Publications by authors named "Richard J Reynolds"

39 Publications

Decreased Levels of STAT1 and Interferon-γ-Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells.

ACR Open Rheumatol 2021 Mar 28. Epub 2021 Mar 28.

The University of Alabama at Birmingham.

Objective: We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon-γ (IFN-γ) signaling in T cells from patients with RA compared with healthy controls (HC).

Methods: Using phosphoflow cytometry, we compared IFN-γ-stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4 and CD8 T-cell populations from patients with RA and HC.

Results: Compared with controls, patients with RA had a higher proportion of CD4 T cells, associated with expansion of the CD4 effector memory subset. Several CD4 T-cell types exhibited reduced IFN-γ-induced phosphoSTAT1 (pSTAT1 ) in patients with RA compared with HC. Engaging the T-cell receptor (TCR) complex on CD4 T cells during IFN-γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1 was similar in CD4 T cells from patients with RA and HC. In contrast to CD4 T cells, IFN-γ-induced pSTAT1 levels in CD8 T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4 and CD8 T cells from patients with RA compared with HC.

Conclusion: We report diminished IFN-γ-induced pSTAT1 levels in CD4 T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN-γ-induced pSTAT1 levels in CD4 T cells because activation in CD8 T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN-γ responsiveness.
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http://dx.doi.org/10.1002/acr2.11244DOI Listing
March 2021

The Shared Genetic Basis of Hyperuricemia, Gout, and Kidney Function.

Semin Nephrol 2020 Nov;40(6):586-599

Department of Biochemistry, University of Otago, Dunedin, New Zealand; Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL. Electronic address:

Increased urate levels and gout correlate with chronic kidney disease with consensus that the primary driver of this relationship is reduced kidney function. However, a comparison of results of genome-wide association studies in serum urate levels and kidney function indicate a more complex situation. Approximately 20% of loci are shared-comprised of those in which the urate-raising allele associates with reduced kidney function, the vice versa situation, and those in which the signals/alleles are different. Although there is very little known regarding the molecular basis of the shared genetic relationship, it is clear that there is no major role for urate transporters and associated transportasome machinery. Some loci, however, do provide clues. The ATXN2 locus, with a shared signal, is one of only a small number of master regulators of expression by chromatin interaction, regulating expression of genes relevant for cholesterol and blood pressure. This suggests a role for systemic metabolic alteration. At HNF4A there is genetic heterogeneity with different genetic variants conferring risk to hyperuricemia and chronic kidney disease, suggesting different pathways. Interestingly, the shared loci congregate in the olfactory receptor pathway. The genome-wide association studies have generated a range of experimentally testable hypotheses that should provide insights into the shared pathogenesis of hyperuricemia/gout and chronic kidney disease.
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http://dx.doi.org/10.1016/j.semnephrol.2020.12.002DOI Listing
November 2020

The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect.

Arthritis Res Ther 2021 03 4;23(1):75. Epub 2021 Mar 4.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Background: Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels.

Methods: Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome.

Results: Adherence to dietary recommendations, BMI (< 25 kg/m), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate.

Conclusions: Diet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.
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http://dx.doi.org/10.1186/s13075-021-02444-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931603PMC
March 2021

Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities.

Eur J Hum Genet 2021 Feb 26. Epub 2021 Feb 26.

Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.
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http://dx.doi.org/10.1038/s41431-021-00830-zDOI Listing
February 2021

Gout is associated with an increased risk for incident heart failure among older adults: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study.

Arthritis Res Ther 2020 04 16;22(1):86. Epub 2020 Apr 16.

Department of Epidemiology, University of Alabama at Birmingham, 1720 2nd Ave South, RPHB 527C, Birmingham, AL, 35294-0013, USA.

Background: Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some prior studies. Few studies have assessed the association of gout with incident heart failure (HF).

