Association of Rheumatoid Arthritis Risk Alleles with Response to Anti-TNF Biologics: Results from the CORRONA Registry and Meta-analysis

Abstract Several studies have investigated associations between overweight/obesity and risk of developing rheumatoid arthritis, however, the evidence is not entirely consistent, and previous meta-analyses mainly included case–control studies, which can be affected by various biases. We therefore conducted a systematic review and meta-analysis of cohort studies on adiposity and risk of rheumatoid arthritis. Relevant studies were identified by searching PubMed and Embase databases. Random effects models were used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) for rheumatoid arthritis in relation to different measures of adiposity. Thirteen cohort studies (10 publications) were included. The summary RR per 5 kg/m2 increase in body mass index (BMI) was 1.11 (95% CI 1.05–1.18, I2 = 50%), but the association was restricted to women (1.15, 95% CI 1.08–1.21, I2 = 17%) and not observed in men (0.89, 95% CI 0.73–1.09, I2 = 58%). The summary RR per 5 kg/m2 increment in BMI at age 18 years was 1.17 (95% CI 1.01–1.36, I2 = 26%, n = 3), and per 10 cm increase in waist circumference was 1.13 (95% CI 1.02–1.25, I2 = 44%, n = 2). Higher BMI in middle age, BMI at age 18 years, and waist circumference were associated with increased rheumatoid arthritis risk, suggesting adiposity could be targeted for primary prevention.

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Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.120170 ◽

2010 ◽

Vol 69 (6) ◽

pp. 1077-1085 ◽

Cited By ~ 64

Author(s):

Elizabeth W Karlson ◽

Lori B Chibnik ◽

Peter Kraft ◽

Jing Cui ◽

Brendan T Keenan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Risk ◽

Genetic Model ◽

Genetic Risk Score ◽

Nucleotide Polymorphisms ◽

Rheumatoid Arthritis Risk ◽

Clinical Model ◽

Risk Alleles ◽

Cumulative Score ◽

Weighted Genetic Risk Score

BackgroundRecent discoveries of risk alleles have made it possible to define genetic risk profiles for patients with rheumatoid arthritis (RA). This study examined whether a cumulative score based on 22 validated genetic risk alleles for seropositive RA would identify high-risk, asymptomatic individuals who might benefit from preventive interventions.MethodsEight human leucocyte antigen (HLA) alleles and 14 single-nucleotide polymorphisms representing 13 validated RA risk loci were genotyped among 289 white seropositive cases and 481 controls from the US Nurses' Health Studies (NHS) and 629 white cyclic-citrullinated peptide antibody-positive cases and 623 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA). A weighted genetic risk score (GRS) was created, in which the weight for each risk allele is the log of the published odds ratio (OR). Logistic regression was used to study associations with incident RA. Area under the curve (AUC) statistics were compared from a clinical-only model and clinical plus genetic model in each cohort.ResultsPatients with GRS >1.25 SD of the mean had a significantly higher OR of seropositive RA in both NHS (OR=2.9, 95%CI 1.8 to 4.6) and EIRA (OR 3.4, 95% CI 2.3 to 5.0) referent to the population average. In NHS, the AUC for a clinical model was 0.57 and for a clinical plus genetic model was 0.66, and in EIRA was 0.63 and 0.75, respectively.ConclusionThe combination of 22 risk alleles into a weighted GRS significantly stratifies individuals for RA risk beyond clinical risk factors alone. Given the low incidence of RA, the clinical utility of a weighted GRS is limited in the general population.

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Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

Nature Genetics ◽

10.1038/ng.582 ◽

2010 ◽

Vol 42 (6) ◽

pp. 508-514 ◽

Cited By ~ 844

Author(s):

Eli A Stahl ◽

◽

Soumya Raychaudhuri ◽

Elaine F Remmers ◽

Gang Xie ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Rheumatoid Arthritis Risk ◽

Genome Wide

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MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

10.1101/2020.08.25.264515 ◽

2020 ◽

Author(s):

Shicheng Guo ◽

Yehua Jin ◽

Jieru Zhou ◽

Qi Zhu ◽

Ting Jiang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Target Genes ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Risk Alleles ◽

Novel Mirna ◽

Chinese Cohort ◽

Target Binding ◽

Immune Related Genes

AbstractObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions.Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs.Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26×10-4) and rs2620381 (miR-627, OR=0.77, P=2.55×10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0×10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0×10-5) and FDA approved drug target genes (P=0.014).Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26×10-4), rs2620381 (miR-627, P=2.55×10-3), rs4285314 (miR-3135b, P=1.10×10-13), rs28477407 (miR-4308, P=3.44×10-5), rs5997893 (miR-3928, P=5.9×10-3) and rs45596840 (miR-4482, P=6.6×10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

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