A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.

BackgroundRheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies (GWAS) have only been published from ACPA-positive subsets of RA or from studies that have not separated the two subsets. The aim of the current study is to provide and compare GWAS data for both subsets.Methods and resultsGWAS using the Illumina 300K chip was performed for 774 ACPA-negative patients with RA, 1147 ACPA-positive patients with RA and 1079 controls from the Swedish population-based case-control study EIRA. Imputation was performed which allowed comparisons using 1,723,056 single nucleotide polymorphisms (SNPs). No SNP achieved genome-wide significance (2.9 × 10⁻⁸) in the comparison between ACPA-negative RA and controls. A case-case association study was then performed between ACPA-negative and ACPA-positive RA groups. The major difference in this analysis was in the HLA region where 768 HLA SNPs passed the threshold for genome-wide significance whereas additional contrasting SNPs did not reach genome-wide significance. However, one SNP close to the RPS12P4 locus in chromosome 2 reached a p value of 2 × 10⁶ and this locus can thus be considered as a tentative candidate locus for ACPA-negative RA.ConclusionsACPA-positive and ACPA-negative RA display significant risk allele frequency differences which are mainly confined to the HLA region. The data provide further support for distinct genetic aetiologies of RA subsets and emphasise the need to consider them separately in genetic as well as functional studies of this disease

Analysis of Neuropeptide S Receptor Gene (NPSR1) Polymorphism in Rheumatoid Arthritis

Polymorphism in the neuropeptide S receptor gene NPSR1 is associated with asthma and inflammatory bowel disease. NPSR1 is expressed in the brain, where it modulates anxiety and responses to stress, but also in other tissues and cell types including lymphocytes, the lungs, and the intestine, where it appears to be up-regulated in inflammation. We sought to determine whether genetic variability at the NPSR1 locus influences the susceptibility and clinical manifestation of rheumatoid arthritis (RA).From the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) case-control study, 1,888 rheumatoid arthritis patients and 888 controls were genotyped for 19 single-nucleotide polymorphisms (SNPs) spanning the entire NPSR1 gene and 220 KB of DNA on chromosome 7p14. The association between individual genetic markers and their haplotypic combinations, respectively, and diagnosis of RA, presence of autoantibodies to citrullinated proteins (ACPA), and disease activity score based on 28 joints (DAS28) was tested. There was no association between diagnosis of RA and NPSR1 variants. However, several associations of nominal significance were detected concerning susceptibility to ACPA-negative RA and disease activity measures (DAS28). Among these, the association of SNP rs324987 with ACPA-negative RA [(p=0.004, OR=0.674 (95% CI 0.512-0.888)] and that of SNP rs10263447 with DAS28 [p=0.0002, OR=0.380 (95% CI 0.227-0.635)] remained significant after correction for multiple comparisons.NPSR1 polymorphism may be relevant to RA susceptibility and its clinical manifestation. Specific alleles at the NPSR1 locus may represent common risk factors for chronic inflammatory diseases, including RA

Genetic variation in the transforming growth factor-β1 gene is associated with susceptibility to IgA nephropathy

Background. There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis

The balance of expression of PTPN22 splice forms is significantly different in rheumatoid arthritis patients compared with controls