Methods: We analyzed data from 5713 black and white men and women ≥ 65.5 years of age in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study who had Medicare coverage without a history of HF, CHD, or stroke at baseline between 2003 and 2007. Gout was defined by ≥ 1 hospitalization or ≥ 2 outpatient visits with a diagnosis code for gout in Medicare claims prior to each participant's baseline study examination. REGARDS study participants were followed for HF hospitalization, CHD, stroke, and all-cause mortality as separate outcomes through December 31, 2016. Analyses were replicated in a random sample of 839,059 patients ≥ 65.5 years of age with Medicare coverage between January 1, 2008, and June 30, 2015, who were followed through December 31, 2017.

Results: Among REGARDS study participants included in the current analysis, the mean age at baseline was 72.6 years, 44.9% were men, 31.4% were black, and 3.3% had gout. Over a median follow-up of 10.0 years, incidence rates per 1000 person-years among participants with and without gout were 13.1 and 4.4 for HF hospitalization, 16.0 and 9.3 for CHD, 9.3 and 8.2 for stroke, and 55.0 and 37.1 for all-cause mortality, respectively. After multivariable adjustment for sociodemographic variables and cardiovascular risk factors, hazard ratios (95% CI) comparing participants with versus without gout were 1.97 (1.22, 3.19) for HF hospitalization, 1.21 (0.79, 1.84) for CHD, 0.83 (0.48, 1.43) for stroke, and 1.08 (0.86, 1.35) for all-cause mortality. The multivariable-adjusted hazard ratio for HF hospitalization with reduced and preserved left ventricular ejection fraction among participants with versus without gout was 1.77 (95% CI 0.83, 3.79) and 2.32 (95% CI 1.12, 4.79), respectively. The multivariable-adjusted hazard ratio for heart failure hospitalization associated with gout among the 839,059 Medicare beneficiaries was 1.32 (95% CI 1.25, 1.39).

Conclusion: Among older adults, gout was associated with an increased risk for incident HF but not for incident CHD, incident stroke, or all-cause mortality.
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http://dx.doi.org/10.1186/s13075-020-02175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164141PMC
April 2020

Variable and sexually conflicting selection on Silene stellata floral traits by a putative moth pollinator selective agent.

Evolution 2020 07 11;74(7):1321-1334. Epub 2020 Jun 11.

Department of Biology and Microbiology, South Dakota State University, Brookings, SD, 57007, USA.

Conflicting selection is an important evolutionary mechanism because it impedes directional evolution and helps to maintain phenotypic variation. It can arise when mutualistic and antagonistic selective agents exert opposing selection on the same trait and when distinct phenotypic optima are favored by different fitness components. In this study, we test for conflicting selection through different sexual functions of the hermaphroditic plant, Silene stellata during its early and late flowering season. We find selection is consistently stronger during the early flowering season, which aligns with the activity peak of the pollinating seed predator Hadena ectypa. Importantly, we observe sex-specific selection on petal dimensions to have opposite signs. We propose that the observed sexually conflicting selection on petal design results from the negative selection through female function for the avoidance of oviposition and the subsequent fruit predation by H. ectypa larvae and the positive selection through male function for pollen export by H. ectypa adults. The Silene-Hadena interaction has previously been considered to be largely parasitic. Our findings suggest a trade-off mechanism that could thwart the evolution of an "escape route" from the nocturnal pollination syndrome by Silene spp. and contribute to the long-term maintenance of the Silene-Hadena system.
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http://dx.doi.org/10.1111/evo.13965DOI Listing
July 2020

Comorbidities in gout and hyperuricemia: causality or epiphenomena?

Curr Opin Rheumatol 2020 03;32(2):126-133

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Purpose Of Review: To review advances in the understanding of potentially causal relationships between gout, hyperuricemia and comorbidities.

