Immunogenetic Risks of Anti-Cyclical Citrullinated Peptide Antibodies in a North American Native Population with Rheumatoid Arthritis and Their First-degree Relatives

El-Gabalawy, Hani; Robinson, David; Hart, Donna; Elias, Brenda; Markland, Janet; Peschken, Christine A.; Smolik, Irene; Montes-Aldana, Gabriela; Schroeder, Marlis L.; Fritzler, Marvin J.; Cheang, Mary; Oen, Kiem

doi:10.3899/jrheum.080855

Cited by 73 publications

(80 citation statements)

References 23 publications

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“…4 Moreover, as is the case with a number of the NAN populations that have been studied, we have shown that the Cree/Ojibway population in Central Canada has a high prevalence of SE alleles, specifically *0404 and *1402. 8 Because of the high prevalence of SE in the population, we looked for SNP associations in non-HLA regions that may further predispose NAN individuals to RA, or alternatively, protect them from the risk associated with SE. In the current study, we show that several non-HLA SNP were marginally associated with RA risk in the NAN population, but that SNPs in the TRAF1-C5 and MMEL1-TNFRSF14 regions interacted significantly with SE, albeit in opposite directions with the former increasing risk and the latter being protective in the presence of the HLA-DRB1 risk.…”

Section: Discussionmentioning

confidence: 99%

“…8 The following DRB1 alleles were included as SE-bearing alleles: DRB1*0101, 0102, 0401, 0404, 0405, 0408, 0410, 1001 and 1402. Other SE-bearing alleles were not found in this population.…”

Section: Study Subjectsmentioning

confidence: 99%

“…In NAN populations, SE-bearing alleles are primarily HLA-DRB1*1402 and *0404. [6][7][8][9][10] High background population frequencies of the SE may, in part, explain the higher prevalence rates of RA in NAN populations, compared with other populations. For example, frequencies of the SE vary from 28 to 38% in United States and United Kingdom Caucasians, but frequencies as high as 60 to 95% have been reported in several NAN populations, where they have been studied.…”

Section: Introductionmentioning

confidence: 99%

“…For example, frequencies of the SE vary from 28 to 38% in United States and United Kingdom Caucasians, but frequencies as high as 60 to 95% have been reported in several NAN populations, where they have been studied. 8,11 In European populations, the contribution of HLA to genetic risk of RA has been estimated at 37%. 12 The availability of the human genome sequence, high throughput single-nucleotide polymorphisms (SNP) technologies and large cohorts of RA patients has allowed the identification of associations with 20-30 new non-HLA gene regions, using both candidate gene and genome wide association scans (GWAS).…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17][18][19][20] Our own studies of the Cree/Ojibway population in Central Canada have suggested a 2-3% prevalence rate of diagnosed RA, and a 60-70% frequency of SE alleles in the background population. 7,8,21 We sought to determine additional non-HLA genes that may contribute to the high frequency of RA detected in this population. We, therefore, genotyped NAN RA patients and controls for a spectrum of SNPs that were shown to be disease associated, using candidate gene and GWAS approaches in other populations.…”

Section: Introductionmentioning

confidence: 99%

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Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

et al. 2011

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Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n ¼ 333) and controls (n ¼ 490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio ¼ 2.2, 95% confidence interval 1.6-3.1, Po0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

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Section: Discussionmentioning

confidence: 99%

“…8 The following DRB1 alleles were included as SE-bearing alleles: DRB1*0101, 0102, 0401, 0404, 0405, 0408, 0410, 1001 and 1402. Other SE-bearing alleles were not found in this population.…”

Section: Study Subjectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

et al. 2011

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The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age‐dependent manner

Deane¹,

O’Donnell²,

Hueber³

et al. 2010

Arthritis & Rheumatism

227

195

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Objective. To evaluate levels of biomarkers in preclinical rheumatoid arthritis (RA) and to use elevated biomarkers to develop a model for the prediction of time to future diagnosis of seropositive RA.Methods. Stored samples obtained from 73 military cases with seropositive RA prior to RA diagnosis and from controls (mean 2.9 samples per case; samples collected a mean of 6.6 years prior to diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines and chemokines (by bead-based assay), and C-reactive protein (CRP).Results. Preclinical positivity for anti-CCP and/or >2 RF isotypes was >96% specific for future RA. In preclinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor ␣, interferon-␥-inducible 10-kd protein, granulocyte-macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA patients who were >40 years old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior to diagnosis than did patients who were <40 years old at diagnosis (P < 0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines were predictive of decreased time to diagnosis, and the predicted time to diagnosis based on cytokines/chemokines was longer in older compared with younger cases.Conclusion. Levels of autoantibodies, cytokines/ chemokines, and CRP are elevated in the preclinical period of RA development. In preclinical autoantibodypositive cases, the number of elevated cytokines/ chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.Multiple studies have demonstrated that levels of disease-related biomarkers may be elevated prior to the onset of symptomatic rheumatoid arthritis (RA). These biomarkers include rheumatoid factor (RF) and antibodies to citrullinated protein antigens, as well as secre-

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Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

El-Gabalawy¹,

Robinson²,

Smolik³

et al. 2012

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of firstdegree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies.Methods. North American Native patients with RA (n ‫؍‬ 105), their first-degree relatives (n ‫؍‬ 273), healthy North American Native controls (n ‫؍‬ 200), and Caucasian controls (n ‫؍‬ 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile.Results. The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of >40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies.Conclusion. Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.

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Immunogenetic Risks of Anti-Cyclical Citrullinated Peptide Antibodies in a North American Native Population with Rheumatoid Arthritis and Their First-degree Relatives

Cited by 73 publications

References 23 publications

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age‐dependent manner

Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

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