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GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans is not fully defined, we used an unbiased computational approach to assess the clinical significance of rare G-protein-coupled receptor 37-like 1 (GPR37L1) genetic variants found among 51,289 whole-exome sequences from the DiscovEHR cohort. Rare GPR37L1 coding variants were binned according to predicted pathogenicity and analyzed by sequence kernel association testing to reveal significant associations with disease diagnostic codes for epilepsy and migraine, among others. Since associations do not prove causality, rare GPR37L1 variants were functionally analyzed in SK-N-MC cells to evaluate potential signaling differences and pathogenicity. Notably, receptor variants exhibited varying abilities to reduce cAMP levels, activate mitogen-activated protein kinase (MAPK) signaling, and/or upregulate receptor expression in response to the agonist prosaptide (TX14(A)), as compared with the wild-type receptor. In addition to signaling changes, knock-out (KO) of GPR37L1 or expression of certain rare variants altered cellular cholesterol levels, which were also acutely regulated by administration of the agonist TX14(A) via activation of the MAPK pathway. Finally, to simulate the impact of rare nonsense variants found in the large patient cohort, a KO mouse line lacking Gpr37l1 was generated. Although KO animals did not recapitulate an acute migraine phenotype, the loss of this receptor produced sex-specific changes in anxiety-related disorders often seen in chronic migraineurs. Collectively, these observations define the existence of rare GPR37L1 variants associated with neuropsychiatric conditions in the human population and identify the signaling changes contributing to pathological processes. [ABSTRACT FROM AUTHOR]

Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON; one standard deviation of MS-GRS increased the Hazard of MS 1.3-fold (95% confidence interval 1.07–1.55, P < 0.01). Participants stratified into quartiles of predicted risk developed incident MS at rates varying from 4% (95%CI 0.5–7%, lowest risk quartile) to 41% (95%CI 33–49%, highest risk quartile). The model replicated across two cohorts (Geisinger, USA, and FinnGen, Finland). This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Sequencing introns in cancer predisposition genes detects novel loss-of-function variants. Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1 -related cancers and cascade testing of family members. However, some patients with DICER1 -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the prevalence, penetrance, and expressivity of UBA1 variants in a health care system cohort? Findings: In this retrospective observational study of 163 096 participants, 11 individuals (1 in 13 591) harbored a UBA1 disease-causing variant and all participants had hematologic features along with a broad spectrum of autoimmune, pulmonary, and dermatologic clinical manifestations. Meaning: This study provides an estimate of the prevalence and a description of the clinical manifestations of VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome, although additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum. Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669). Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum. This retrospective observational study evaluates UBA1 variants in exome data from individuals in the Geisinger MyCode Community Health Initiative. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the genetic basis and phenotypic expression of autosomal dominant polycystic kidney disease (ADPKD) within a single regional health system in the US? Findings: In this retrospective observational study that included 174 172 unselected participants, 109 of 111 patients (98%) with large deletions or truncating PKD1 and PKD2 variants had ADPKD, whereas only 24 of 77 patients (31.2%) with previously described "likely pathogenic" missense PKD1 variants had ADPKD. Exome sequencing demonstrated that 19 of 235 patients (8%) clinically diagnosed with ADPKD had variants in genes other than PKD1 and PKD2. Meaning: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US. Importance: Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression. Objective: To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort. Design, Setting, and Participants: This retrospective observational study used an unselected health system–based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review. Exposures: Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2. Main Outcomes and Measures: Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease. Results: Of 174 172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P <.001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign. Conclusions and Relevance: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US. This retrospective study assesses the prevalence of autosomal dominant polycystic kidney disease and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort of patients. [ABSTRACT FROM AUTHOR]

We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context. [ABSTRACT FROM AUTHOR]

Simple Summary: Prevalence and cancer risk estimates derived from the evaluation of affected individuals in the clinic are subject to ascertainment bias. This limitation can be mitigated using a genome-first approach in which genotypic data is analyzed before knowing a patient's phenotype. Our study aimed to analyze two large cohorts with available exome and phenotype data unselected for a specific diagnosis from a genome-first perspective focusing on six pancreatic cancer predisposition genes. We provide estimates of (1) prevalence of heterozygotes for the general population and for individuals with pancreatic cancer and (2) cancer risk for pancreatic cancer for each gene evaluated. For mutation carriers, we found an elevated risk of pancreatic cancer for most genes evaluated, with variation among genes. This work expands our knowledge of the complex genetics of this cancer and will help identify patients at the highest risk who could benefit from future screening or therapeutic strategies. Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes. [ABSTRACT FROM AUTHOR]

