Lars Alfredsson

Karolinska Institutet | KI · Institute of Environmental Medicine - IMM

Objective: Smoking and Swedish smokeless tobacco (snus) are associated with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Our aim was to investigate whether genetic susceptibility to T2D, insulin resistance (IR), and insulin secretion (IS) aggravate these associations. Research design and methods: We used data from two p...

Multiple sclerosis is a complex autoimmune disease that causes neuronal demyelination and debilitating physical and cognitive symptoms. Epigenetic factors can mediate genetic and environmental effects on disease risk. Here we profiled blood-based DNA methylation in 583 MS cases and 643 healthy controls representing 3 independent study groups. An ep...

Background: The associaton between socioeconomic status (SES) and the risk of multiple sclerosis (MS) is unclear. We aimed at studying whether a potential association between indicators of SES and MS risk in Sweden is explained by lifestyle/environmental factors. Method: Using the Swedish MS-registry and the Swedish patient registries, we perfor...

Background Shift work, which often results in sleep deprivation and circadian desynchrony, has been associated with increased risk of multiple sclerosis (MS). We aimed at studying the impact of sleep duration, circadian disruption and sleep quality on MS risk. Methods We used a Swedish population-based case-control study (2075 cases, 3164 controls...

We investigate a 2,000-year genetic transect through Scandinavia spanning the Iron Age to the present, based on 48 new and 249 published ancient genomes and genotypes from 16,638 modern individuals. We find regional variation in the timing and magnitude of gene flow from three sources: the eastern Baltic, the British-Irish Isles, and southern Europ...

Background Spasticity is common among people with multiple sclerosis (MS), but there are few studies of spasticity treatment patterns. We aim to describe associations with spasticity treatment measured primarily by oral baclofen use. Methods This cohort study using Swedish registers included 1826 and 3519 people with incident and prevalent MS (pwI...

Objectives To assess the effects of occupational inhalable exposures on rheumatoid arthritis (RA) development and their interactions with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA). Methods Data came from the Swedish Epidemiological Investigation of RA, consisting of 4033 incident RA cases and...

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 s...

Objectives: To assess the association between venous thromboembolic (VTE) events and autoantibodies, following patients from rheumatoid arthritis (RA) diagnosis, measuring occurrence, levels and collective load of different autoantibodies against post-translational protein-modifications, in particular recognizing citrullination (e.g. citrullinated...

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.¹ It is assumed that this high mortality affect...

Objective: Inconclusive findings have been reported regarding the influence of smoking on outcomes in established rheumatoid arthritis (RA). We aimed to study the influence of smoking habits on disease activity and health-related quality of life in patients with RA. Methods: Patients with newly diagnosed RA (N=1531) from the population-based cas...

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...

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 w...

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control da...

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. Me...

Background Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease, including venous thromboembolic events (VTE) ¹ . The reason behind the increased VTE risk is incompletely understood, but inherent features of RA, such as RA specific autoantibodies, could potentially play a role. For example, studies have linked o...

Background Despite being the anchor drug for treating rheumatoid arthritis (RA), methotrexate (MTX) provides a good response only in some of the treated patients [1]. If MTX treatment outcome has a substantial genetic component, genetic variants could provide useful predictors for identification of patients likely to respond and remain on treatment...

Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through eff...

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 g...

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. O...

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 Epidemiologica...

Objective To determine the association of allergic conditions with incident rheumatoid arthritis (RA), especially in relation to smoking history and anti-citrullinated peptide antibody (ACPA) status. Methods This case–control study included 3515 incident RA cases and 5429 matched controls from the Epidemiological Investigation of Rheumatoid Arthri...

Objective Most studies of rheumatoid arthritis (RA) and sleep have focused on established RA. We here investigate sleep quality and sleep duration in patients with newly diagnosed RA and during 1–12 years after diagnosis. Methods Data were collected on sleep 1–12 years after diagnosis from patients diagnosed 1998–2018 in the Swedish study Epidemio...

Trans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-anal...

Background Elevated 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 occu...

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, 28...

Introduction Several cross-sectional studies indicate that occupations such as physicians, nurses, dentists, physiotherapists, bus- and taxi drivers, bartenders, waiters, chefs and shop assistants either have higher risks of dying or be tested positive due to COVID-19. Objectives The aim of this study was to analyse if employees in occupations cha...

Background The latitude gradient in multiple sclerosis incidence indicates that low sun exposure and therefore vitamin D deficiency is associated with multiple sclerosis risk. Objective Investigation of the effect of month of birth, which influences postnatal vitamin D levels, on multiple sclerosis risk and severity in Sweden. Methods Patients an...