Recent Findings: Observational studies reveal 4-5 comorbidity clusters in gout patients. There tend to be gout alone, gout with chronic kidney disease and gout with other metabolic comorbidities. However, heterogeneous study populations and confounding make inference difficult for causal relationships. Mendelian randomization leverages genetic information as an instrumental variable to indicate putatively causal relationships between traits of epidemiological interest. Thus far, Mendelian randomization has not indicated widespread causal relationships of serum urate for comorbid traits. However, BMI has a small causal effect on serum urate, which may partially explain the increased prevalence of metabolic syndrome and cardiovascular disease among those with gout and hyperuricemia. There is a lack of robust and sufficiently powered Mendelian randomization studies for many serum urate-associated traits, such as hypertension. No adequately powered studies have been completed for gout and its comorbidities.

Summary: Although observational studies indicate putative causal effects of serum urate on comorbidities, Mendelian randomization studies suggest that serum urate does not have a causal role on the various tested comorbidities. There remains work to be done in clarifying the causal role of gout per se on the same traits.
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http://dx.doi.org/10.1097/BOR.0000000000000691DOI Listing
March 2020

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

Hypertension 2020 01 2;75(1):246-256. Epub 2019 Dec 2.

Division of Clinical Immunology and Rheumatology (S.L.B., K.G.S., E.J.R., J.R.C., A.G., R.J.R., J.A.S.), University of Alabama at Birmingham.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to <6.8 mg/dL versus <6.0 mg/dL (reference) with incident stroke. Analyses were stratified by race, gender, and age. Mediation of cardiovascular disease comorbidities on the serum urate-stroke association was tested. Hyperuricemia was associated with stroke (hazard ratio, 1.40 [95% CI, 1.10-1.78]) after adjustment for demographic variables and systolic and diastolic blood pressure. This association was substantially attenuated (hazard ratio, 1.17 [95% CI, 0.90-1.51]) by additional covariate adjustment. In particular, apparent treatment-resistant hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on 3 antihypertensive medications or use of ≥4 antihypertensive medications) and the count of antihypertensive medication classes significantly reduced the effect of hyperuricemia on ischemic stroke. Specifically, apparent treatment-resistant hypertension and number of antihypertensive, respectively, mediate 45% and 43% of the association. There was no effect modification in the association between hyperuricemia and stroke by age, race, or gender. We conclude that hyperuricemia may be a risk factor for stroke. The substantial attenuation of this association by apparent treatment-resistant hypertension and number of antihypertensive suggests that severe hypertension may be a mediator.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122733PMC
January 2020

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.

Hum Mol Genet 2019 03;28(5):858-874

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA < 5 × 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.
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http://dx.doi.org/10.1093/hmg/ddy395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381313PMC
March 2019

HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Arthritis in Black South Africans.

J Rheumatol 2019 02 1;46(2):138-144. Epub 2018 Nov 1.

From the Division of Rheumatology, and Division of Human Genetics, Faculty of Health Sciences, and the Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; University of Cape Town, Cape Town, South Africa.

Objective: To investigate the association of specific amino acid positions, residues, and haplotypes of HLA-DRB1 in black South Africans with autoantibody-positive rheumatoid arthritis (RA).

Methods: High-resolution genotyping was performed in 266 black South Africans with autoantibody-positive RA and 362 ethnically and geographically matched controls. The alleles were converted to specific amino acid residues at polymorphic sites for downstream analyses. Logistic regression models were used to test whether variability at site, specific amino acid residues, and haplotypes (constructed from positions 11, 71, and 74) were associated with RA.

Results: Of the 29 amino acid positions examined, positions 11, 13, and 33 (permutation p = 3.4, 1.2, and 2.1, respectively) showed the strongest association with RA. Univariate analyses of individual amino acid residues showed valine at position 11 (OR 5.1, 95% CI 3.7-7.0) and histidine at position 13 (OR 6.1, 95% CI 4.2-8.6) conferred the highest risk. The valine containing haplotypes of position 11, 71, 74, V_K_A conferred the most risk (OR 4.52, 95% CI 2.68-7.61) and conversely the haplotype with serine at this position, S_K_R, conferred the most protection (OR 0.83, 95% CI 0.61-1.15).

