption were smaller. Funding: Medical Research Council, National Institute on Aging, NordForsk, Academy of Finland, Finnish Work Environment Fund.

Abstract Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA. Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (N case = 14,361, N control = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions. Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98–1.15]; ORper-SD increment in ANM = 1.05 [0.98–1.11], OR per-SD increment in AFB = 0.85 [0.65–1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97–1.15], ORper-SD increment in ANM = 1.05 [0.98–1.13], ORper-SD increment in AFB = 0.81 [0.61–1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94–1.12], ORper-SD increment in ANM = 1.04 [0.95–1.14]). No outlying instrument was identified through the leave-one-out analysis. Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p

Abstract Background Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. Methods We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. Results We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30–5.49, P GWAS = 7.22 × 10−29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37–0.62, P GWAS = 2.58 × 10−08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09–0.30, P GWAS = 1.60 × 10−09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. Conclusions Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

Tobacco smoke is an important modifiable environmental risk factor for multiple sclerosis (MS) risk. The population attributable fraction (AF) of MS due to smoking can be used to assess the contribution of smoking to the risk of MS development. We conducted a matched case-control study, including individuals with MS and population-based controls. Overall, sex- and genetic risk score-stratified AF due to smoking were calculated by fitting logistic regression models. We included 9,419 individuals with MS and 9,419 population-based matched controls. At the time of MS onset 44.1% of persons with MS and 35.9% of controls ever regularly smoked of which 38.1% and 29.2% were still smoking. The overall AF was 13.1% (95%CI: 10.7 to 15.4). The AF was 10.6% (95%CI: 7.4 to 13.7) in females and 19.1% (95%CI: 13.1 to 25.1) in males. The AF was 0.6% (95%CI: 0.0 to 2) in ex-smokers. In those having human leucocyte antigen (HLA) and non-HLA risk scores above the median levels of controls, the AF was 11.4% (95%CI: 6.8 to 15.9) and 12% (95%CI: 7.7 to 16.3), respectively. The AF was 17.6% (95%CI: 10.2 to 24.9) and 18.6% (95%CI: 5.5 to 31.6) in those with HLA and non-HLA risk scores below the median levels in controls, respectively. We noticed a decline in AF in recent birth cohorts. This study indicates that at least 13% of cases of MS could be prevented through the avoidance of tobacco smoking. Considering the prevalence of MS, this represents a very large group of people in absolute number.

Abstract It is unclear whether smoking interacts with different aspects of Epstein–Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case–control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p

Abstract Background Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome. Conclusions “Seronegative” RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.

Abstract Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology. It has been shown that genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors. Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality. Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data. The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design. In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis. We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions. The application of MR design in the field of rheumatology remains limited. Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found. Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results. Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers). As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered. Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates. To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.

Abstract Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals’ Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.

SUMMARY: Background: Studies on the association between long working hours and health have captured only a narrow range of outcomes (mainly cardiometabolic diseases and depression) and no outcome-wide studies on this topic are available. To achieve wider scope of potential harm, we examined long working hours as a risk factor for a wide range of disease and mortality endpoints. Methods: The data of this multicohort study were from two population cohorts from Finland (primary analysis, n=59 599) and nine cohorts (replication analysis, n=44 262) from Sweden, Denmark, and the UK, all part of the Individual-participant Meta-analysis in Working Populations (IPD-Work) consortium. Baseline-assessed long working hours (≥55 hours per week) were compared to standard working hours (35-40 h). Outcome measures with follow-up until age 65 years were 46 diseases that required hospital treatment or continuous pharmacotherapy, all-cause, and three cause-specific mortality endpoints, ascertained via linkage to national health and mortality registers. Findings: 2747 (4·6%) participants in the primary cohorts and 3027 (6·8%) in the replication cohorts worked long hours. After adjustment for age, sex, and socioeconomic status, working long hours was associated with increased risk of cardiovascular death (hazard ratio 1·68; 95% confidence interval 1·08-2·61 in primary analysis and 1·52; 0·90-2·58 in replication analysis), infections (1·37; 1·13-1·67 and 1·45; 1·13-1·87), diabetes (1·18; 1·01-1·38 and 1·41; 0·98-2·02), injuries (1·22; 1·00-1·50 and 1·18; 0·98-1·18) and musculoskeletal disorders (1·15; 1·06-1·26 and 1·13; 1·00-1·27). Working long hours was not associated with all-cause mortality. Interpretation: Follow-up of 50 health outcomes in four European countries suggests that working long hours is associated with an elevated risk of early cardiovascular death and hospital-treated infections before age 65. Associations, albeit weak, were also observed with diabetes, musculoskeletal disorders and injuries. In these data working long hours was not related to elevated overall mortality. Funding: NordForsk, the Medical Research Council, the National Institute on Aging, the Wellcome Trust, Academy of Finland, and Finnish Work Environment Fund.

