Susceptibility to childhood onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of five genetic risk variants
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ABSTRACT:
SUBMITTER: Prahalad S
PROVIDER: S-EPMC3402942 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:Children with childhood-onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. To test the hypothesis that adult-onset RA-associated variants are also associated with childhood-onset RA, we investigated RA-associated variants at 5 loci in a cohort of patients with childhood-onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood-onset RA using a weighted genetic risk score (wGRS). METHODS:A total of 155 children with childhood-onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood-onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood-onset RA. RESULTS:Childhood-onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06-1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10(-16) ). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood-onset RA, especially among males. CONCLUSION:The magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood-onset RA are similar to those observed in RA, suggesting that adult-onset RA and childhood-onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA-associated variants with susceptibility to childhood-onset RA.
| S-EPMC3683854 | biostudies-literature
Project description:BackgroundThere is currently great interest in the incorporation of genetic susceptibility loci into screening models to identify individuals at high risk of disease. Here, we present the first risk prediction model including all 46 known genetic loci associated with rheumatoid arthritis (RA).MethodsA weighted genetic risk score (wGRS) was created using 45 RA non-human leucocyte antigen (HLA) susceptibility loci, imputed amino acids at HLA-DRB1 (11, 71 and 74), HLA-DPB1 (position 9) HLA-B (position 9) and gender. The wGRS was tested in 11 366 RA cases and 15 489 healthy controls. The risk of developing RA was estimated using logistic regression by dividing the wGRS into quintiles. The ability of the wGRS to discriminate between cases and controls was assessed by receiver operator characteristic analysis and discrimination improvement tests.ResultsIndividuals in the highest risk group showed significantly increased odds of developing anti-cyclic citrullinated peptide-positive RA compared to the lowest risk group (OR 27.13, 95% CI 23.70 to 31.05). The wGRS was validated in an independent cohort that showed similar results (area under the curve 0.78, OR 18.00, 95% CI 13.67 to 23.71). Comparison of the full wGRS with a wGRS in which HLA amino acids were replaced by a HLA tag single-nucleotide polymorphism showed a significant loss of sensitivity and specificity.ConclusionsOur study suggests that in RA, even when using all known genetic susceptibility variants, prediction performance remains modest; while this is insufficiently accurate for general population screening, it may prove of more use in targeted studies. Our study has also highlighted the importance of including HLA variation in risk prediction models.
| S-EPMC4283663 | biostudies-literature
Project description:BackgroundCumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.Methods/principal findingsWe evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II. We created a weighted genetic risk score (GRS) and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking) to assess the relationship between GRS group and odds of developing seronegative (RF- and CCP-), seropositive (RF+ or CCP+), erosive, and seropositive, erosive RA phenotypes. In separate case only analyses, we assessed the relationships between GRS and age of symptom onset. In 542 RA cases, 317 (58%) were seropositive, 163 (30%) had erosions and 105 (19%) were seropositive with erosions. Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8-2.1) for seronegative RA, 3.0 (95% CI = 1.9-4.7) for seropositive RA, 3.2 (95% CI = 1.8-5.6) for erosive RA, and 7.6 (95% CI = 3.6-16.3) for seropositive, erosive RA. No significant relationship was seen between GRS and age of onset.Conclusions/significanceResults suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.
| S-EPMC3171415 | biostudies-literature
Project description:Recent 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.Eight 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.Patients 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.The 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.
| S-EPMC2933175 | biostudies-literature
Project description:Multiple genetic and environmental factors have been associated with an increased risk for rheumatoid arthritis (RA). Of these, the strongest associations have been seen with female sex, a family history of RA, the genetic factor the "shared epitope," and exposure to tobacco smoke. There is also renewed interest in mucosal inflammation and microbial factors as contributors to the development of RA. However, the identification of a "preclinical" period of RA that can be defined as local or systemic autoimmunity as measured by autoantibodies and other biomarkers prior to the development of clinically apparent synovitis suggests that the risk factors for RA are acting long prior to first clinical evidence of IA. As such, a major challenge to the field will be to investigate the full spectrum of the development of RA, from initiation and propagation of autoimmunity during preclinical RA and transition to clinically apparent synovitis and classifiable RA, to determine which genetic and environmental factors are important at each stage of disease development. Understanding the exact role and timing of action of risk factors for RA is especially important given the advent of prevention trials in RA, and the hope that a full understanding of genetic and environmental factors in RA could lead to effective preventive interventions.