To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3. Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10−15) and KLHDC7B (OR = 2.14, P = 5.2 × 10−30). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk. A GWAS and exome-wide association study meta-analysis identifies 53 loci affecting hearing loss risk from over half a million individuals across five cohorts. Rare variants in Mendelian hearing loss genes contribute to hearing loss risk in adults. [ABSTRACT FROM AUTHOR]

We evaluated the utility of leucocyte epigenomic-biomarkers for Alzheimer's Disease (AD) detection and elucidates its molecular pathogeneses. Genome-wide DNA methylation analysis was performed using the Infinium MethylationEPIC BeadChip array in 24 late-onset AD (LOAD) and 24 cognitively healthy subjects. Data were analyzed using six Artificial Intelligence (AI) methodologies including Deep Learning (DL) followed by Ingenuity Pathway Analysis (IPA) was used for AD prediction. We identified 152 significantly (FDR p<0.05) differentially methylated intragenic CpGs in 171 distinct genes in AD patients compared to controls. All AI platforms accurately predicted AD with AUCs ≥0.93 using 283,143 intragenic and 244,246 intergenic/extragenic CpGs. DL had an AUC = 0.99 using intragenic CpGs, with both sensitivity and specificity being 97%. High AD prediction was also achieved using intergenic/extragenic CpG sites (DL significance value being AUC = 0.99 with 97% sensitivity and specificity). Epigenetically altered genes included CR1L & CTSV (abnormal morphology of cerebral cortex), S1PR1 (CNS inflammation), and LTB4R (inflammatory response). These genes have been previously linked with AD and dementia. The differentially methylated genes CTSV & PRMT5 (ventricular hypertrophy and dilation) are linked to cardiovascular disease and of interest given the known association between impaired cerebral blood flow, cardiovascular disease, and AD. We report a novel, minimally invasive approach using peripheral blood leucocyte epigenomics, and AI analysis to detect AD and elucidate its pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Empirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment of pre-existing clinical phenotypes associated with COVID-19-related hospitalization. Methods: Phenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization). Results: Of 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (P<1.60x10-4), including: six kidney phenotypes, e.g. end stage renal disease or stage 5 CKD (OR = 11.07, p = 1.96x10-8), six cardiovascular phenotypes, e.g. congestive heart failure (OR = 3.8, p = 3.24x10-5), five respiratory phenotypes, e.g. chronic airway obstruction (OR = 2.54, p = 3.71x10-5), and three metabolic phenotypes, e.g. type 2 diabetes (OR = 1.80, p = 7.51x10-5). Additional analyses defining CKD based on estimated glomerular filtration rate, confirmed high risk of hospitalization associated with pre-existing stage 4 CKD (OR 2.90, 95% CI: 1.47, 5.74), stage 5 CKD/dialysis (OR 8.83, 95% CI: 2.76, 28.27), and kidney transplant (OR 14.98, 95% CI: 2.77, 80.8) but not stage 3 CKD (OR 1.03, 95% CI: 0.71, 1.48). Conclusions: This study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells.Methods: The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array.Results: Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment.Conclusions: Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients. [ABSTRACT FROM AUTHOR]

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ∼1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine. [ABSTRACT FROM AUTHOR]

