Dataset Information

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

ABSTRACT: OBJECTIVE:Genetic polymorphisms within the HLA region explain only a modest proportion of anti-cyclic citrullinated peptide (anti-CCP)-negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP-negative RA with non-HLA genetic polymorphisms demonstrated in a previous study. METHODS:The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP-negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case-control replication study of the anti-CCP-negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP-negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel. RESULTS:After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P?=?2.8 × 10(-13) ) and BLK (OR 1.13; P?=?7.0 × 10(-6) ) and identified new and specific markers of anti-CCP-negative RA (prolactin [PRL] [OR 1.13; P?=?2.1 × 10(-6) ] and NFIA [OR 0.85; P?=?2.5 × 10(-6) ]). Neither of these loci is associated with other common, complex autoimmune diseases. CONCLUSION:Anti-CCP-negative RA and anti-CCP-positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti-CCP-negative RA.

SUBMITTER: Viatte S

PROVIDER: S-EPMC4924598 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

Viatte Sebastien S Massey Jonathan J Bowes John J Duffus Kate K Eyre Stephen S Barton Anne A Worthington Jane J

Arthritis & rheumatology (Hoboken, N.J.) 20160701 7

<h4>Objective</h4>Genetic polymorphisms within the HLA region explain only a modest proportion of anti-cyclic citrullinated peptide (anti-CCP)-negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP-negative RA with non-HLA genetic polymorphisms demonstrated in a previous study.<h4>Methods</h4>The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-rel ...[more]

PMID: 26895230

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Project description:ObjectiveTo evaluate the incidence of cardiovascular disease (CVD) morbidity and mortality over the course of 10 years among the more than 160,000 postmenopausal women in the Women's Health Initiative (WHI) in relation to self-reported rheumatoid arthritis (RA), taking disease-modifying antirheumatic drugs (DMARDs), anti-cyclic citrullinated peptide (anti-CCP) positivity, rheumatoid factor (RF) positivity, CVD risk factors, joint pain, and inflammation (white blood cell count and interleukin-6 levels).MethodsAnti-CCP and RF were measured in a sample of WHI participants with self-reported RA (n = 9,988). RA was classified as self-reported RA plus anti-CCP positivity and/or taking DMARDs. Anti-CCP-negative women with self-reported RA and not taking DMARDs were classified as having "unverified RA."ResultsAge-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD, and total mortality were higher in women with RA than in women with no reported RA, with multivariable-adjusted hazard ratios of 1.46 (95% confidence interval [95% CI] 1.17-1.83) for CHD and 2.55 (95% CI 1.86-3.51) for fatal CVD. Among women with RA, anti-CCP positivity and RF positivity were not significantly associated with higher risk of any outcomes, despite slightly higher risk of death for those who were anti-CCP positive than for those who were anti-CCP negative. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even in women with no reported RA. CVD incidence was increased in women with RA versus women with no reported RA at almost all risk factor levels, except for low levels of joint pain or inflammation. Among women with RA, inflammation was more strongly associated with fatal CVD and total mortality than with CHD or CVD.ConclusionAmong postmenopausal women, RA was associated with 1.5-2.5-fold higher CVD risk. CVD risk was strongly associated with CVD risk factors, joint pain severity, and inflammation, but not with anti-CCP positivity or RF positivity.

Dataset Information

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

Publications

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

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