BackgroundElevated apolipoprotein B (apoB) and elevated apoB/apoA-1 ratio increase the risk of myocardial infarction (MI) and stroke, whereas high apoA-1 is protective. We study how these apolipoproteins are associated with major adverse cardiovascular events (MACEs), whether apoA-1 contributes to this association, and whether abnormal values occur decades before such events develop.Methods and findingsIn the Swedish AMORIS (Apolipoprotein-related MOrtality RISk) cohort study, 137,100 men and women aged 25-84 years were followed an average 17.8 years. ApoB, apoA-1, and the apoB/apoA-1 ratio were analysed in relation to MACEs (non-fatal MI, stroke, and cardiovascular [CV] mortality), yielding 22,473 events. Hazard ratios (HRs) were estimated using Cox regression. Kaplan-Meier estimates were used to investigate the relationship of MACEs with increasing quintiles of the apoB/apoA-1 ratio in all age groups for both sexes. In nested case-control analyses, cases were randomly matched to age- and sex-matched controls, yielding population trajectories for apolipoproteins. Increased level of apoB and increased apoB/apoA-1 ratio were associated with risk of MACE and all clinical sub-components in both men and women across all ages (10th versus first decile in both sexes combined: HR 1.7 for MACE and 2.7 for non-fatal MI). Decreased values of apoA-1 potentiated the impact of apoB at all levels of apoB (on average across apoB range: 40% increase in HR for MACE and 72% increase in HR for non-fatal MI), indicating that the apoB/apoA-1 ratio covers a broader range of persons with dyslipidaemia at risk than apoB alone. In both men and women, MACEs occurred earlier on average for each increasing quintile of the apoB/apoA-1 ratio. Individuals with the highest levels of apoB/apoA-1 ratio experienced CV events on average several years earlier than those with lower ratios. Higher apoB/apoA-1 ratio in cases of MACE versus controls was seen already about 20 years before the event. A limitation of this study was that adjustment for tobacco smoking and hypertension was only possible in a small validation study.ConclusionsAn imbalance between apoB and apoA-1 resulting in an increased apoB/apoA-1 ratio is strongly associated with the outcome MACE and its sub-components, in both men and women of all ages. An increased apoB/apoA-1 ratio already 2 decades before events calls for early recognition and primary prevention. Simple evidence-based cut values should be considered in future cardiovascular guidelines.

Purpose: Observational studies have suggested a protective effect of alcohol intake with autoimmune disorders, which was not supported by Mendelian randomization (MR) analyses that used only a few (

Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the “Cit-umbrella” similar to ACPA fine-specificities, while MAA reactivity is distinctly different.

Abstract Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

Background Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjögren’s syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.Methods Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case–control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.Results The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.Conclusion The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85–1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03–1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.

Introduction Respiratory inflammation has been proposed as a risk factor for MS. This study aims to determine if hospital-diagnosed pneumonia in adolescence (before age 20 years) is associated with subsequent multiple sclerosis (MS).Methods This case-control study included incident MS cases after age 20 years identified using the Swedish national registers. Cases were matched with 10 general population controls by age, sex and region. Pneumonia diagnoses were identified between 0–5, 6–10, 11–15 and 16–20 years of age. Conditional logistic regression models adjusted for infectious mononucleosis (IM) and education calculated ORs with 95% CIs. Urinary tract infections (UTIs), a common complication of MS, before age 20 years were included as a control diagnosis for reverse causation.Results There were 6109 cases and 49 479 controls included. Pneumonia diagnosed between age 11–15 years was associated with subsequent MS (adj OR 2.00, 95% CI 1.22 to 3.27). Although not statistically significant, sensitivity analyses showed similar magnitude associations of pneumonia between age 11–15 years and MS. No statistically significant associations with MS for pneumonia at other age groups were observed. Adjustment for IM had no notable effect on associations, but was statistically significantly associated with MS. UTIs were not associated with MS.Conclusion Pneumonia at 11–15 years of age was associated with MS, suggesting a possible role for inflammation of the respiratory system in the aetiology of MS during a period of susceptibility in adolescence. Further research on respiratory infections prior to MS onset should be conducted to replicate this finding and determine explanatory causal mechanisms.

