High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.

1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. [2] National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK. [3].
Nature Genetics (Impact Factor: 29.65). 11/2012; DOI: 10.1038/ng.2462
Source: PubMed

ABSTRACT Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

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    ABSTRACT: Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA) is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This paper is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphisms (SNPs) approaches to express the significance of their results. Although, haplotype blocks methods are expected to play a complementary role in the future of that field.
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    ABSTRACT: Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation characterized by painful inflammation of synovial joints. Despite advances in its management afforded by biologic drug development, efforts to improve outcomes for patients are confounded by the condition's heterogeneous pathobiology, and consequent variability in therapeutic responses. Great strides have been made in understanding the genetic epidemiology of rheumatoid arthritis since its association with the HLA locus was established in the 1980s, with over 100 additional disease-associated variants now confirmed through cumulative genome-wide association studies. Yet translation of this new knowledge for patient benefit – whether as a route to predicting disease risk, drug development or personalized medicine – has been slow. To address this, collaborating teams of interdisciplinary scientists will need to pool resources, including ever larger, well-characterized patient cohorts and sophisticated biostatistical approaches. Recent advances suggest that the fruits of these endeavors are beginning to come within reach.
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    ABSTRACT: IntroductionInterleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. We previously demonstrated reduced levels of circulating IL-7 in rheumatoid arthritis (RA), although high amounts are expressed in joints, suggesting differences between systemic and synovial effects. We observed healthy levels of IL-7 in 48% of RA patients in clinical remission (CR) and aimed to investigate the consequences of IL-7 deficiency on T-cell responses.Methods We used RA patients with active disease and in CR presenting various levels of IL-7, to investigate its modulatory effects on T-cells by analysing responses to phyto-haemagglutinin (PHA), expression of polarization or survival factors, or suppression by regulatory T-cells (Tregs).ResultsIL-7 levels were normal (>10 pg/ml) in 48% of RA patients in CR. Amongst 63 CR patients followed-up for 18 months, lack of IL-7 recovery was observed in 13/15 (86%) patients experiencing relapse but only 11/48 (23%) of those who did not (P¿=¿0.0002). Binary regressions showed high significance for below normal IL-7 levels for self-reported maternal family history of arthritis (odds ratio (OR): 7.66, P¿=¿0.006) and a trend for smoking (OR: 3.33, P¿=¿0.068) with no further demographic or clinical associations. Serum IL-7 correlated with restored CD4+T-cell response to PHA (rho¿=¿0.879); this was not related to an increase in T-cell proliferation capacity or expression of survival factors B-cell lymphoma 2 (BCL2) and BCL2-associated protein X (BAX). Expression of Th1 polarization factor (TBET) was also dependent on exposure to IL-7 in vivo (rho¿=¿0.600). In contrast CD25highTregs¿ response to PHA was not affected by in vivo IL-7, but their suppression capabilities were related to circulating IL-7 (rho¿=¿0.589). Co-stimulation with IL-7 (mimicking the joint environment) increased responsiveness of CD4+T-cells to PHA, lowering the ability of CD25highTregs to suppress them.Conclusion Our data demonstrate that IL-7 has a critical role in modulating T-cell function in vivo, possibly explaining opposing effects observed systemically and in the joint. Lack of IL-7 recovery in CR by maintaining a suppressed immune system may be a determinant factor in the occurrence of relapse.
    Arthritis Research & Therapy 12/2014; 16(6):511. DOI:10.1186/s13075-014-0511-3 · 4.12 Impact Factor

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