Conclusion: Autoantibody-positive RA in black South Africans is associated with histidine at position 13 and valine at position 11 of HLA-DRB1, and haplotypes with valine at position 11 conferred the highest risk; conversely, serine at position 11 conveyed protection.
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http://dx.doi.org/10.3899/jrheum.180107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820986PMC
February 2019

Untangling the complex relationships between incident gout risk, serum urate, and its comorbidities.

Arthritis Res Ther 2018 05 3;20(1):90. Epub 2018 May 3.

Department of Epidemiology and Biostatistics, Michigan State University, 220 Trowbridge Rd, East Lansing, MI 48824, USA.

Background: Many gout comorbidities (e.g., hypertension) are correlated with serum urate. In this investigation, we identified risk factors (e.g., systolic blood pressure [SBP]), that (1) are associated with incident gout, (2) have effects on gout risk that cannot be fully explained by correlated differences in serum urate, and (3) may modulate the relationship between gout and serum urate.

Methods: Using data from the Atherosclerosis Risk in Communities (ARIC) study, we estimated the unadjusted associations between gout and risk factors by calculating ORs and using chi-square tests. The adjusted associations were analyzed using logistic regression by sequentially adding (1) one risk factor at a time or (2) all risk factors, to a baseline model that includes serum urate only. Stepwise selection was used to select main effects. Two-way interactions of variables from the main effects model were also analyzed.

Results: Average gout incidence was 2.7 per 1000 people per year. Serum urate was highly associated with incident gout, with odd ratios of 3.16 [95% CI 2.11, 4.76] and 25.9 [95% CI 17.2, 38.4] for moderately high (6-8 mg/dl) and high serum urate (> 8 mg/dl), relative to normal serum urate (< 6 mg/dl), respectively. Ethnicity and SBP were independently and additively associated with gout after accounting for serum urate levels. No significant interactions were found between serum urate and ethnicity or SBP.

Conclusions: Ethnicity and hypertension are predictive of gout risk, and the associations cannot be fully explained by serum urate. For serum urate levels near the crystallization threshold (6-8 mg/dl) African Americans and people with hypertension are at two to three times greater risk for developing gout. The gout risk for this group appears to increase before the onset of severe hyperuricemia.
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http://dx.doi.org/10.1186/s13075-018-1558-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932762PMC
May 2018

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans.

Mol Med 2017 09 29;23:177-187. Epub 2017 Jun 29.

University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology.

Over 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody positive RA and 933 African American controls on the ImmunoChip (iChip) array. Using multivariable regression we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (OR = 1.97, p = 1.28 × 10) near was the most strongly associated risk SNP for RA susceptibility; SNPs in , , and loci were suggestively associated (10 < p < 3.1 × 10). Trans-ethnic fine mapping of identified a 90% credible set containing previously studied variants including rs9653442, rs7608424, and rs6712515 as well as the novel candidate variant rs11681966; several of these likely influence gene expression level. Variants in , , , , and - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in and beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of , , and .
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http://dx.doi.org/10.2119/molmed.2017.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583066PMC
September 2017

Association of anti-peptidyl arginine deiminase antibodies with radiographic severity of rheumatoid arthritis in African Americans.

Arthritis Res Ther 2016 10 22;18(1):241. Epub 2016 Oct 22.

University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower 850, Birmingham, AL, 35294-3408, USA.

Background: Evidence suggests that the presence of peptidyl arginine deiminase type 4 (PAD4) antibodies is associated with radiographic-severity rheumatoid arthritis (RA) among Caucasian patients. The presence of anti-PAD4 antibodies that were cross-reactivity against PAD3 was associated with more aggressive erosive disease (compared with the presence of anti-PAD4 antibodies without anti-PAD3 crossreactivity) in Caucasian RA patients. The objectives of this study were to determine the prevalence of serum anti-PAD4 and anti-PAD4/PAD3 cross-reactive autoantibodies in African Americans with RA and whether these antibodies associate with radiographic severity and radiographic progression.

