Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?

Scott, Ian C.; Rijsdijk, Frühling; Walker, Jemma; Quist, Jelmar; Spain, Sarah L.; Tan, Rachael; Steer, Sophia; Okada, Yukinori; Raychaudhuri, Soumya; Cope, Andrew P.; Lewis, Cathryn M.

doi:10.3899/jrheum.141211

Cited by 19 publications

(16 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In GENRA the association appeared independent of ACPA, which was included as a modelling covariate. More recently we, along with other research groups, have demonstrated a significant association between the presence of Valine at position 11 (external to the SE) in HLA-DRβ1 and radiological damage in European ancestry RA patients [17, 30]. Testing this position in GENRA also revealed a significant association with erosions (OR = 2.15, 95% CI: 1.02, 4.53; P = 0.047), although we could not confirm this was independent of the SE owing to our limited sample size.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case–control study

et al. 2017

Self Cite

View full text Add to dashboard Cite

Objectives. To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals. Methods. A case–control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture. Results. European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 −7). HLA haplotype ORs in European and African ancestry individuals were highly correlated (r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 −4). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 −4) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 −5) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 −3). Conclusion. Gene–environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.

show abstract

Section: Discussionmentioning

confidence: 97%

“…Both cohorts have been described previously [16, 17]. CARDERA comprises 524 patients with early, active RA enrolled in two clinical trials.…”

Section: Methodsmentioning

confidence: 99%

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case–control study

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…It has been described in detail previously (13). In brief, it comprises European ancestry RA patients enrolled to two multicenter randomized controlled trials (RCTs): CARDERA-1 and CARDERA-2 (14,15).…”

Section: Methodsmentioning

confidence: 99%

“…CARDERA patients were genotyped on the Illumina ImmunoChip array (described in detail previously (13)). Single nucleotide polymorphism (SNP) markers were removed that had more than 5% missingness, were duplicates, were not in Hardy-Weinberg equilibrium (HWE, p < .00001), and had a minor allele frequency (MAF) of less than 0.01.…”

Section: Methodsmentioning

confidence: 99%

The Relationship Between Mental Health, Disease Severity, and Genetic Risk for Depression in Early Rheumatoid Arthritis

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among the known loci associated with RA, the signal transducer and activator of transcription 4 ( STAT4 ) could be one of most interesting candidate genes to study in relation to drug response [17]. A recent meta-analysis demonstrated that SNPs in STAT4 confer susceptibility to RA in total subjects and in major ethnic groups.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis

et al. 2017

View full text Add to dashboard Cite

ObjectiveRheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients.MethodsIn 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)].ResultsSTAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients.ConclusionsFor the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population.

show abstract

Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?

Abstract: HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.

Cited by 19 publications

References 46 publications

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case–control study

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case–control study

The Relationship Between Mental Health, Disease Severity, and Genetic Risk for Depression in Early Rheumatoid Arthritis

Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis

Contact Info

Product

Resources

About