| S-EPMC5726551 | biostudies-other
Project description:The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smoking's impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively.
| S-EPMC3778023 | biostudies-literature
Project description:Higher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring's own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73-1.07, p = 0.21; offspring's own PRS on autism: RR 1.11, 95%CI 0.88-1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98-1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.
| S-EPMC8755835 | biostudies-literature
Project description:Two recent genome-wide association studies (GWASs) identified five single nucleotide polymorphisms (SNPs; rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs.We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio and 1795 PTC cases and 2090 controls from Poland. Cumulative genetic risk scores were calculated using unweighted and weighted approaches.All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls (p<2.2×10(-16)). Each additional risk allele increased the risk of having PTC by 1.51 [95% confidence interval (CI) 1.4, 1.64] in Ohio and by 1.35 [95% CI 1.27, 1.44] in Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to three weighted risk score groups, low (?2), medium (2-5), and high (>5). Individuals in the high group were significantly more susceptible to PTC compared with individuals in the low group with an odds ratio of 8.7 [95% CI 5.8, 13.3] in Ohio and 4.24 [95% CI 3.10, 5.84] in Poland. Almost identical results were obtained when follicular variant PTCs and microPTCs were omitted. These five SNPs explained 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort.As the genetic risk score increases, the risk of having PTC increases. However, the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected.
| S-EPMC3868253 | biostudies-literature
Project description:ObjectivePatients at high risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high-resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA-ILD.MethodsOur study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA-ILD was developed in the discovery population and tested for validation in the replication population.ResultsThe discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA-ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA-ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70-0.94) for the discovery population and 0.78 (95% CI 0.65-0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01).ConclusionWe developed and validated a risk score that could help identify patients at high risk of subclinical RA-ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA-ILD risk.
| S-EPMC9828082 | biostudies-literature
Project description:BackgroundTo evaluate incidence of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with abatacept in clinical trials.MethodsThis pooled analysis of 16 randomized, double-blind/open-label trials, with ≥ 1 abatacept (intravenous or subcutaneous) arm, and with/without placebo control covered cumulative (controlled short-term and open-label long-term) abatacept exposure periods. OIs were analyzed separately in controlled (abatacept and placebo individually) and cumulative periods. OIs were identified using a prespecified list; events were independently adjudicated. Unadjusted incidence rates (IRs; per 100 patient-years) with 95% confidence intervals (CIs) were calculated.ResultsIn cumulative periods, 7044 patients received abatacept, with a mean (standard deviation) duration of exposure of 36.9 (26.2) months (21,274 patient-years of exposure). IRs (95% CIs) of OIs were 0.17 (0.05-0.43) for abatacept and 0.56 (0.22-1.15) for placebo during the controlled periods and 0.21 (0.15-0.28) for abatacept during the cumulative periods. There was 1 case of tuberculosis in both the abatacept (IR [95% CI] 0.04 [0.00-0.24]) and placebo (IR [95% CI] 0.08 [0.00-0.44]) groups during the controlled periods; 13 verified tuberculosis cases (IR [95% CI] 0.06 [0.03-0.10]) were reported in the cumulative period. Herpes zoster was reported numerically more often with abatacept (IR 1.9 [1.4-2.5]), versus placebo (1.7 [1.1-2.6]) in the controlled periods; within the cumulative period, herpes zoster IR (95% CI) was 1.53 (1.36-1.71) for abatacept-treated patients.ConclusionIn controlled periods of the clinical trials, abatacept-treated patients had similarly low rates of OIs compared with placebo-treated patients. Overall, OI rates were similar among abatacept-treated patients in the controlled and cumulative periods and consistent with the ranges reported in the literature.
| S-EPMC7798209 | biostudies-literature