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...

Background Suicide is a leading cause of death worldwide, and non-fatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genom...

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consor...

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...

Background Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus infection in MS etiology is unclear. We aimed to investigate potential synergistic effe...

Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. Design Multicohort study with three sets of analyses. Setting United Kingdom, Europe, and the United States. Participants Three associations were examined: cognitive stimulation and dem...

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 consump...

Panic disorder (PD) has a lifetime prevalence of 2–4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically we...

Objectives Production of anti-citrullinated peptide/protein antibodies (ACPA) is characteristic for rheumatoid arthritis (RA) and may inform about biological pathways involved in disease development in specific subgroups. Since multiple loci in genome wide association screens have been implicated in RA risk, we investigated the association between...

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 (<20) instrumental variables. Methods: We systemically interrogated a putative causal relationship between alcohol consumption and four common autoimmune...

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied. Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 cont...

Background 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), anti-acetylated (KAc), and anti-malondialdehyde acetaldehyde...

Background UV-B radiation has known immunomodulatory properties, but to what extent UV-B radiation exposure might affect the occurrence of rheumatoid arthritis (RA) has been relatively little studied, and with partially contradictory results. Objectives To investigate the association between sun- and travel habits, as proxy markers for UV-B radiat...

Background The role of psychosocial conditions on the disease course of rheumatoid arthritis (RA) is getting increased attention. In our previous study, low social support and low decision latitude at work were associated with known modifiable risk factors for RA disease development, such as smoking and low educational level (1). Further, smoking a...

Background Dengue infection is associated with joints pain mimicking disease onset symptom of rheumatoid arthritis (RA). However, there is lack of epidemiological studies on exposure to dengue infection and risk of future RA. Objectives We investigated the relationship between exposure to dengue infection and risk of developing different subsets o...

Background Presence of autoantibodies such as anti-cyclic citrullinated peptide (anti-CCP2) and rheumatoid factor (RF) is of considerable diagnostic and prognostic value in patients with rheumatoid arthritis (RA). Limited data are available for autoantibody profile changes over time in patients with RA. Objectives Thus, we compared the presence of...

Background The mechanisms affecting anti-RA33 antibody’s involvement in RA pathogenesis is still unclear. Refining our understanding of anti-RA33’s role in RA in relation to known RA-associated genes and serological elements is needed. Objectives We investigated the relationship between RA-associated HLA-DRB1 epitope (SE) allele and presence of an...

Background Only few studies have looked at the association between tea consumption and risk of rheumatoid arthritis (RA) with inconclusive results. Objectives To estimate the association between tea consumption and risk of RA in a large population-based case-control study. Methods We used data from the Swedish Epidemiological Investigation of RA...

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the...

Objective It has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with...

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 prot...

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), an...

Zhao et al. conducted a two‐sample Mendelian randomization (MR) to investigate a causal relationship between body fat composition and rheumatoid arthritis (RA). Five anthropometric traits, including body mass index (BMI), body fat percentage, whole‐body fat mass, whole‐body fat‐free mass and appendicular lean mass, were included as exposures. The s...

Objectives: To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset. Methods: Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based...

Objective We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01 . Methods Using population-based...

PurposeRed meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes.Methods Analyses were based on Swedish case–con...

Aims We investigated the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes in relation to a healthy lifestyle, the proportion of patients attributable to an unhealthy lifestyle, and the influence of family history of diabetes (FHD) and genetic susceptibility. Methods The population-based study included incident LADA (n=571),...

Objective: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality of life (HRQoL), and clinical and demographic risk factors for WNP. Method: Incident cases with RA, from the Swedish population-based study Epidemiologic...

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...

Objectives: To investigate whether low social support or low decision latitude at work correlate with risk of rheumatoid arthritis (RA), and whether and how those factors are associated with known modifiable risk factors for RA. Method: The Swedish population-based EIRA study included, from 1996 to 2015, 3724 incident RA cases and 5935 controls, ma...

Background There are few (if any) practical guidelines for predictive and falsifiable multi-omics 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....

Objective Because obesity affects the cellular immune response to infections, we aimed to investigate whether high body mass index (BMI) in young adulthood and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels interact with regard to MS risk. We also aimed at exploring potential 3-way interactions between BMI at age 20 years, aspects of...

Background The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborat...

Suicide is a leading cause of death worldwide and non-fatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both are known to have a substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. We conducted a genome-wide...