Methods: Serum anti-PAD4 and anti-PAD4/PAD3 antibodies were measured by immunoprecipitation, and the temporal trends in titers were analyzed. We compared total radiographic scores among anti-PAD4-positive, anti-PAD4/PAD3-positive, and anti-PAD4-negative patients and used a zero-inflated negative binomial model to determine associations between radiographic severity and antibody status. Logistic regression was used to analyze radiographic progression.

Results: Of 192 African-American patients with RA, 73 % were anti-citrullinated peptide/protein antibody (ACPA)-positive, 46 out of 192 (24 %) of whom had serum anti-PAD4 antibodies. Median (interquartile range) total Sharp van der Heijde radiographic scores were 2 (1-97.5) in ACPA-positive patients and 0 (0-3) in ACPA-negative patients (P < 0.001). Of the 46 anti-PAD4-positive patients, 20 had anti-PAD4 antibodies that cross-reacted with PAD3. In patients with early RA, anti-PAD4 and anti-PAD4/PAD3 antibody titers increased over time (P = 0.006, P = 0.001, respectively). Median (interquartile range) total radiographic scores were higher for anti-PAD4-positive than for anti-PAD4-negative patients (3 (1-115) versus 2 (0-11), respectively; P = 0.005). Median (interquartile range) total radiographic score for anti-PAD4/PAD3-positive patients was 76 (3-117) (P < 0.001) versus anti-PAD4-negative patients. Only anti-PAD4/PAD3 antibodies associated with radiographic severity (incidence rate ratio = 2.81; 95 % confidence interval 1.23, 6.43).

Conclusion: This analysis suggests that autoantibodies against PAD4 and PAD3 proteins may serve as biomarkers for identifying African-American patients with RA and higher radiographic severity.
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http://dx.doi.org/10.1186/s13075-016-1126-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075170PMC
October 2016

Coronary Artery Calcification and Rheumatoid Arthritis: Lack of Relationship to Risk Alleles for Coronary Artery Disease in the General Population.

Arthritis Rheumatol 2017 03;69(3):529-541

Columbia University, New York, New York.

Objective: Coronary artery disease (CAD) in the general population is characterized by an increased frequency of particular susceptibility single-nucleotide polymorphisms (SNPs). Because the frequency of CAD is increased among patients with rheumatoid arthritis (RA), we sought to determine whether the frequency of these SNPs is increased in RA patients with CAD, hypothesizing that RA could enhance CAD risk by acting through established genetic pathways predisposing to CAD.

Methods: Coronary artery calcification (CAC) as detected by computed tomography was used as a measure of CAD in 561 patients with RA. One hundred SNPs associated with CAD in the general population were genotyped or imputed, and their relationship to CAC was established through multiple regression analysis for individual SNPs and a genetic risk score representing their cumulative effect.

Results: Ninety-one CAD-related SNPs were genotyped successfully; of these, 81 exhibited no association with CAC (Agatston units) or different CAC categorizations, either individually or collectively, in the genetic risk score. Only rs579459 (ABO) and rs17676451 (HAL) had a consistent positive association between genotype and CAC, with a significant increase in the frequency of the effect allele in both homozygous and heterozygous genotype distributions. Five were variably negatively associated. Furthermore, a positive association between the Disease Activity Score in 28 joints and CAC was observed, and after adjustment for traditional cardiovascular risk factors, it was not modified by correcting for the CAD-related SNP genetic risk score.

Conclusion: The increased risk of CAC in patients with RA does not appear to operate primarily through established genetically regulated atherogenic mechanisms that are preponderant in the general population.
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http://dx.doi.org/10.1002/art.39862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553209PMC
March 2017

Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis.

J Allergy Clin Immunol 2016 11 21;138(5):1495-1498. Epub 2016 Sep 21.

Department of Microbiology, the University of Alabama at Birmingham, Birmingham, Ala; Department of Medicine, the University of Alabama at Birmingham, Birmingham, Ala. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104182PMC
November 2016

Modelling heterogeneity among fitness functions using random regression.

Methods Ecol Evol 2016 Jan 11;7(1):70-79. Epub 2015 Aug 11.

