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Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.

ABSTRACT: Cumulative 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.We 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.Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.

SUBMITTER: Chibnik LB

PROVIDER: S-EPMC3171415 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.

Chibnik Lori B LB Keenan Brendan T BT Cui Jing J Liao Katherine P KP Costenbader Karen H KH Plenge Robert M RM Karlson Elizabeth W EW

PloS one 20110912 9

<h4>Background</h4>Cumulative 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.<h4>Methods/principal findings</h4>We 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 ...[more]

PMID: 21931699

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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.

Project description:ImportanceThe association of rheumatoid arthritis (RA) with cognitive and psychiatric phenotypes has been recognized. However, it is not known whether these phenotypes are a consequence of disease-related factors, such as pain, or reflect shared etiological factors.ObjectiveTo investigate whether genomic risk for RA is associated with cognitive and psychiatric symptoms in children and adolescents.Design, setting, and participantsThis cohort study analyzed data from 3296 to 5936 adolescents (depending on outcome) from the Avon Longitudinal Study of Parents and Children. Clinical and questionnaire data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 21, 2017, to May 21, 2018.ExposuresPolygenic risk scores (PRSs) for RA.Main outcomes and measuresMeasures of cognition (including IQ, working memory, verbal learning, processing speed, problem solving, selective attention, and attentional control) and psychopathology (including anxiety, depression, negative symptoms, psychotic experiences, attention-deficit/hyperactivity disorder, and hyperactive and inattentive symptoms) in childhood and adolescence.ResultsPolygenic risk scores for RA were generated for 7977 children and adolescents (3885 [48.7%] female). Of these 7977 participants, 9 (0.11%) had a known diagnosis of RA at age 22 years. Increased PRS for RA was associated with lower total IQ (β, -0.05; 95% CI, -0.07 to -0.02; P < .001), performance IQ (β, -0.03; 95% CI, -0.06 to -0.005; P = .02), and verbal IQ (β, -0.05; 95% CI, -0.08 to -0.02; P < .001) at age 8 years (mean [SD] age at measurement, 8.6 [0.3] years) and symptoms of hyperactivity and inattention from ages 4 to 16 years, with the strongest evidence of association at age 13 years (mean [SD] age at assessment, 13.2 [0.2] years). The odds ratio at this age per SD increase in PRS was 1.25 (95% CI, 1.12-1.39) (P < .001). There was little evidence of association between the RA PRS and other measures of cognition and psychopathology. Gene-based analyses indicated that polygenic signal for RA was enriched for immune pathways (q ≤ 0.05). No equivalent associations were seen for polygenic risk associated with inflammatory bowel disease or multiple sclerosis.Conclusions and relevanceThese findings support an association between genetic risk for RA and neural phenotypes, suggesting that cognitive impairment in RA is not simply secondary to disease-related processes or treatment effects. These results may suggest that genetic susceptibility for RA might affect psychological well-being in early life and reinforce the emerging link between mental health and the immune system.

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Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.

Publications

Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.

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