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Genetic studies in rheumatoid arthritis: familial studies and analysis of relationships to atherothrombotic comorbidity
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Rheumatoid arthritis (RA) is an autoimmune disease mainly affecting the joints but has also extra articular manifestations and an increased cardiovascular (CV) co-morbidity. Rheumatoid factor (RF) and antibodies against citrullinated proteins/peptides (ACPA) are diagnostically important and are related to a more severe disease. The aetiology is unknown but RA is considered a complex disease caused by both genetic and environmental factors. The heritability is estimated to be 60% with the main contribution from the HLA region. The relative homogeneity of the population in northern Sweden due to low immigration and founder effects has shown to be suitable for genetic studies.

Objectives. The aim of this thesis has been to identify genes contributing to the susceptibility of RA and the CV co-morbidity in particular. To achieve this, multi-case families from the four northern most counties of Sweden were collected for linkage studies to identify susceptibility genes. Association studies with genetic polymorphisms in genes, involved in inflammation or being of importance for atherothrombotic manifestations (ATM) in the general population, were performed in RA-patients concerning ATM e.g. myocardial infarction, angina pectoris with intervention, stroke/TIA, deep vein thrombosis/pulmonary embolism (DVT/PE) at follow-up.

Methods & Results. 47 families with 134 affected and 216 unaffected relatives were included in a genome-wide linkage study (GWL) performed with microsatellite markers at an average of 10cM resolution analysed using ABI PRISM 3730 DNA sequencer and non-parametric multipoint linkage in the Merlin program. Eight linked loci were identified with HLA as the most significant and a novel region on chromosome 14. In a follow-up analysis on a custom Illumina chip, with 13 additional families, yielding a total of 198 affected and 197 unaffected relatives. The majority of the 1536 single nucleotide polymorphisms (SNPs) used in the Illumina follow-up analyses was focused on chromosome 14. Statistical analyses with linkage and transmission disequilibrium test narrowed the region to 4 cM, a region containing multiple plausible RA candidate genes (Paper I). In Paper II  serum samples from 163 affected and 157 first degree relatives were analysed with EliA ACPA assay on ImmunoCAP250 for ACPA (IgA, IgG, IgM) and RF (IgA, IgM) isotypes. Both concentrations and frequencies were increased among the relatives compared with controls but lower compared with RA-patients and with a different relative distribution of the isotypes.

The genetic contribution to ATM was studied in Paper III and IV using selected SNPs analysed using ABI PRISM 7900HT sequence detector system. In Paper III, RA-patients (n=467) were compared with age and sex matched controls (n=696) with respect to SNPs in tumor necrosis factor receptor II (TNFRII)(M196R), ß-fibrinogen -455 (G-455A), plasminogen activator inhibitor type-1 (PAI-1) (4G/5G) and Factor XIIIA (Val34Leu). Hypertension was predicted by TNFRII R allele and to a higher extent in combination with the A-allele in ß-fibrinogen. The 4G allele in PAI-1 was more frequent in patients with ischemic heart disease (IHD) and the FXIIIA Leu34 variant in patients with DVT/PE. In Paper IV, the minor allele of the polymorphism in growth differentiation factor 15 (GDF15) was found to be associated with RA (n=696) per se but also to ATM, a SNP in the 9p21.3 locus was also associated with ATM. A significant association to stroke was found in female patients homozygote for the minor allele of GDF15. Stoke among male patients was significantly associated with carrying the major allele of two SNPs in the CD40 gene. DVT/PE was associated with the minor allele of GDF15.