Population and Conservation Biology Program, Department of Biology, Texas State University, San Marcos, Texas 78666, (512-245-2321).

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http://dx.doi.org/10.1111/2041-210X.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776641PMC
January 2016

Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index.

Rheumatol Int 2016 Feb 1;36(2):263-70. Epub 2015 Oct 1.

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Faculty Office Tower 805B, 510 20th Street S, Birmingham, AL, 35294, USA.

We hypothesized that serum urate-associated SNPs, individually or collectively, interact with BMI and renal disease to contribute to risk of incident gout. We measured the incidence of gout and associated comorbidities using the original and offspring cohorts of the Framingham Heart Study. We used direct and imputed genotypes for eight validated serum urate loci. We fit binomial regression models of gout incidence as a function of the covariates, age, type 2 diabetes, sex, and all main and interaction effects of the eight serum urate SNPs with BMI and renal disease. Models were also fit with a genetic risk score for serum urate levels which corresponds to the sum of risk alleles at the eight SNPs. Model covariates, age (P = 5.95E-06), sex (P = 2.46E-39), diabetes (P = 2.34E-07), BMI (P = 1.14E-11) and the SNPs, rs1967017 (P = 9.54E-03), rs13129697 (P = 4.34E-07), rs2199936 (P = 7.28E-03) and rs675209 (P = 4.84E-02) were all associated with incident gout. No BMI by SNP or BMI by serum urate genetic risk score interactions were statistically significant, but renal disease by rs1106766 was statistically significant (P = 6.12E-03). We demonstrated that minor alleles of rs1106766 (intergenic, INHBC) were negatively associated with the risk of incident gout in subjects without renal disease, but not for individuals with renal disease. These analyses demonstrate that a significant component of the risk of gout may involve complex interplay between genes and environment.
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http://dx.doi.org/10.1007/s00296-015-3364-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724568PMC
February 2016

Simple regression for correcting ΔCt bias in RT-qPCR low-density array data normalization.

BMC Genomics 2015 Feb 14;16:82. Epub 2015 Feb 14.

Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.

Background: Reverse transcription quantitative PCR (RT-qPCR) is considered the gold standard for quantifying relative gene expression. Normalization of RT-qPCR data is commonly achieved by subtracting the Ct values of the internal reference genes from the Ct values of the target genes to obtain ΔCt. ΔCt values are then used to derive ΔΔCt when compared to a control group or to conduct further statistical analysis.

Results: We examined two rheumatoid arthritis RT-qPCR low density array datasets and found that this normalization method introduces substantial bias due to differences in PCR amplification efficiency among genes. This bias results in undesirable correlations between target genes and reference genes, which affect the estimation of fold changes and the tests for differentially expressed genes. Similar biases were also found in multiple public mRNA and miRNA RT-qPCR array datasets we analysed. We propose to regress the Ct values of the target genes onto those of the reference genes to obtain regression coefficients, which are then used to adjust the reference gene Ct values before calculating ΔCt.

Conclusions: The per-gene regression method effectively removes the ΔCt bias. This method can be applied to both low density RT-qPCR arrays and individual RT-qPCR assays.
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http://dx.doi.org/10.1186/s12864-015-1274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335788PMC
February 2015

Quantifying hummingbird preference for floral trait combinations: The role of selection on trait interactions in the evolution of pollination syndromes.

Evolution 2015 05 27;69(5):1113-27. Epub 2015 Apr 27.

Department of Biology, University of Maryland, College Park, College Park, Maryland, 20742.

