48 research outputs found
A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis
Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case–control study
The aim of the present study was to investigate the association between exposure to mineral oil and the risk of developing rheumatoid arthritis (RA), and in addition to perform a separate analysis on the major subphenotypes for the disease; namely, rheumatoid factor (RF)-positive RA, RF-negative RA, anticitrulline-positive RA and anticitrulline-negative RA, respectively. A population-based case–control study of incident cases of RA was performed among the population aged 18–70 years in a defined area of Sweden during May 1996–December 2003. A case was defined as an individual from the study base who for the first time received a diagnosis of RA according to the American College of Rheumatology criteria of 1987. Controls were randomly selected from the study base with consideration taken for age, gender and residential area. Cases (n = 1,419) and controls (n = 1,674) answered an extensive questionnaire regarding lifestyle factors and occupational exposures, including different types of mineral oils. Sera from cases and controls were investigated for RF and anticitrulline antibodies. Among men, exposure to any mineral oil was associated with a 30% increased relative risk of developing RA (relative risk = 1.3, 95% confidence interval = 1.0–1.7). When cases were subdivided into RF-positive RA and RF-negative RA, an increased risk was only observed for RF-positive RA (relative risk = 1.4, 95% confidence interval 1.0–2.0). When RA cases were subdivided according to the presence of anticitrulline antibodies, an increased risk associated with exposure to any mineral oil was observed only for anticitrulline-positive RA (relative risk = 1.6, 95% confidence interval = 1.1–2.2). Analysis of the interaction between oil exposure and the presence of HLA-DR shared epitope genes regarding the incidence of RA indicated that the increased risk associated with exposure to mineral oil was not related to the presence of shared epitope genotypes. In conclusion, our study shows that exposure to mineral oil is associated with an increased risk to develop RF-positive RA and anticitrulline-positive RA, respectively. The findings are of particular interest since the same mineral oils can induce polyarthritis in rats
Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile
OBJECTIVES:
To increase understanding of the aetiology and pathogenesis of rheumatoid arthritis (RA), genetic and environmental risk factors for RA subsets, defined by the presence or absence of different anticitrullinated protein/peptide antibodies (ACPAs) targeting citrullinated peptides from α-enolase, vimentin, fibrinogen and collagen type II, were investigated.
METHODS:
1985 patients with RA and 2252 matched controls from the EIRA case-control cohort were used in the study. Serum samples were assayed by ELISA for the presence of anticyclic citrullinated peptides (anti-CCP) antibodies and four different ACPA fine specificities. Cross-reactivity between ACPAs was examined by peptide absorption experiments. Genotyping was performed for HLA-DRB1 shared epitope (SE) alleles and the PTPN22 gene, while information regarding smoking was obtained by questionnaire. The association of genetic and environmental risk factors with different subsets of RA was calculated by logistic regression analysis.
RESULTS:
Limited cross-reactivity was observed between different ACPA fine specificities. In total, 17 RA subsets could be identified based on their different ACPA fine specificity profiles. Large differences in association with genetic and environmental determinants were observed between subsets. The strongest association of HLA-DRB1 SE, PTPN22 and smoking was identified for the RA subset which was defined by the presence of antibodies to citrullinated α-enolase and vimentin.
CONCLUSION:
This study provides the most comprehensive picture to date of how HLA-DRB1 SE, PTPN22 and smoking are associated with the presence of specific ACPA reactivities rather than anti-CCP levels. The new data will form a basis for molecular studies aimed at understanding disease development in serologically distinct subsets of RA.The Swedish Research CouncilVinnovaKing Gustaf V's 80-year foundationGums&Joints (FP7-Health-2010-261460)MasterSwitch (FP6-Health-2007-2.4.5-12)The Swedish Rheumatic FoundationThe Swedish Council for Working Life and Social ResearchThe IMI program BTCure (115142-2)Publishe
The Genetic Interacting Landscape of 63 Candidate Genes in Major Depressive Disorder: An Explorative Study
Background:
Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear.
This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results:
Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (\u3c 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (\u3c 0.15). Conclusions:
We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied
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The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA
Objective: To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. Methods: We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. Results: GWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10−11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10−8, and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10−7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. Conclusions: Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels
GEIRA: gene-environment and gene–gene interaction research application
The GEIRA (Gene-Environment and Gene–Gene Interaction Research Application) algorithm and subsequent program is dedicated to genome-wide gene-environment and gene–gene interaction analysis. It implements concepts of both additive and multiplicative interaction as well as calculations based on dominant, recessive and co-dominant genetic models, respectively. Estimates of interactions are incorporated in a single table to make the output easily read. The algorithm is coded in both SAS and R. GEIRA is freely available to non-commercial users at http://www.epinet.se. Additional information, including user’s manual and example datasets is available online at http://www.epinet.se
Parity influences the severity of ACPA-negative early rheumatoid arthritis: a cohort study based on the Swedish EIRA material
Role of genes and environment for the development of rheumatoid arthritis : Results from the Swedish EIRA study
Rheumatoid arthritis (RA) is a complex disease with autoimmune features
primarily causing destruction in the joints of the body. Knowledge
regarding risk indicators and causes are increasing but so far only a few
genetic and very few environmental risk factors have been consistently
identified.
The overall aim of this thesis is to investigate interaction between
genetic and environmental factors for different phenotypes of RA.
Specific aims are to investigate:
1. gene-environment interaction between HLA-DRB1 SE alleles and smoking.
2. Gene-gene interaction between HLA-DRB1 SE and R620W PTPN22 alleles.
3. Interaction between alcohol consumption, smoking and HLA-DRB1 SE
alleles.
4. Dose dependency between smoking and risk of developing RA with
consideration taken to interaction between smoking and HLA-DRB1 SE
alleles.
In all the above aims different phenotypes for RA as defined by presence
or absence of antibodies to citrullinated protein antigens (ACPA+, ACPA-
RA respectively) is considered.
This thesis is primarily based on data from a Swedish study named
Epidemiological Investigation of Rheumatoid Arthritis (EIRA). EIRA is a
population based case-control study which consists of information from
incident cases and controls matched on age, sex and living area. Cases
and controls were given the opportunity to fill in an extensive
questionnaire and to provide a blood sample for genetic and serological
analysis. In paper II additional studies from USA (the NARAC study) and
the Netherlands (Leiden EAC) was used to investigate potential gene-gene
interaction between HLA-DRB1 SE and R620W PTPN22 alleles. In paper III
information from the Danish case-control study of rheumatoid arthritis
(the CACORA study) in addition to EIRA, was used to investigate
interaction between alcohol consumption, smoking and HLA-DRB1 SE alleles.
Smoking and alcohol consumption patterns and dosage were estimated
through self-reported information in questionnaires. Interaction was
primarily defined in terms of deviance from additivity of effects.
A strong interaction between smoking and HLA-DRB1 SE alleles was observed
regarding risk of developing ACPA+ RA. The most pronounced interaction
was observed for the combination of smoking and homozygosity for HLA-DRB1
SE alleles. Smoking was also associated, in a dose dependent manner with
increased risks of developing ACPA+ RA with consideration taken to
HLA-DRB1 SE alleles.
Interaction between HLA-DRB1 SE and R620W PTPN22 alleles regarding risk
of developing ACPA+ RA was observed in three different studies (EIRA,
NARAC and Leiden EAC). No associations between HLA-DRB1 SE or R620W
PTPN22, and only a minor association for smoking regarding risk of ACPA-
RA were observed.
Alcohol consumption was inversely associated with risk of developing RA
in a dose dependent manner in both EIRA and CACORA. Lack of alcohol
consumption was also associated with interaction with smoking and
HLA-DRB1 SE alleles regarding risk of developing ACPA+ RA
Perceived knowledge gained from school-based sexuality education : results from a national population-based survey among young people in Sweden
Background School-based sexuality education is a core component of securing young people’s right to attain health equity regarding sexual and reproductive health and rights. This paper aims to explore how perceived knowledge (sufficient or insufficient) of taking care of one’s sexual health is associated with knowledge gained from school-based sexuality education and social determinants. Methods The data material is drawn from a population-based survey conducted in Sweden in 2015. The survey had 7755 respondents and a response rate of 26%. To explore the aim descriptive statistics and logistic regression models were used. Results Our results show that perceived insufficient knowledge from school-based sexuality education was associated with higher odds of reporting not being able to take care of one’s sexual health. The highest significant excess risk for insufficient knowledge was found among young people from sexual minorities. Conclusions Young people in Sweden do not have equal abilities to receive knowledge needed to take care of their sexual health and thus attain sexual health literacy. There is an unequal distribution of perceived knowledge, and LGBTQI+ youth particularly face barriers in using school-based sexuality education as a resource for sexual health literacy.CC BY 4.0</p
The effect of shoulder and knee exercise programmes on the risk of shoulder and knee injuries in adolescent elite handball players : A three-armed cluster randomised controlled trial
BACKGROUND: The risk of injury in adolescent handball is high, and shoulder and knee injuries are among the most frequent and burdensome. The Swedish Knee Control programme reduced the risk of anterior cruciate ligament injuries in female youth football players and traumatic knee injuries in male and female youth floorball players. However, to date, Knee Control has not been evaluated in an elite youth sport setting. The literature on the prevention of shoulder injuries in sport is scarce, and there are to our knowledge no previous studies evaluating the preventative efficacy of injury prevention exercise programmes (IPEPs) on shoulder injuries in adolescent handball players. OBJECTIVES: To study the preventive efficacy of IPEPs on shoulder and knee injuries in adolescent elite handball players. METHODS: Eighteen Swedish handball-profiled secondary schools (clusters) with players aged 15-19 years, 54% males were randomised into either the Shoulder Group or Knee Group (interventions) or a Control Group. Players in the Shoulder Group were instructed to perform the Shoulder Control programme, and players in the Knee Group to perform the Knee Control programme, three times per week during May 2018 to May 2019. Control Group players continued their usual training. Outcomes were shoulder and knee injuries defined by the Oslo Sports Trauma Research Center Overuse Injury Questionnaire. Intention-to-treat analyses were performed using Cox regression models with hazard rate ratios (HRRs) with corresponding 95% confidence intervals (CI). RESULTS: Six clusters (199 players) in the Shoulder Group, six clusters (216 players) in the Knee Group and six clusters (212 players) in the Control Group were included. There were 100 shoulder injuries and 156 knee injuries. The Shoulder Group had a 56% lower shoulder injury rate, HRR 0.44 (95% CI 0.29 to 0.68), and the Knee Group had a 31% lower knee injury rate, HRR 0.69 (95% CI 0.49 to 0.97) than the Control Group. The absolute risk reduction was 11% and 8%, and the number needed to treat was 9 and 13, respectively. CONCLUSIONS: Adolescent elite handball players who performed the Shoulder Control and the Knee Control programmes had a lower risk of shoulder and knee injuries, respectively, than players who continued their usual training. Further research on how these two programmes can be combined to reduce knee and shoulder injuries in a time effective way is warranted. Trial registration ISRCTN15946352. Key points The burden of knee and shoulder injuries in handball is high. The Shoulder Control programme reduces the risk and overall burden of shoulder injuries in adolescent elite handball players. The Knee Control programme reduces the risk and overall burden of knee injuries in adolescent elite handball players