Complex disease is characterized by the interplay of multiple genetic and environmental factors. Rheumatoid arthritis (RA) is a complex autoimmune disease with a pronounced genetic component, mainly due to HLA-DRB1 gene, but also a multitude of loci outside the HLA region. In this work we strive to contribute to the understanding of the functional involvement of these susceptibility loci in the pathogenesis of RA. This study is based on a large material of whole blood samples and peripheral blood mononuclear cells (PBMCs) from RA patients and matched healthy controls from Sweden. The main methods used in this work included probe-based genotyping and gene-expression assays, cell cultures, RNA-sequencing, gene-gene interaction and pathway analysis, as well as a plethora of common molecular genetics and bioinformatics methods. We investigated the role of expression of known genetic risk factors PTPN22 and PTPN2 in RA, with a special attention to the splicing profile of these genes. Our data indicates significant differences in the expression ratio of splice variants for PTPN22 in whole blood samples from RA patients and healthy controls. For PTPN2 we demonstrate a significant difference in the relative mRNA expression of' transcript TC48 in PBMCs of healthy controls and RA patients. Additionally, we identified new susceptibility SNPs in the PTPN2 locus: rs657555 and rs11080606, by addressing the interaction of PTPN2 variants with HLA-DRB1 shared-epitope (SE) alleles in autoantibody positive RA patients in two independent cohorts. In this work, we also address the functional genetic role of the members of the MAP signaling pathway upstream of p38 and JNK – crucial enzymes in RA – with a regard to splicing profile and their connection to HLA-DRB1. We found a significant statistical interaction for rs10468473 from MAP2K4 locus with SE alleles in autoantibody-positive RA. Importantly, individuals heterozygous for rs10468473 demonstrated higher expression of total MAP2K4 mRNA in blood, compared to A-allele homozygous. We also describe a novel, putatively translated RNA splice form of MAP2K4, that is differentially expressed in peripheral blood mononuclear cells from 88 RA cases and controls, and is modulated in response to TNF in Jurkat cell line. Finally, we performed an expression analysis of multiple validated RA risk loci, and pathway analysis to assess functional relationship between RA susceptibility genes and predict new potential study candidates. New candidate molecules suggested by the pathway analysis, genes ERBB2 and HSPB1, as well as HLA-DRB1, were differentially expressed between RA patients and healthy individuals in RNA-seq data. ERBB2 expression profile was similar in whole blood of both treated and untreated patients compared to healthy individuals. A similar expression profile was replicated for ERBB2 in PBMCs in an independent material. In this work, we approached the task of elucidating the functional aspects of genetic susceptibility of RA, by integrating genetic epidemiology, transcriptomics, proteomics, cellmodels, and bioinformatics. We maintain, that such integrative approach provides the rationale to prioritize genes and genetic events for further functional studies. Our findings also outline the need to consider potential clinical significance of alternative splicing in gene expression studies

R|S Atlas: Identifying Existing Cohort Study Data Resources to Accelerate Epidemiological Research on the Influence of Religion and Spirituality on Human Health

OBJECTIVE: Many studies have documented significant associations between religion and spirituality (R/S) and health, but relatively few prospective analyses exist that can support causal inferences. To date, there has been no systematic analysis of R/S survey items collected in US cohort studies. We conducted a systematic content analysis of all surveys ever fielded in 20 diverse US cohort studies funded by the National Institutes of Health (NIH) to identify all R/S-related items collected from each cohort\u27s baseline survey through 2014. DESIGN: An R|S Ontology was developed from our systematic content analysis to categorise all R/S survey items identified into key conceptual categories. A systematic literature review was completed for each R/S item to identify any cohort publications involving these items through 2018. RESULTS: Our content analysis identified 319 R/S survey items, reflecting 213 unique R/S constructs and 50 R|S Ontology categories. 193 of the 319 extant R/S survey items had been analysed in at least one published paper. Using these data, we created the R|S Atlas (https://atlas.mgh.harvard.edu/), a publicly available, online relational database that allows investigators to identify R/S survey items that have been collected by US cohorts, and to further refine searches by other key data available in cohorts that may be necessary for a given study (eg, race/ethnicity, availability of DNA or geocoded data). CONCLUSIONS: R|S Atlas not only allows researchers to identify available sources of R/S data in cohort studies but will also assist in identifying novel research questions that have yet to be explored within the context of US cohort studies

Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis

Introduction: Genetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04. Methods: We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen. Results: Our data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P = 0.0001, P corrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P = 0.0004, P corrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02). Conclusion: These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA