Clinical associations with a polygenic predisposition to benign lower white blood cell counts.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Background: Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. Methods: A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis. Results: Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70-1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21-2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74-1.81; p=0.52]). Conclusions: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. Funding: This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

When the body is fighting off an infection, the processes it uses to protect itself can sometimes overreact. This results in a condition known as sepsis which can cause life-threatening damage to multiple organs. In the United States, Black patients are 60-80% more likely to develop sepsis compared to individuals who identify as White; differences remain even after accounting for socio-economic status and presence of other illnesses. Recent work has suggested that two variants of the APOL1 gene which are almost exclusively found in people with African ancestry may be a contributing factor to this disparity. These 'high-risk' genetic variants have also been shown to increase the likelihood of kidney diseases. It is therefore possible that the elevated chance of sepsis is not directly linked to these variations of APOL1, but rather is the result of patients already having reduced kidney function. To understand the relationship between APOL1 and sepsis, Jiang et al. analyzed data from patients admitted to Vanderbilt University Medical Centre in the United States between 2000 and 2020. This included 2,242 patients who identified as Black and had been hospitalized with an infection. The analyses showed that 16% of these individuals were carriers of the APOL1 high-risk variants. The high-risk patients were more likely to experience sepsis and demonstrate kidney damage. But other organs commonly damaged by sepsis were not affected more in these individuals compared to the other 84% of patients who did not have these variants. Furthermore, when individuals with pre-existing kidney diseases were removed from this high-risk group, the increased likelihood of sepsis was no longer prominent. These findings suggest that the APOL1 variants do not directly increase the risk of sepsis, and this association is primarily due to patients with these genetic variations being more susceptible to kidney diseases. There are new drugs under development targeting the APOL1 variants. While these may provide protection against kidney diseases, they are unlikely to be successful at preventing or treating sepsis once a patient has been hospitalized with an infection.

Identification of novel biomarkers for the prediction of subclinical coronary artery atherosclerosis in patients with rheumatoid arthritis: an exploratory analysis.

BACKGROUND: Cardiovascular (CV) risk estimation calculators for the general population underperform in patients with rheumatoid arthritis (RA). The purpose of this study was to identify relevant protein biomarkers that could be added to traditional CV risk calculators to improve the capacity of coronary artery calcification (CAC) prediction in individuals with RA. In a second step, we quantify the improvement of this prediction of CAC when these circulating biomarkers are added to standard risk scores. METHODS: A panel of 141 serum and plasma proteins, which represent a broad base of both CV and RA biology, were evaluated and prioritized as candidate biomarkers. Of these, 39 proteins were selected and measured by commercial ELISA or quantitative mass spectroscopy in 561 individuals with RA in whom a measure of CAC and frozen sera were available. The patients were randomly split 50:50 into a training/validation cohort. Discrimination (using area under the receiver operator characteristic curves) and re-classification (through net reclassification improvement and integrated discrimination improvement calculation) analyses were performed first in the training cohort and replicated in the validation cohort, to estimate the increase in prediction accuracy for CAC using the ACA/AHA (American College of Cardiology and the American Heart Association) score with, compared to without, addition of these circulating biomarkers. RESULTS: The model containing ACC/AHA score plus cytokines (osteopontin, cartilage glycoprotein-39, cystatin C, and chemokine (C-C motif) ligand 18) and plus quantitative mass spectroscopy biomarkers (serpin D1, paraoxonase, and clusterin) had a statistically significant positive net reclassifications index and integrated discrimination improvement for the prediction of CAC, using ACC/AHA score without any biomarkers as the reference category. These results were confirmed in the validation cohort. CONCLUSION: In this exploratory analysis, the addition of several circulating CV and RA biomarkers to a standard CV risk calculator yielded significant improvements in discrimination and reclassification for the presence of CAC in individuals with RA.

Clinical consequences of a polygenic predisposition to benign lower white blood cell counts: Consequences of benign WBC count genetics.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio=0.55 per standard deviation increase in PGSWBC [95%CI, 0.30 - 0.94], p=0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n=1,724, hazard ratio [HR]=0.78 [0.69 - 0.88], p=4.0×10-5) or immunosuppressant (n=354, HR=0.61 [0.38 - 0.99], p=0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n=1,466, HR=0.62 [0.44 - 0.87], p=0.006). Collectively, these findings suggest that a WBC count polygenic score identifies individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Concurrent Gabapentin and Opioid Use and Risk of Mortality in Medicare Recipients with Non-Cancer Pain.

Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new-user design retrospective cohort study, in Medicare enrollees ages 65-89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin (n = 233,060) or duloxetine (n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all-cause mortality (primary) and out-of-hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person-years of follow-up, 1,379 patients died. All-cause mortality rate in gabapentin users was 12.16 per 1,000 person-years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80-1.31) or low-dose daily opioids (aHR = 1.06, 95% CI: 0.63-1.76). However, gabapentin users receiving concurrent high-dose daily opioids had an increased rate of all-cause mortality compared with duloxetine users on high-dose opioids (aHR = 2.03, 95% CI: 1.19-3.46). Out-of-hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high-dose opioids and gabapentin was associated with a higher all-cause mortality risk than that for concurrent use of high-dose opioids and duloxetine.

Clinical diagnoses associated with a positive antinuclear antibody test in patients with and without autoimmune disease.

BACKGROUND: Antinuclear antibodies (ANA) are antibodies present in several autoimmune disorders. However, a large proportion of the general population (20%) also have a positive test; very few of these individuals will develop an autoimmune disease, and the clinical impact of a positive ANA in them is not known. Thus, we test the hypothesis that ANA + test reflects a state of immune dysregulation that alters risk for some clinical disorders in individuals without an autoimmune disease. METHODS: We performed high throughput association analyses in a case-control study using real world data from the de-identified electronic health record (EHR) system from Vanderbilt University Medical Center. The study population included individuals with an ANA titer ≥ 1:80 at any time (ANA +) and those with negative results (ANA-). The cohort was stratified into sub-cohorts of individuals with and without an autoimmune disease. A phenome-wide association study (PheWAS) adjusted by sex, year of birth, race, and length of follow-up was performed in the study cohort and in the sub-cohorts. As secondary analyses, only clinical diagnoses after ANA testing were included in the analyses. RESULTS: The cohort included 70,043 individuals: 49,546 without and 20,497 with an autoimmune disease, 26,579 were ANA + and 43,464 ANA-. In the study cohort and the sub-cohort with autoimmune disease, ANA + was associated (P ≤ 5 × 10-5) with 88 and 136 clinical diagnoses respectively, including lupus (OR ≥ 5.4, P ≤ 7.8 × 10-202) and other autoimmune diseases and complications. In the sub-cohort without autoimmune diseases, ANA + was associated with increased risk of Raynaud's syndrome (OR ≥ 2.1) and alveolar/perialveolar-related pneumopathies (OR ≥ 1.4) and decreased risk of hepatitis C, tobacco use disorders, mood disorders, convulsions, fever of unknown origin, and substance abuse disorders (OR ≤ 0.8). Analyses including only diagnoses after ANA testing yielded similar results. CONCLUSION: A positive ANA test, in addition to known associations with autoimmune diseases, Raynaud's phenomenon, and idiopathic fibrosing alveolitis related disorders, is associated with decreased prevalence of several non-autoimmune diseases.

Duloxetine, Gabapentin, and the Risk for Acute Myocardial Infarction, Stroke, and Out-of-Hospital Death in Medicare Beneficiaries With Non-Cancer Pain.

OBJECTIVE: Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important. MATERIALS AND METHODS: We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting. RESULTS: During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics. DISCUSSION: In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Background: Two risk variants in the apolipoprotein L1 gene ( APOL1 ) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. Methods: A retrospective cohort study of 2,242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality and organ failure related to sepsis. Results: Of 2,242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR=1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR=0.99 [95% CI, 0.70-1.39; p=0.95]. APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR=1.64 [95% CI, 1.21-2.22; p=0.001], but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR=1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR=1.16 [95% CI, 0.74-1.81; p=0.52]). Conclusion: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. Funding: This study was supported by R01GM120523 (Q.F.), R01HL163854 (Q.F.), R35GM131770 (C.M.S.), HL133786 (W.Q.W.), and Vanderbilt Faculty Research Scholar Fund (Q.F.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126).The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Association Between Genetically Predicted Expression of TPMT and Azathioprine Adverse Events.

Polymorphisms thiopurine-S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) can increase the risk of azathioprine myelotoxicity, but little is known about other genetic factors that increase risk for azathioprine-associated side effects. PrediXcan is a gene-based association method that estimates the expression of individuals' genes and examines their correlation to specified phenotypes. As proof of concept for using PrediXcan as a tool to define the association between genetic factors and azathioprine side effects, we aimed to determine whether the genetically predicted expression of TPMT or NUDT15 was associated with leukopenia or other known side effects. In a retrospective cohort of 1364 new users of azathioprine with EHR-reported White race, we used PrediXcan to impute expression in liver tissue, tested its association with pre-specified phecodes representing known side effects (e.g., skin cancer), and completed chart review to confirm cases. Among confirmed cases, patients in the lowest tertile (i.e., lowest predicted) of TPMT expression had significantly higher odds of developing leukopenia (OR=3.30, 95%CI: 1.07-10.20, p=0.04) versus those in the highest tertile; no other side effects were significant. The results suggest that this methodology could be deployed on a larger scale to uncover associations between genetic factors and drug side effects for more personalized care.