Background Job strain is implicated in many atherosclerotic diseases, but its role in peripheral artery disease (PAD) is unclear. We investigated the association of job strain with hospital records of PAD, using individual‐level data from 11 prospective cohort studies from Finland, Sweden, Denmark, and the United Kingdom. Methods and Results Job strain (high demands and low control at work) was self‐reported at baseline (1985–2008). PAD records were ascertained from national hospitalization data. We used Cox regression to examine the associations of job strain with PAD in each study, and combined the study‐specific estimates in random effects meta‐analyses. We used τ2, I2, and subgroup analyses to examine heterogeneity. Of the 139 132 participants with no previous hospitalization with PAD, 32 489 (23.4%) reported job strain at baseline. During 1 718 132 person‐years at risk (mean follow‐up 12.8 years), 667 individuals had a hospital record of PAD (3.88 per 10 000 person‐years). Job strain was associated with a 1.41‐fold (95% CI, 1.11–1.80) increased average risk of hospitalization with PAD. The study‐specific estimates were moderately heterogeneous (τ2=0.0427, I2: 26.9%). Despite variation in their magnitude, the estimates were consistent in both sexes, across the socioeconomic hierarchy and by baseline smoking status. Additional adjustment for baseline diabetes mellitus did not change the direction or magnitude of the observed associations. Conclusions Job strain was associated with small but consistent increase in the risk of hospitalization with PAD, with the relative risks on par with those for coronary heart disease and ischemic stroke.

Objective: Elevated levels of anti-EBNA-1 antibodies and infectious mononucleosis (IM) history have consistently been associated with multiple sclerosis (MS) risk. We aimed to study whether these aspects of Epstein–Barr virus (EBV) infection represent separate risk factors for MS and whether they both interact with MS-associated HLA genes in disease development.Methods: Two Swedish-population-based case–control studies were used, comprising 5,316 cases and 5,431 matched controls. Subjects with different HLA alleles, EBNA-1, and IM status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Causal mediation analysis was used to assess to what extent the relationship between IM history and MS risk was mediated by high anti-EBNA-1 antibody levels and vice versa.Results: The causal mediation analysis revealed that both aspects of EBV infection mainly act directly on MS risk. The direct effect of elevated anti-EBNA-1 antibody levels on MS risk, expressed on the OR scale, was 2.8 (95% CI 2.5–3.1), and the direct effect of IM history on MS risk was 1.7 (95% CI 1.5–2.0). A significant interaction between the two aspects of EBV infection was observed (RERI 1.2, 95% CI 0.3–2.0), accounting for about 50% of the total effect. Further, both aspects of EBV infection interacted with DRB1*15:01 and absence of A*02:01.Interpretation: Elevated anti-EBNA-1 antibody levels and IM history are different risk factors for MS. The two aspects of EBV infection act synergistically to increase MS risk, indicating that they partly are involved in the same biological pathways.

