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.

Angular dependent terahertz emission from the interplay between nanocrystal diamond film and plasmonic metasurface.

Composite structures integrated with metasurfaces and nonlinear films have emerged as alternative candidates to enhance nonlinear response. The cooperative interaction between the two components is complicated. Herein, a split-ring resonator (SRR)-type metasurface was fabricated on a free-standing nanocrystal diamond (NCD) film utilizing electron beam lithography, electron beam evaporation, and a lift-off process. The terahertz (THz) radiation from the SRR-NCD under normal incidence originates from the high-order magnetic resonance of SRR because the NCD film cannot produce detectable THz radiation at this incident angle. As increasing the incident angle, the contribution of the THz radiation from the NCD film gradually increases until reaching 40° incident angle limitation. The results indicate that this angular-dependent THz radiation is induced by the interplay between the NCD film and SRR. This study offers a new approach to investigate nonlinear processes in composite structures.

Branched-chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis.

OBJECTIVE: Genetic studies have suggested that the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs. METHODS: Instrumental variables (IVs) for each BCAA were constructed and validated using large well-powered data sets and their association with T2D was tested using a two-sample inverse-variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D. RESULTS: Estimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (ß = 0.14 change in log-odds per SD change in valine, 95% CI: -0.06 to 0.33, p = 0.17), leucine (ß = 0.15, 95% CI: -0.02 to 0.32, p = 0.09), and isoleucine (ß = 0.13, 95% CI: -0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (ß = 0.08 per SD change in levels per log-odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10-9 ), leucine (ß = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10-8 ), and isoleucine (ß = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10-8 ). CONCLUSIONS: These data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes.

Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size.

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

Genotype-based "virtual" metabolomics in a clinical biobank identifies novel metabolite-disease associations.

Circulating metabolites act as biomarkers of dysregulated metabolism, and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based "virtual" metabolomics approach can identify novel metabolite-disease associations. We examined the association between polygenic scores for 726 metabolites (derived from OMICSPRED) with 1,247 clinical phenotypes in 57,735 European ancestry and 15,754 African ancestry participants from the BioVU DNA Biobank. We probed significant relationships through Mendelian randomization (MR) using genetic instruments constructed from the METSIM Study, and validated significant MR associations using independent GWAS of candidate phenotypes. We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes among African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolite-phenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p<0.05). Validated findings included the metabolites bilirubin and X-21796 with cholelithiasis, phosphatidylcholine(16:0/22:5n3,18:1/20:4) and arachidonate(20:4n6) with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.

Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels.

BACKGROUND: Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known. METHODS: Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45-59 years, and 60-70 years old). Association estimates are per standard deviation change in the PGS. FINDINGS: The median age was 56.6 years, and 2118 (68%) participants were 45-59 years. The median (IQR) baseline PSA level was 1.0 (0.6-1.7) ng/mL. Among men ages 45-59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17-1.57], p = 4.5 × 10-5), an ICD code for elevated PSA (HR = 1.30 [1.12-1.52], p = 8.0 × 10-4), a urological evaluation (HR = 1.34 [1.14-1.57], p = 4.8 × 10-4), and undergoing a prostate biopsy (HR = 1.35 [1.11-1.64], p = 0.002). Among men ages 60-70, association effect sizes were smaller and not significant. INTERPRETATION: A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years. FUNDING: National Institutes of Health (NIH).

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.

Circulating extracellular vesicles in human cardiorenal syndrome promote renal injury in a kidney-on-chip system.

BACKGROUNDCardiorenal syndrome (CRS) - renal injury during heart failure (HF) - is linked to high morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear.METHODSWe investigated the role of circulating EVs from patients with CRS on renal epithelial/endothelial cells using a microfluidic kidney-on-chip (KOC) model. The small RNA cargo of circulating EVs was regressed against serum creatinine to prioritize subsets of functionally relevant EV-miRNAs and their mRNA targets investigated using in silico pathway analysis, human genetics, and interrogation of expression in the KOC model and in renal tissue. The functional effects of EV-RNAs on kidney epithelial cells were experimentally validated.RESULTSRenal epithelial and endothelial cells in the KOC model exhibited uptake of EVs from patients with HF. HF-CRS EVs led to higher expression of renal injury markers (IL18, LCN2, HAVCR1) relative to non-CRS EVs. A total of 15 EV-miRNAs were associated with creatinine, targeting 1,143 gene targets specifying pathways relevant to renal injury, including TGF-ß and AMPK signaling. We observed directionally consistent changes in the expression of TGF-ß pathway members (BMP6, FST, TIMP3) in the KOC model exposed to CRS EVs, which were validated in epithelial cells treated with corresponding inhibitors and mimics of miRNAs. A similar trend was observed in renal tissue with kidney injury. Mendelian randomization suggested a role for FST in renal function.CONCLUSIONPlasma EVs in patients with CRS elicit adverse transcriptional and phenotypic responses in a KOC model by regulating biologically relevant pathways, suggesting a role for EVs in CRS.TRIAL REGISTRATIONClinicalTrials.gov NCT03345446.FUNDINGAmerican Heart Association (AHA) (SFRN16SFRN31280008); National Heart, Lung, and Blood Institute (1R35HL150807-01); National Center for Advancing Translational Sciences (UH3 TR002878); and AHA (23CDA1045944).