Phenome-Wide Association Study of UMOD Gene Variants and Differential Associations With Clinical Outcomes Across Populations in the Million Veteran Program a Multiethnic Biobank.

Introduction: Common variants in the UMOD gene are considered an evolutionary adaptation against urinary tract infections (UTIs) and have been implicated in kidney stone formation, chronic kidney disease (CKD), and hypertension. However, differences in UMOD variant-phenotype associations across population groups are unclear. Methods: We tested associations between UMOD/PDILT variants and up to 1528 clinical diagnosis codes mapped to phenotype groups in the Million Veteran Program (MVP), using published phenome-wide association study (PheWAS) methodology. Associations were tested using logistic regression adjusted for age, sex, and 10 principal components of ancestry. Bonferroni correction for multiple comparisons was applied. Results: Among 648,593 veterans, mean (SD) age was 62 (14) years; 9% were female, 19% Black, and 8% Hispanic. In White patients, the rs4293393 UMOD risk variant associated with increased uromodulin was associated with increased odds of CKD (odds ratio [OR]: 1.22, 95% CI: 1.20-1.24, P = 5.90 × 10-111), end-stage kidney disease (OR: 1.17, 95% CI: 1.11-1.24, P = 2.40 × 10-09), and hypertension (OR: 1.03, 95% CI: 1.05-1.05, P = 2.11 × 10-06) and significantly lower odds of UTIs (OR: 0.94, 95% CI: 0.92-0.96, P = 1.21 × 10-10) and kidney calculus (OR: 0.85, 95% CI: 0.83-0.86, P = 4.27 × 10-69). Similar findings were observed across UMOD/PDILT variants. The rs77924615 PDILT variant had stronger associations with acute cystitis in White female (OR: 0.73, 95% CI: 0.59-0.91, P = 4.98 × 10-03) versus male (OR: 0.99, 95% CI: 0.89-1.11, P = 8.80 × 10-01) (P interaction = 0.01) patients. In Black patients, the rs77924615 PDILT variant was significantly associated with pyelonephritis (OR: 0.65, 95% CI: 0.54-0.79, P = 1.05 × 10-05), whereas associations with UMOD promoter variants were attenuated. Conclusion: Robust associations were observed between UMOD/PDILT variants linked with increased uromodulin expression and lower odds of UTIs and calculus and increased odds of CKD and hypertension. However, these associations varied significantly across ancestry groups and sex.

Race, Genotype, and Azathioprine Discontinuation : A Cohort Study.

BACKGROUND: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries. OBJECTIVE: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. DESIGN: Retrospective cohort study. SETTING: Two tertiary care centers. PATIENTS: Thiopurine users with White or Black race. MEASUREMENTS: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count. RESULTS: The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013). LIMITATIONS: Unmeasured confounding; data limited to tertiary centers. CONCLUSION: Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race. PRIMARY FUNDING SOURCE: National Institutes of Health.

Identifying Potential Therapeutic Applications and Diagnostic Harms of Increased Bilirubin Concentrations: A Clinical and Genetic Approach.

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.

TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real-World Clinical Results.

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.

Polygenic Risk Score to Identify Subclinical Coronary Heart Disease Risk in Young Adults.

BACKGROUND: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. METHODS: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. RESULTS: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor-based model were 0.015 (0.004-0.028) and 0.020 (0.001-0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033-0.109) and 0.051 (0.017-0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (-0.006 to 0.054) in CARDIA and 0.039 (0.0005-0.072) in FOS. CONCLUSIONS: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.

Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients.

Importance: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count. Objective: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count. Design, Setting, and Participants: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children's Hospital of Philadelphia from January 1, 1998, to December 31, 2020. Exposure: The rs2814778-CC genotype. Main Outcomes and Measures: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result. Results: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001). Conclusions and Relevance: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.

Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis.

OBJECTIVES: To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders. METHODS: Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis. RESULTS: The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10-5). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold. CONCLUSION: A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.

Effect of SLCO1B1 Polymorphisms on High-Dose Methotrexate Clearance in Children and Young Adults With Leukemia and Lymphoblastic Lymphoma.

High-dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function-altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (P < 0.001). The addition of the SLCO1B1 variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

OBJECTIVE: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data. MATERIALS AND METHODS: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis. RESULTS: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online. CONCLUSION: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.

Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome-Wide Association Study and Inverse Variance-Weighted Meta-Analysis.

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.

Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low-Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis.

OBJECTIVE: Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS: RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS: Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION: RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.