Conclusion. A novel locus on chromosome 14 of importance for RA susceptibility in northern Sweden was found. The minor allele of TNFRII separately and together with the minor allele of ß-fibrinogen -455 was associated with hypertension and the 4G allele in PAI-1 was associated with IHD and  the Leu34 variant was associated with DVT/PE in RA patients. The GDF15 minor allele was associated with RA per se, ATM and DVT/PE in RA patients and a genotype in the SNP on 9p21.3 was associated with ATM. Stroke among females was associated with GDF15 and stroke among males with two SNPs in CD40.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2012. , 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1484
Keyword [en]
Rheumatoid arthritis, genetics, familial studies, ACPA and cardiovascular co-morbidity
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology; Genetics; Medicine, cardiovascular disease
Identifiers
URN: urn:nbn:se:umu:diva-52956ISBN: 978-91-7459-383-9 (print)OAI: oai:DiVA.org:umu-52956DiVA: diva2:508252
Public defence
2012-03-30, Norrlands universitetssjukhus, Tandläkarhögskolan, byggnad 1D, 9 trappor, Sal D, Umeå Universitet, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-03-09 Created: 2012-03-07 Last updated: 2012-03-12Bibliographically approved
List of papers
1. Novel risk locus on chromosome 14 in multi-case families with rheumatoid arthritis from northern Sweden
Open this publication in new window or tab >>Novel risk locus on chromosome 14 in multi-case families with rheumatoid arthritis from northern Sweden
(English)Manuscript (preprint) (Other academic)
Keyword
Rheumatoid arthritis, genetics, familial studies and linkage
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology; Genetics
Identifiers
urn:nbn:se:umu:diva-52924 (URN)
Available from: 2012-03-07 Created: 2012-03-06 Last updated: 2012-03-08Bibliographically approved
2. Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden
Open this publication in new window or tab >>Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden
Show others...
2012 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, 825-829 p.Article in journal (Refereed) Published
Abstract [en]

Background Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.

Objective To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.

Methods 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

Results The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

Conclusions All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

Place, publisher, year, edition, pages
BMJ Publishing Group, 2012
Keyword
Rheumatoid arthritis, familial studies, ACPA and RF
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-52926 (URN)10.1136/annrheumdis-2011-200668 (DOI)
Note

Published Online First 29 November 2011

Available from: 2012-03-07 Created: 2012-03-06 Last updated: 2017-12-07Bibliographically approved
3. Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis
Open this publication in new window or tab >>Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis
2007 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 25, no 6, 866-871 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To analyze candidate genes, related to cardiovascular disease (CVD) in general, and potentially involved in the inflammatory process, in RA patients from northern Sweden.

METHODS: Four hundred and sixty-seven individuals (345 females; 122 males) with RA (ACR criteria), having a mean age of 61.8 +/- 13.0 years and mean disease duration of 16.2 +/- 12.1 years, were consecutively recruited and followed-up for 3 years. The prevalence of CVD, [(ischemic heart disease (IHD), deep vein thromboses/pulmonary embolism (DVT/PE) and/or stroke/TIA] and hypertension was registered. Candidate genes encoding for Beta-fibrinogen (G-455A), Factor XIIIA (Val34Leu), plasminogen activator inhibitor type-1 (PAI-1 4G/5G), and tumor necrosis factor receptor (TNFR)II (M196R) were analysed. Controls (n = 672) were randomly selected according to age and gender from the Medical Biobank of Northern Sweden. Polymorphisms were genotyped using a TaqMan 9700HT and the 5'nuclease allelic discrimination assay.

RESULTS: The genotypes, carriers and alleles did not differ in distribution between patients and controls. Carriage of the TNFRII R variant was more frequent among patients with hypertension (p = 0.018). The genotype distribution of PAI-1 in patients with IHD differed significantly (p = 0.002) because carriage of 4G was more frequent (p = 0.024). Combined carriage of TNFRII 196R variant and Beta-fibrinogen-455A was a stronger predictor for hypertension than each genotype separately. The distribution of FXIIIA genotypes deviated significantly in RA patients with DVT/PE (p = 0.028) with an increased frequency of the Leu34 variant.

CONCLUSION: The unusual alleles of TNFRII, PAI-1 and FXIIIA were associated with CVD in RA patients. The combination of several of the rare types further increased the predictive values for CVD.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-7228 (URN)18173921 (PubMedID)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2017-12-14Bibliographically approved
4. Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular disease
Open this publication in new window or tab >>Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular disease
(English)Manuscript (preprint) (Other academic)
Keyword
Rheumatoid arthritis, genetics and cardiovascular comorbidity
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology; Genetics
Identifiers
urn:nbn:se:umu:diva-52928 (URN)
Funder
Swedish Research Council, K2010-52X-20307-04-3
Note
Accepted for Journal of Rheumatology, ISSN 0315-162X, EISSN 1499-2752.Available from: 2012-03-07 Created: 2012-03-06 Last updated: 2012-03-08Bibliographically approved

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