Genetics of Pulmonary Pressure and Right Ventricle Stress Identify Diabetes as a Causal Risk Factor.

Background Epidemiologic studies have identified risk factors associated with pulmonary hypertension and right heart failure, but causative drivers of pulmonary hypertension and right heart adaptation are not well known. We sought to leverage unbiased genetic approaches to determine clinical conditions that share genetic architecture with pulmonary pressure and right ventricular dysfunction. Methods and Results We leveraged Vanderbilt University's deidentified electronic health records and DNA biobank to identify 14 861 subjects of European ancestry who underwent at least 1 echocardiogram with available estimates of pulmonary pressure and right ventricular function. Analyses of the study were performed between 2020 and 2022. The final analytical sample included 14 861 participants (mean [SD] age, 63 [15] years and mean [SD] body mass index, 29 [7] kg/m2). An unbiased phenome-wide association study identified diabetes as the most statistically significant clinical International Classifications of Diseases, Ninth Revision (ICD-9) code associated with polygenic risk for increased pulmonary pressure. We validated this finding further by finding significant associations between genetic risk for diabetes and a related condition, obesity, with pulmonary pressure estimate. We then used 2-sample univariable Mendelian randomization and multivariable Mendelian randomization to show that diabetes, but not obesity, was independently associated with genetic risk for increased pulmonary pressure and decreased right ventricle load stress. Conclusions Our findings show that genetic risk for diabetes is the only significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress. These findings suggest that therapies targeting genetic risk for diabetes may also potentially be beneficial in treating pulmonary hypertension and right heart dysfunction.

Broadband All-Optical THz Modulator Based on Bi2Te3/Si Heterostructure Driven by UV-Visible Light.

All-optical terahertz (THz) modulators have received tremendous attention due to their significant role in developing future sixth-generation technology and all-optical networks. Herein, the THz modulation performance of the Bi2Te3/Si heterostructure is investigated via THz time-domain spectroscopy under the control of continuous wave lasers at 532 nm and 405 nm. Broadband-sensitive modulation is observed at 532 nm and 405 nm within the experimental frequency range from 0.8 to 2.4 THz. The modulation depth reaches 80% under the 532 nm laser illumination with a maximum power of 250 mW and 96% under 405 nm illumination with a high power of 550 mW. The mechanism of the largely enhanced modulation depth is attributed to the construction of a type-II Bi2Te3/Si heterostructure, which could promote photogenerated electron and hole separation and increase carrier density dramatically. This work proves that a high photon energy laser can also achieve high-efficiency modulation based on the Bi2Te3/Si heterostructure, and the UV-Visible control laser may be more suitable for designing advanced all-optical THz modulators with micro-level sizes.

A Polygenic Risk Score for Prostate Cancer Risk Prediction.

This retrospective cohort study compares 2 risk calculator systems that compute the probabilities of finding high-grade or any cancer on biopsy results in men undergoing a first prostate biopsy.

The effect of short-form video addiction on undergraduates' academic procrastination: a moderated mediation model.

Background: Short-form videos have become one of the most popular ways for people to entertain and relax. However, the intense interest in short-form videos has given rise to short-video addiction, which poses risks to both physical and mental health of individuals. Undergraduates are one of the important users for short-form videos, and the influence of short-form video addiction calls for more attention. This study aimed to investigate the association between short-form video addiction and academic procrastination among undergraduates, exploring the role of executive functions (i.e., attentional control) and personality traits (i.e., boredom proneness) in the association. Methods: Using stratified random cluster sampling method, the data of 1,047 college students were used in the study. All variables were measured by empirical instruments, and all instruments were highly reliable. Mediation and moderation analysis was conducted using Model 4 and 7 in PROCESS macro powered by SPSS. Results: Results revealed that short-form video addiction not only directly impacted academic procrastination but also placed indirect effect on academic procrastination through attentional control. Furthermore, the mediating effect of attentional control was contingent upon individuals' boredom proneness. Higher levels of boredom proneness weakened the impact of short-form video addiction on attentional control. Conclusion: The findings expand our knowledge of the negative effects of short-form video addiction and the underlying mechanisms, providing implications for mitigating undergraduates' academic procrastination.

Genetic Determinants of Body Mass Index and Fasting Glucose Are Mediators of Grade 1 Diastolic Dysfunction.