Darwin recognized the flower's importance for the study of adaptation and emphasized that the flower's functionality reflects the coordinated action of multiple traits. Here we use a multitrait manipulative approach to quantify the potential role of selection acting on floral trait combinations underlying the divergence and maintenance of three related North American species of Silene (Caryophyllaceae). We artificially generated 48 plant phenotypes corresponding to all combinations of key attractive traits differing among the three Silene species (color, height, inflorescence architecture, flower orientation, and corolla-tube width). We quantified main and interaction effects of trait manipulation on hummingbird visitation preference using experimental arrays. The main effects of floral display height and floral orientation strongly influenced hummingbird visitation, with hummingbirds preferring flowers held high above the ground and vertically to the sky. Hummingbirds also prefer traits in a nonadditive manner as multiple two-way and higher order interaction effects were important predictors of hummingbird visitation. Contemporary trait combinations found in hummingbird pollinated S. virginica are mostly preferred. Our study demonstrates the likelihood of pollination syndromes evolving due to selection on trait combinations and highlights the importance of trait interactions in understanding the evolution of complex adaptations.
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http://dx.doi.org/10.1111/evo.12639DOI Listing
May 2015

Expression of Interferon-γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans.

Arthritis Rheumatol 2015 May;67(5):1165-70

University of Alabama at Birmingham and Second Xiangya Hospital of Central South University, Changsha, China.

Objective: The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA.

Methods: In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (≤2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration.

Results: We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)] = 6 × 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) = 0.03 for erosions, P(adj) = 0.04 for joint space narrowing, and P(adj) = 0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) = 0.0024 by Spearman's correlation analysis).

Conclusion: These findings have important implications with respect to the role of interferon-γ (IFNγ) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNγ receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.
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http://dx.doi.org/10.1002/art.39056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414815PMC
May 2015

HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues.

Arthritis Rheumatol 2014 Dec;66(12):3274-82

University of Alabama at, Birmingham.

Objective: To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries.

Methods: Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues.

Results: TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 × 10(-12)) and Mattey (P = 6.5 × 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 ≤ permutation P ≤ 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans.

Conclusion: With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans.
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http://dx.doi.org/10.1002/art.38855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273668PMC
December 2014

Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.

Mol Med 2014 Aug 14;20:341-9. Epub 2014 Aug 14.

Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
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http://dx.doi.org/10.2119/molmed.2014.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153842PMC
August 2014

Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis.

Arthritis Rheumatol 2014 May;66(5):1090-100

Omaha VA Medical Center and University of Nebraska Medical Center, Omaha.

Objective: To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA.

Methods: Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single-nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression.

Results: Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA)-positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection.

Conclusion: Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.
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http://dx.doi.org/10.1002/art.38348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115329PMC
May 2014

Comparison of the disease activity score using erythrocyte sedimentation rate and C-reactive protein in African Americans with rheumatoid arthritis.

J Rheumatol 2013 Nov 15;40(11):1812-22. Epub 2013 Aug 15.

From the University of Alabama at Birmingham, Birmingham, Alabama; Emory University, Atlanta, Georgia; The University of North Carolina, Chapel Hill, North Carolina; The Medical University of South Carolina, Charleston, South Carolina; Washington University at St. Louis, St. Louis, Missouri; The University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objective: The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in patients with RA. However, such comparison is lacking in African Americans with RA.

Methods: This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry, which enrolls self-declared African Americans with RA. Using tender and swollen joint counts, separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient's assessment of disease activity. The scores were compared using paired t-test, simple agreement and κ, correlation coefficient, and Bland-Altman plots.

Results: Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs 3.9; p < 0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs 3.9; p < 0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.

Conclusion: There was significant discordance between the ESR-based and CRP-based DAS28, a situation that could affect clinical treatment decisions for African Americans with RA.
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http://dx.doi.org/10.3899/jrheum.121225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987124PMC
November 2013

Clinical response within 12 weeks as a predictor of future low disease activity in patients with early RA: results from the TEAR Trial.

J Rheumatol 2013 May 15;40(5):572-8. Epub 2013 Apr 15.

From the University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: Rapidly predicting future outcomes based on short-term clinical response would be helpful to optimize rheumatoid arthritis (RA) management in early disease. Our aim was to derive and validate a clinical prediction rule to predict low disease activity (LDA) at 1 year among patients participating in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial escalating RA therapy by adding either etanercept or sulfasalazine + hydroxychloroquine [triple therapy (TT)] after 6 months of methotrexate (MTX) therapy.