Abstract Background The Mediterranean diet has been associated with lower mortality and lower risk of cardiovascular diseases and cancer. Although its components have been analysed in several studies, only one study has specifically investigated the association between Mediterranean diet and risk of rheumatoid arthritis (RA), and reported no association. Methods Data on 1721 patients with incident RA (cases) and 3667 controls, matched on age, gender and residential area, from the Swedish epidemiological investigation of RA (EIRA), a population-based case-control study, were analysed using conditional logistic regression. The Mediterranean diet score, ranging from 0 to 9, was calculated from a 124-item food frequency questionnaire. Results In the EIRA study (median age of participants 53 years), 24.1% of the patients and 28.2% of the controls had high adherence to the Mediterranean diet (a score between 6 and 9). After adjustments for body mass index, educational level, physical activity, use of dietary supplements, energy intake, and smoking, high adherence reduced the odds of developing RA by 21% (OR 0.79; 95% CI 0.65–0.96) as compared to low adherence (a score between 0 and 2). The OR was even lower among men (OR 0.49; 95% CI 0.33–0.73), but no significant association was found among women (OR 0.94; 95% CI 0.74–1.18). An association between high diet score and low risk of RA was observed in rheumatoid factor (RF)-positive (OR 0.69; 95% CI 0.54–0.88), but not RF-negative RA (OR 0.96; 95% CI 0.68–1.34), and in RA characterised by presence of antibodies to citrullinated peptides (ACPA), but not in ACPA-negative RA. Conclusions In this large population-based case-control study, the Mediterranean diet score was inversely associated with risk of RA. However, an association was only found among men and only in seropositive RA.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10−22), and increased risk of future MS (OR = 2.22, p = 2 × 10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10−11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

OBJECTIVES: This systematic review and meta-analysis combined published study-level data and unpublished individual-participant data with the aim of quantifying the relation between long working hours and the onset of depressive symptoms. METHODS: We searched PubMed and Embase for published prospective cohort studies and included available cohorts with unpublished individual-participant data. We used a random-effects meta-analysis to calculate summary estimates across studies. RESULTS: We identified ten published cohort studies and included unpublished individual-participant data from 18 studies. In the majority of cohorts, long working hours was defined as working ≥55 hours per week. In multivariable-adjusted meta-analyses of 189 729 participants from 35 countries [96 275 men, 93 454 women, follow-up ranging from 1–5 years, 21 747 new-onset cases), there was an overall association of 1.14 (95% confidence interval (CI) 1.03–1.25] between long working hours and the onset of depressive symptoms, with significant evidence of heterogeneity (I^2=45.1%, P=0.004). A moderate association between working hours and depressive symptoms was found in Asian countries (1.50, 95% CI 1.13–2.01), a weaker association in Europe (1.11, 95% CI 1.00–1.22), and no association in North America (0.97, 95% CI 0.70–1.34) or Australia (0.95, 95% CI 0.70–1.29). Differences by other characteristics were small. CONCLUSIONS: This observational evidence suggests a moderate association between long working hours and onset of depressive symptoms in Asia and a small association in Europe.

Abstract Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms.

Abstract Background Infection by common viruses has long been discussed in the aetiology of a number of autoimmune diseases, including rheumatoid arthritis (RA). However, studies investigating this hypothesis in RA show conflicting results. These studies often lack well-matched control populations, and many do not include data on autoantibodies, genetic risk factors and other environmental factors, which are known to contribute to disease only in subgroups of patients. In the present study, we have therefore examined the role of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and parvovirus B19 (B19) in RA aetiology, by analysing anti-viral antibodies in relation to anti-citrullinated protein antibodies (ACPA), smoking, HLA-DRB1 shared epitope (SE) alleles, and clinical parameters, in both RA patients and matched controls. Methods Anti-viral antibodies were measured by ELISA in serum samples from 990 RA patients and 700 controls from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort. Data on ACPA, smoking, SE, inflammation (C-reactive protein) and disease activity score in 28 joints (DAS28) was obtained from the EIRA database. Fisher’s exact test, the chi-squared test, and the Mann-Whitney U test were used to calculate differences in anti-viral antibody frequencies and levels; unconditional logistic regression was used to determine the association of anti-viral antibodies with different RA subsets. Results Antibodies against all viruses were highly prevalent in EIRA, with no major differences detected between ACPA-positive RA, ACPA-negative RA and controls. However, both anti-B19 and anti-EBV IgG levels were significantly lower in ACPA-positive RA compared to controls, and there were significant interactions between low levels of anti-B19 and anti-EBV antibodies and SE in the development of ACPA-positive RA. Conclusion We could not detect an association between RA and elevated anti-viral antibody levels, for any of the three common viruses, EBV, CMV or B19. On the contrary, our study demonstrated association between low anti-EBV/anti-B19 antibody levels and ACPA-positive RA, in particular when HLA-DRB1 SE was present. These data could potentially suggest that high anti-viral antibody levels would be protective against ACPA-positive RA. Further investigations are required to address the mechanisms behind these findings.