Background Early (grade 1) cardiac left ventricular diastolic dysfunction (G1DD) increases the risk for heart failure with preserved ejection fraction and may improve with aggressive risk factor modification. Type 2 diabetes, obesity, hypertension, and coronary heart disease are associated with increased incidence of diastolic dysfunction. The genetic drivers of G1DD are not defined. Methods and Results We curated genotyped European ancestry G1DD cases (n=668) and controls with normal diastolic function (n=1772) from Vanderbilt's biobank. G1DD status was explored through (1) an additive model genome-wide association study, (2) shared polygenic risk through logistic regression, and (3) instrumental variable analysis using 2-sample Mendelian randomization (the inverse-variance weighted method, Mendelian randomization-Egger, and median) to determine potential modifiable risk factors. There were no common single nucleotide polymorphisms significantly associated with G1DD status. A polygenic risk score for BMI was significantly associated with increased G1DD risk (odds ratio [OR], 1.20 for 1-SD increase in BMI [95% CI, 1.08-1.32]; P=0.0003). The association was confirmed by the inverse-variance weighted method (OR, 1.89 [95% CI, 1.37-2.61]). Among the candidate mediators for BMI, only fasting glucose was significantly associated with G1DD status by the inverse-variance weighted method (OR, 4.14 for 1-SD increase in fasting glucose [95% CI, 1.55-11.02]; P=0.005). Multivariable Mendelian randomization showed a modest attenuation of the BMI association (OR, 1.84 [95% CI, 1.35-2.52]) when adjusting for fasting glucose. Conclusions These data suggest that a genetic predisposition to elevated BMI increases the risk for G1DD. Part of this effect may be mediated through altered glucose homeostasis.

Microbiome-associated human genetic variants impact phenome-wide disease risk.

Human genetic variation associates with the composition of the gut microbiome, yet its influence on clinical traits remains largely unknown. We analyzed the consequences of nearly a thousand gut microbiome-associated variants (MAVs) on phenotypes reported in electronic health records from tens of thousands of individuals. We discovered and replicated associations of MAVs with neurological, metabolic, digestive, and circulatory diseases. Five significant MAVs in these categories correlate with the relative abundance of microbes down to the strain level. We also demonstrate that these relationships are independently observed and concordant with microbe by disease associations reported in case-control studies. Moreover, a selective sweep and population differentiation impacted some disease-linked MAVs. Combined, these findings establish triad relationships among the human genome, microbiome, and disease. Consequently, human genetic influences may offer opportunities for precision diagnostics of microbiome-associated diseases but also highlight the relevance of genetic background for microbiome modulation and therapeutics.

Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol.

Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (rs=-0.53, P<0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.

ABO O blood group as a risk factor for platelet reactivity in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10-8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10-209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10-9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.

The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene.

Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3-/- mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.

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.

A Mendelian Randomization Approach Using 3-HMG-Coenzyme-A Reductase Gene Variation to Evaluate the Association of Statin-Induced Low-Density Lipoprotein Cholesterol Lowering With Noncardiovascular Disease Phenotypes.

Importance: Observational studies suggest that statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may be associated with beneficial effects in many noncardiovascular diseases. Objective: To construct a weighted HMG-CoA reductase (HMGCR) gene genetic risk score (GRS) using variants in the HMGCR gene affecting low-density lipoprotein cholesterol as an instrumental variable for mendelian randomization analyses to test associations with candidate noncardiovascular phenotypes previously associated with statin use in observational studies. Design, Setting, and Participants: This cohort study included 53 385 unrelated adults of European ancestry with genome-wide genotypes available from BioVU (a practice-based biobank, used for discovery) and 30 444 unrelated adults with European ancestry available in the Electronic Medical Records and Genomics (eMERGE; a research consortium that conducts genetic research using electronic medical records, used for replication). The study was conducted from February 6, 2015, through April 31, 2019; data analysis was performed from August 26, 2019, through December 22, 2020. Interventions: An HMGCR GRS was calculated. Main Outcomes and Measures: The association between the HMGCR GRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies. Results: Of the 53 385 individuals in BioVU, 29 958 (56.1%) were women; mean (SD) age was 59.9 (15.6) years. The finding between the HMGCR GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An HMGCR GRS equivalent to a 10-mg/dL decrease in the low-density lipoprotein cholesterol level was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.09; 95% CI, 1.04-1.15; P = 5.58 × 10-4). The HMGCR GRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58; P = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34; P = .008). Of the 30 444 individuals in eMERGE, 16 736 (55.0%) were women; mean (SD) age was 68.7 (15.4) years. The association between the HMGCR GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17; P = .02); however, the HMGCR GRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16; P = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41; P = .08) in the eMERGE cohort. Conclusions and Relevance: A mendelian randomization approach using variants in the HMGCR gene replicated the association between statin use and increased type 2 diabetes risk but provided no strong evidence for pleiotropic effects of statin-induced decrease of the low-density lipoprotein cholesterol level on other diseases.

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.