Methods: Eligible subjects included in the derivation cohort (used for model building, n = 186) were participants with moderate or higher disease activity [Disease Activity Score 28-erythrocyte sedimentation rate (DAS-ESR) > 3.2] despite 24 weeks of MTX monotherapy who added either etanercept or sulfasalazine + hydroxychloroquine. Clinical characteristics measured within the next 12 weeks were used to predict LDA 1 year later using multivariable logistic regression. Validation was performed in the cohort of TEAR patients randomized to initially receive either MTX + etanercept or TT.

Results: The derivation cohort yielded 3 prediction models of varying complexity that included age, DAS28 at various timepoints, body mass index, and ESR (area under the receiver-operator characteristic curve up to 0.83). Accuracy of the prediction models ranged between 80% and 95% in both derivation and validation cohorts, depending on the complexity of the model and the cutpoints chosen for response and nonresponse. About 80% of patients could be predicted to be responders or nonresponders at Week 12.

Conclusion: Clinical data collected early after starting or escalating disease-modifying antirheumatic drug/biologic treatment could accurately predict LDA at 1 year in patients with early RA. For patients predicted to be nonresponders, treatment could be changed at 12 weeks to optimize outcomes.
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http://dx.doi.org/10.3899/jrheum.120715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694569PMC
May 2013

Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12.

Am J Hum Genet 2012 Mar 23;90(3):524-32. Epub 2012 Feb 23.

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.
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http://dx.doi.org/10.1016/j.ajhg.2012.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309197PMC
March 2012

Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis.

Rheumatol Int 2013 Jan 12;33(1):129-37. Epub 2012 Jan 12.

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, SHEL 178, Birmingham, AL 35294-2182, USA.

Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease.
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http://dx.doi.org/10.1007/s00296-011-2355-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769702PMC
January 2013

Association of single-nucleotide polymorphisms in CCR6, TAGAP, and TNFAIP3 with rheumatoid arthritis in African Americans.

Arthritis Rheum 2012 May;64(5):1355-8

Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-2182, USA.

Objective: We previously reported an analysis of single-nucleotide polymorphisms (SNPs) in 3 validated European rheumatoid arthritis (RA) susceptibility loci, TAGAP, TNFAIP3, and CCR6, in African American patients with RA. Unexpectedly, the disease-associated alleles were different in African Americans from those in Europeans. In an effort to better define their contribution, we performed additional SNP genotyping in these genes.

Methods: Seven SNPs were genotyped in 446 African American patients with RA and in 733 African American control subjects. Differences in minor allele frequency between the RA cases and controls were analyzed after controlling for the global proportion of European admixture, and pairwise linkage disequilibrium (LD) was estimated among the SNPs.

Results: Three SNPs were significantly associated with RA: the TNFAIP3 rs719149 A allele (OR 1.22 [95% confidence interval (95% CI) 1.03-1.44], P = 0.02), the TAGAP rs1738074 G allele (OR 0.75 [95% CI 0.63-0.89, P = 0.0012), and the TAGAP rs4709267 G allele (OR 0.74 [95% CI 0.60-0.91], P = 0.004). Pairwise LD between the TAGAP SNPs was low (r(2) = 0.034). The haplotype containing minor alleles for both TAGAP SNPs was uncommon (4.5%). After conditional analysis of each TAGAP SNP, its counterpart remained significantly associated with RA (rs1738074 for rs4709267 P = 0.00001 and rs4709267 for rs1738074 P = 0.00005), suggesting independent effects.

Conclusion: SNPs in regulatory regions of TAGAP and an intronic SNP (TNFAIP3) are potential susceptibility loci in African Americans. Pairwise LD, haplotype analysis, and SNP conditioning analysis suggest that these 2 SNPs in TAGAP are independent susceptibility alleles. Additional fine-mapping of this gene and functional genomic studies of these SNPs should provide further insight into the role of these genes in RA.
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http://dx.doi.org/10.1002/art.33464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299842PMC
May 2012