Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis.
ABSTRACT The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti-citrullinated protein antibody (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA-DRB1 shared epitope (SE) alleles in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles.
One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA-DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences.
The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44-75%). For ACPA-positive RA, the heritability was 68% (95% CI 55-79%), and for ACPA-negative RA it was 66% (95% CI 21-82%). Presence of the HLA SE alleles explained 18% (95% CI 16-19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6-10%) of the genetic variance of ACPA-negative RA.
The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified.
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ABSTRACT: Bone marrow transplantation (BMT) is used to treat hematological disorders, autoimmune diseases (ADs) and lymphoid cancers. Intra bone marrow-BMT (IBM-BMT) has been proven to be a powerful strategy for allogeneic BMT due to the rapid hematopoietic recovery and the complete restoration of T cell functions. IBM-BMT not only replaces hematopoietic stem cells (HSCs) but also mesenchymal stromal cells (MSCs). MSCs are multi-potent stem cells that can be isolated from bone marrow (BM), umbilical cord blood (UCB), and adipose tissue. MSCs play an important role in the support of hematopoiesis, and modify and influence the innate and adaptive immune systems. MSCs also differentiate into mesodermal, endodermal and ectodermal lineage cells to repair tissues. This review aims to summarize the functions of BM-derived-MSCs, and the treatment of intractable diseases such as rheumatoid arthritis (RA) and malignant tumors with IBM-BMT.Frontiers in Cell and Developmental Biology 09/2014; 2:48. DOI:10.3389/fcell.2014.00048
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease sustained by genetic factors. Various aspects of the genetic contribution to the pathogenetics and outcome of RA are still unknown. Several genes have been indicated so far in the pathogenesis of RA. Apart from human leukocyte antigen, large genome wide association studies have identified many loci involved in RA pathogenesis. These genes include protein tyrosine phosphatase, nonreceptor type 22, Peptidyl Arginine Deiminase type IV, signal transducer and activator of transcription 4, cytotoxic T-lymphocyte-associated protein 4, tumor necrosis factor-receptor associated factor 1/complement component 5, tumor necrosis factor and others. It is important to determine whether a combination of RA risk alleles are able to identify patients who will develop certain clinical outcomes, such myocardium infarction, severe infection or lymphoma, as well as to identify patients who will respond to biological medication therapy.09/2014; 5(4):544-9. DOI:10.5312/wjo.v5.i4.544
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ABSTRACT: IntroductionApproximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they only explain a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) X protein tyrosine phosphatase non-receptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including replication in a second sample collection. One of them has identified interactions between PTPN22 and seven single nucleotide polymorphisms (SNPs). The other showed interaction between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide positive (anti-CCP+) patients. The current study aimed to replicate association with RA susceptibility of interactions described in these two studies of high quality.MethodsA total of 1744 patients with RA and 1650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single base extension; SE genotypes of 736 patients were available from previous studies. Interaction analysis was done with multiple methods that included the originally reported and the most powerful described.ResultsGenotypes of one of the SNPs (rs4695888) failed quality control. Call rate for the other eight polymorphisms was 99.9%. Their frequencies were similar in RA patients and controls, except for PTPN22. None of the interactions between PTPN22 and the six SNPs was replicated as a significant interaction term, the originally reported finding, or with any of the other methods. Neither was replicated the interaction between GSTM1 and SE as a departure from additivity in anti-CCP+ patients or with any of the other methods.Conclusions None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that we still do not know whether interactions are a significant contribution to RA susceptibility or not, and that we need to apply strict standards for claiming interaction.Annals of the Rheumatic Diseases 09/2014; 16(5):436. DOI:10.1186/s13075-014-0436-x · 9.27 Impact Factor