Multiple sclerosis: Sequence variants discovered by meta-analysis informed by genetic correlation Combining studies and comparing across diseases turned up 14 novel gene variants linked to multiple sclerosis (MS). A team led by Kári Stefánsson and Ingileif Jónsdóttir from deCODE genetics in Reykjavík, Iceland, amalgamated data from a large international study of MS with three smaller ones from Sweden, Norway and Iceland. They conducted a meta-analysis on the combined data set — which encompassed around 21,000 MS patients and 372,000 population controls — and uncovered seven new genetic risk variants linked to MS. The researchers then compared the genetic overlap between various autoimmune diseases in the Icelandic cohort, and documented a close relationship between MS and primary biliary cirrhosis (PBC). They looked more closely at variants linked to PBC, and found that seven also increased the risk for MS, bringing the tally of novel gene variants up to fourteen.

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3′ UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3′ UTR of ERAP1 A variant, but not the 3′ UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.

In this paper we develop a general framework for quantifying how binary risk factors jointly influence a binary outcome. Our key result is an additive expansion of odds ratios as a sum of marginal effects and interaction terms of varying order. These odds ratio expansions are used for estimating the excess odds ratio, attributable proportion and synergy index for a case-control dataset by means of maximum likelihood from a logistic regression model. The confidence intervals associated with these estimates of joint effects and interaction of risk factors rely on the delta method. Our methodology is illustrated with a large Nordic meta dataset for multiple sclerosis. It combines four studies, with a total of 6265 cases and 8401 controls. It has three risk factors (smoking and two genetic factors) and a number of other confounding variables.

Abstract Background Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA. Methods We investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA. Results We identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723. Conclusions We showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to the damage of myelin and axons. As a multi-factorial complex trait, both genetic background and environmental factors are involved in MS etiology. The disease is more prevalent among women, and an overall female-to-male sex ratio of around 3 is usually reported. The fact that the female preponderance is only apparent among patients with disease onset after age 12 points toward a role of puberty in MS. A key marker of female pubertal development is menarche, however, evidence from previous epidemiological investigations has been sparse and conflicting: although some studies have linked earlier age at menarche (AAM) to an increased risk of MS, others have found no association or an inverse association. Understanding the effect of AAM in MS could increase our knowledge to the disease etiology, as well as deliver meaningful implication to patients' care by aiding clinical diagnosis. Therefore, we reviewed all the currently available epidemiological studies conducted for AAM and risk of MS in adult human populations. We found evidence supporting a possible favorable role of late AAM on MS risk, but this should be further confirmed by well-designed large-scale epidemiological studies and meta-analysis. Future work may be focused on Mendelian randomization analysis incorporating genetic markers to provide additional evidence of a putative causal relationship between AAM and MS. More work should be conducted for non-European populations to increase generalizability, and among the males to complementary with results from females. Future work may also be conducted focusing on hormonal reproductive factors other than menarche, and their effects in MS prognosis, severity, and drug response.

Summary: Background: Obesity increases the risk of several chronic diseases, but the extent to which the obesity-related loss of disease-free years varies by lifestyle category and across socioeconomic groups is unclear. We estimated the number of years free from major non-communicable diseases in adults who are overweight and obese, compared with those who are normal weight. Methods: We pooled individual-level data on body-mass index (BMI) and non-communicable diseases from men and women with no initial evidence of these diseases in European cohort studies from the Individual-Participant-Data Meta-Analysis in Working Populations consortium. BMI was assessed at baseline (1991–2008) and non-communicable diseases (incident type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease) were ascertained via linkage to records from national health registries, repeated medical examinations, or self-report. Disease-free years from age 40 years to 75 years associated with underweight (BMI

Both high body mass index (BMI) and smoking tobacco are known risk factors for developing multiple sclerosis (MS). However, it is unclear whether BMI, like smoking, is a risk factor for the secondary progressive (SP) course. We, therefore, sought to determine if high/low BMI at age 20 is associated to risk of SP development, in the context of smoking status. Using data from MS patients with BMI and smoking information available, we examined relapsing onset patients with MS onset after 20 years of age. Cox regressions were conducted on smokers and non-smokers, with BMI as the main exposure. In total, 5,598 relapsing onset MS patients were included. The models demonstrated that BMI > 30 was associated to increased risk of SPMS in smokers (hazard ratio 1.50, p = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97, p = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.

