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Bilirubin has antioxidant and anti-inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n = 61,281) and clinical (n = 234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P = 2.2 × 10 -16 ) but there was no significant association with any of the 19 conditions. In a phenome-wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of "jaundice-not of newborn." Carriers of the variant allele were more likely to undergo an abdominal ultrasound (odds ratio = 1.04, [1.00-1.08], P = 0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P < 0.003) and with 431 clinical diagnoses in the pheWAS (P < 1 × 10 -5 adjusted for sex, age, and follow-up). With additional adjustment for smoking and body mass index, 7 of 19 conditions and 260 pheWAS diagnoses remained significantly associated with bilirubin levels. In conclusion, bilirubin does not protect against inflammatory or other diseases using a genetic approach; the many putative beneficial associations reported clinically are likely due to confounding., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Objective: This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA., Methods: Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders. Additionally, a phenome-wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance-weighted regression (IVWR) meta-analysis was used to characterize the association between genetic susceptibility to RA and the prespecified disorders, with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs)., Results: The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04-1.16]; P = 9.82 × 10 -4 ) and multiple sclerosis (OR 0.82 [95% CI 0.77-0.88]; P = 1.73 × 10 -8 ), but not with other cardiometabolic phenotypes. In the PheWAS, wGRS was also associated with an increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with a decreased risk of demyelinating disorders. In the IVWR meta-analyses, RA was significantly associated with an increased risk of type 1 DM (P = 1.15 × 10 -14 ), with evidence of horizontal pleiotropy (Mendelian Randomization-Egger intercept estimate P = 0.001) likely driven by rs2476601, a PTPN22 variant. The association between type 1 DM and RA remained significant (P = 9.53 × 10 -9 ) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate P = 0.939). RA was also significantly associated with type 2 DM and C-reactive protein levels. These associations were driven by variation in the major histocompatibility complex region., Conclusion: This study presents evidence of pleiotropy between the genetic predisposition to RA and associated phenotypes found in other autoimmune and cardiometabolic disorders, including type 1 DM., (© 2020, American College of Rheumatology.)

Objective: Patients with rheumatoid arthritis (RA) have increased risk of atherosclerotic cardiovascular disease that is underestimated by the Framingham Risk Score (FRS). We undertook this study to test the hypothesis that the 2013 American College of Cardiology/American Heart Association (ACC/AHA) 10-year risk score would perform better than the FRS and the Reynolds Risk Score (RRS) in identifying RA patients known to have elevated cardiovascular risk based on high coronary artery calcification (CAC) scores., Methods: Among 98 RA patients eligible for risk stratification using the ACC/AHA risk score, we identified 34 patients with high CAC (defined as ≥300 Agatston units or ≥75th percentile of expected coronary artery calcium for age, sex, and ethnicity) and compared the ability of the 10-year FRS, RRS, and ACC/AHA risk scores to correctly assign these patients to an elevated risk category., Results: All 3 risk scores were higher in patients with high CAC (P < 0.05). The percentage of patients with high CAC correctly assigned to the elevated risk category was similar among the 3 scores (FRS 32%, RRS 32%, ACC/AHA risk score 41%) (P = 0.223). The C statistics for the FRS, RRS, and ACC/AHA risk score predicting the presence of high CAC were 0.65, 0.66, and 0.65, respectively., Conclusion: The ACC/AHA 10-year risk score does not offer any advantage compared to the traditional FRS and RRS in the identification of RA patients with elevated risk as determined by high CAC. The ACC/AHA risk score assigned almost 60% of patients with high CAC to a low risk category. Risk scores and standard risk prediction models used in the general population do not adequately identify many RA patients with elevated cardiovascular risk.