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Some autoimmune (AI) conditions affect white blood cell (WBC) counts. Whether a genetic predisposition to AI disease associates with WBC counts in populations expected to have low numbers of AI cases is not known. We developed genetic instruments for 7 AI diseases using genome-wide association study summary statistics. Two-sample inverse variance weighted regression (IVWR) was used to determine associations between each instrument and WBC counts. Effect size represents change in transformed WBC counts per change in log odds-ratio of the disease. For AI diseases with significant associations by IVWR, polygenic risk scores (PRS) were used to test for associations with measured WBC counts in individuals of European ancestry in a community-based (ARIC, n = 8926), and a medical-center derived cohort (BioVU, n = 40,461). The IVWR analyses revealed significant associations between 3 AI diseases and WBC counts: systemic lupus erythematous (Beta = − 0.05 [95% CI, − 0.06, − 0.03]), multiple sclerosis (Beta =  − 0.06 [− 0.10, − 0.03]), and rheumatoid arthritis (Beta = 0.02 [0.01, 0.03]). PRS for these diseases showed associations with measured WBC counts in ARIC and BioVU. Effect sizes tended to be larger among females, consistent with the known higher prevalence of these diseases among this group. This study shows that genetic predisposition to systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis was associated with WBC counts, even in populations expected to have very low numbers of disease cases.

Leukopenia is a common dose‐dependent side effect of azathioprine, often leading to drug discontinuation. Variants in TPMT and NUDT15 are associated with azathioprine‐induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome‐wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from All of Us, an NIH‐funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior TPMT or NUDT15 testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In All of Us, 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in PTPN2, rs11664064, reached genome‐wide significance in BioVU (OR = 3.61; p = 1.96E‐8) and replicated in All of Us (OR = 2.42, p = 0.039). Our finding suggests an association between rs11664064 in PTPN2 and azathioprine‐induced leukopenia. PTPN2 plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.

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.

Hypoglycemia is a common complication among type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea therapy. The aim of this study was to determine if genetic contributions to sulfonylurea pharmacokinetics or pharmacodynamics substantially affect the risk of hypoglycemia in these patients. In a retrospective case–control study in European American patients with T2DM, we examined the potential association between CYP2C9 reduced-function variants and sulfonylurea-related hypoglycemia. We also explored the relationship between sulfonylurea-related hypoglycemia and several candidate genetic variants previously reported to alter the response to sulfonylureas. We detected no evidence of association between CYP2C9 reduced-function alleles or any of the candidate genetic variants and sulfonylurea-related hypoglycemia. In conclusion, we identified no clinically significant predictors of hypoglycemia among genes associated with sulfonylurea pharmacokinetics or pharmacodynamics.

Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE ( n  = 117) or RA ( n  = 164) and in inflammatory disease-free control subjects ( n  = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10 , TYK2 , and CD40L in SLE and DRB1 , NOD2 , and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2 , DRB1 , and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.

TPMT and NUDT15 variants explain less than 25% of azathioprine‐associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed Least Absolute Shrinkage and Selection Operator (LASSO) regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1. Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.11–4.19, p = 0.024). Results remained significant after adjusting for a propensity score, including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data (HR = 2.11, 95% CI = 1.08–4.13, p = 0.030). We validated the results in a cohort (N = 517 non‐White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR = 2.00, (95% CI = 1.09–3.65, p = 0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity.

: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. : Using Vanderbilt's DNA biobank we compared the prevalence of , and variants in 250 cases with major bleeding and 259 controls during warfarin therapy. : was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). : The allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.

ObjectiveWe defined the genetic factors associated with a positive ANA test (ANA+) in the absence of autoimmune disease and tested the association with SLE.MethodsUsing a case-control design, we performed a genome-wide association study (GWAS) in individuals of European ancestry without an autoimmune disease who had ANA tested as part of clinical care from DNA biobanks linked to de-identified electronic medical records: BioVU and Electronic Medical Records and Genomics. GWAS results were meta-analysed and single nucleotide polymorphism (SNP) heritability was calculated. A polygenic risk score (PRS) for ANA+ and for SLE was constructed and compared in patients with SLE, ANA+ and ANA negative (ANA−) individuals without autoimmune disease and general controls who never had ANA testing performed.ResultsA total of 7287 individuals of European ancestry were included in the meta-analyses (2169 ANA+ and 5118 ANA−); an SNP upstream of the TSBP1 in the HLA locus (rs1967688) was associated with ANA+ (p=4.84×10−8). SNP heritability for ANA+ was low (h2SNP= 0.04), and the PRS for ANA+ was not significantly different in ANA+ and ANA− individuals. In contrast, the PRS for SLE was significantly higher in SLE compared with ANA+ individuals (p<2.2×10−16) but did not differ among ANA+, ANA− and general control groups (p=0.17).ConclusionsANA+ occurring in the absence of autoimmune disease has a genetic association with the HLA region, but overall heritability is low. In addition, few SLE-associated SNPs were associated with ANA+, and the PRS for SLE was not associated with ANA+, indicating limited genetic overlap.

Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54–0.64), 0.75 (0.71–0.80), 0.66 (0.61–0.71), and 0.78 (0.74–0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59–0.70 and AUC = 0.63, 95% CI: 0.58–0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.

Aim: Sympathetic activation suppresses insulin secretion via pancreatic ADRA2A. Because sympathetic activity and insulin demand increase during pregnancy, we tested the hypothesis that ADRA2A variants are associated with gestational diabetes (GDM). Patients & methods: Among Caucasian pregnant women without pre-existing diabetes, we genotyped 458 who had GDM and 1537 without GDM for seven ADRA2A variants. Results: rs1800038 (OR: 2.34; p = 0.020) and rs3750625 (OR: 1.56; p = 0.010) increased the risk of GDM, and rs11195418 decreased it (OR: 0.62; p = 0.025). The associations remained significant after adjustment for maternal age, maternal BMI, parity and a genetic risk score that included variants previously associated with Type 2 diabetes mellitus and GDM. Conclusion:ADRA2A genetic variation contributes independently to the risk of GDM in Caucasian women.