Summary: Background: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. Methods: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0–24·9 kg/m2), overweight (25·0–29·9 kg/m2), class I (mild) obesity (30·0–34·9 kg/m2), and class II and III (severe) obesity (≥35·0 kg/m2). We used an inclusive definition of underweight (

OBJECTIVE: The aim of this study was to investigate whether shift work (with or without night work) is associated with increased risk of breast cancer. METHODS: The population consisted of 4036 women. Data were obtained from WOLF (Work, Lipids, and Fibrinogen), a longitudinal cohort study. Information about baseline characteristics was based on questionnaire responses and medical examination. Cancer incidence from baseline to follow-up was obtained from the national cancer registry. Two exposure groups were identified: shift work with and without night work. The group with day work only was used as the reference group in the analysis. Cox regression analysis was used to calculate relative risk. RESULTS: In total, 94 women developed breast cancer during follow-up. The average follow-up time was 12.4 years. The hazard ratio for breast cancer was 1.23 [95% confidence interval (95% CI) 0.70–2.17] for shifts without night work and 2.02 (95% CI 1.03–3.95) for shifts with night work. When including only women

INTRODUCTION:The possible hypothesis of a link between periodontitis and rheumatoid arthritis (RA), specifically anti-citrullinated protein antibody (ACPA) positive RA, prompted us to investigate the prevalence of periodontitis in the Swedish Epidemiological Investigation of RA (EIRA), a well-characterised population-based RA case-control cohort. METHODS:Periodontal status of 2,740 RA cases and 3,942 matched controls was retrieved through linking EIRA with the National Dental Health Registry (DHR), where dental diagnostic- and treatment codes on the adult Swedish population have been registered. Dental records from 100 cases and controls were reviewed to validate the periodontal diagnostic codes in DHR. RESULTS:The reviewed dental records confirmed 90% of the periodontitis diagnoses in DHR among RA cases, and 88% among controls. We found the positive predictive value of periodontitis diagnoses in the DHR to be 89% (95% CI 78 to 95%) with a sensitivity of 77% (95% CI: 65 to 86%). In total, 86% of EIRA participants were identified in DHR. The risk for periodontitis increased by age and current smoking status in both cases as well as controls. No significant differences in prevalence of periodontal disease in terms of gingivitis, periodontitis, peri-implantitis or increased risk for periodontitis or peri-implantitis were observed between RA cases and controls. In addition, there was no difference on the basis of seropositivity, ACPA or rheumatoid factor (RF), among patients with RA. CONCLUSIONS:Our data verify that smoking and ageing are risk factors for periodontitis, both in RA and controls. We found no evidence of an increased prevalence of periodontitis in patients with established RA compared to healthy controls, and no differences based on ACPA or RF status among RA subjects.

OBJECTIVE: The aim of this study was to evaluate mortality and acute myocardial infarction (AMI) incidence among commercial and military flying personnel in Sweden. METHODS: Flying personnel, employed at the Swedish part of Scandinavian Airlines and the Swedish Armed Forces at some point between 1957–1994, were included. The cohort was followed regarding mortality and AMI incidence using national registers of hospital discharges and deaths. The observed mortality and AMI incidence was compared with the expected rate in the general Swedish population through standardized mortality ratios (SMR) and standardized incidence ratios (SIR) taking age, gender, and calendar year into account. RESULTS: Swedish flying personnel, except male cabin crew, had a lower-than-expected all-cause mortality (SMR ranging from 0.57 among female cabin crew to 0.79 among navigators and mechanics; male cabin crew 0.89) and cardiovascular mortality (SMR from 0.31 among female cabin crew to 0.79 among navigators and mechanics). We observed an elevated mortality in aircraft accidents (SMR ranging from 23.87 among commercial pilots to 165.68 among military pilots). Male cabin attendants had a higher-than-expected mortality for alcohol-related death causes and acquired immunodeficiency syndrome (AIDS). AMI incidence was reduced in all groups and across the lifespan (SIR between 0.13 among female cabin crew and 0.61 among navigators and mechanics). CONCLUSIONS: Swedish flying personnel have a low all-cause mortality. This is mostly due to a reduced cardiovascular mortality reflecting a low AMI incidence during the working life as well as after retirement.