Investigation of genetic susceptibility to cerebrovascular disease has been of growing interest. A systematic review of human studies assessing neurogenomic aspects of cerebrovascular disease was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Any association study exploring genetic variants located in the exome associated with one of the major cerebrovascular diseases with at least 500 subjects was eligible for inclusion. Of 6874 manuscripts identified, 35 studies met the inclusion criteria. Most studies of interest focused on ischemic stroke and cerebrovascular occlusive disease. Large cohort genetic association studies on hemorrhagic cerebrovascular disease were less common. In addition to rare, well-established monogenic conditions with significant risk for cerebrovascular disease, a number of genetic variants are also relevant to cerebrovascular pathogenesis as part of a multifactorial process. The 45 polymorphisms identified were located in genes involved in processes related to endothelial and vascular health (15 (33.4%) variants), plasma lipid metabolism (10 (22.2%) variants), inflammation (9 (20%) variants), coagulation (3 (6.7%) variants), and blood pressure modulation (2 (4.4%) variants), and other (6 (13.3%) variants). This work represents a comprehensive overview of genetic variants in the exome relevant to ischemic and hemorrhagic stroke pathophysiology. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine the association between BMI categories, stratified by metabolic health status, and the risk of kidney function decline (KFD). Methods: In this study, 42,128 adult patients with a stable BMI were classified over a 3‐year baseline window by BMI and metabolic health status (assessed by Adult Treatment Panel‐III criteria). KFD was defined as an estimated glomerular filtration rate (eGFR) decline ≥ 30%, eGFR < 15 mL/min/1.73 m2, or receipt of dialysis and/or transplant. Results: Over a median of 5.1 years (interquartile range 2.1‐8.9), 6,533 (15.5%) individuals developed KFD. Compared with the normal weight, metabolically healthy category, metabolically healthy obesity was associated with a higher risk of KFD (adjusted hazard ratio [aHR] 1.52; 95% CI: 1.22‐1.89). aHRs for KFD were 1.17 (95% CI: 0.89‐1.53), 2.21 (95% CI: 1.59‐3.08), and 2.20 (95% CI: 1.55‐3.11) for metabolically healthy obesity with BMI 30 to 34.9, BMI 35 to 39.9, and BMI ≥ 40 kg/m2. These associations were consistent among men and women, patients with eGFR ≥ or < 90 mL/min/1.73 m2, and age ≥ or < 55 years. The risk of KFD was highest among metabolically unhealthy individuals with BMI ≥ 40 (aHR 4.02; 95% CI: 3.40‐4.75 vs. metabolically healthy individuals with normal weight). Conclusions: Obesity, whether in the presence or absence of metabolic health, is a risk factor for KFD. [ABSTRACT FROM AUTHOR]

Objective: This study assessed all-cause and specific-cause mortality after Roux-en-Y gastric bypass (RYGB) and in matched control subjects, stratified by diabetes status.Research Design and Methods: RYGB patients were matched by age, BMI, sex, and diabetes status at time of surgery to nonsurgical control subjects using data from the electronic health record. Kaplan-Meier curves and Cox regression were used to assess differences in all-cause and specific-cause mortality between RYGB patients and control subjects with and without diabetes.Results: Of the 3,242 eligible RYGB patients enrolled from January 2004 to December 2015, control subjects were identified for 2,428 (n = 625 with diabetes and n = 1,803 without diabetes). Median postoperative follow-up was 5.8 years for patients with diabetes and 6.7 years for patients without diabetes. All-cause mortality was reduced in RYGB patients compared with control subjects only for those with diabetes at the time of surgery (adjusted hazard ratio 0.44; P < 0.0001). Mortality was not significantly improved in RYGB patients without diabetes compared with control subjects without diabetes (adjusted hazard ratio 0.84; P = 0.37). Deaths from cardiovascular diseases (P = 0.011), respiratory conditions (P = 0.017), and diabetes P = 0.011) were more frequent in control subjects with diabetes than in RYGB patients with diabetes. RYGB patients without diabetes were less likely to die of cancer (P = 0.0038) and respiratory diseases (P = 0.046) than control subjects without diabetes but were at higher risk of death from external causes (P = 0.012), including intentional self-harm (P = 0.025), than control subjects without diabetes.Conclusions: All-cause mortality benefits of RYGB are driven predominantly by patients with diabetes at the time of surgery. RYGB patients with diabetes were less likely to die of cardiovascular diseases, diabetes, and respiratory conditions than their counterparts without RYGB. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer's disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease. Methods: Here we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases. Results: We discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ε4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ε4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio = 0.45 (p = 0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined. Conclusions: Taken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ε4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations. [ABSTRACT FROM AUTHOR]

Background Using abdominal aortic aneurysm (AAA) as a model, this case-control study used electronic medical record (EMR) data to assess known risk factors and identify new associations. Methods The study population consisted of cases with AAA (n =888) and controls (n =10,523) from the Geisinger Health System EMR in Central and Northeastern Pennsylvania. We extracted all clinical and diagnostic data for these patients from January 2004 to December 2009 from the EMR. From this sample set, bootstrap replication procedures were used to randomly generate 2,500 iterations of data sets, each with 500 cases and 2000 controls. Estimates of risk factor effect sizes were obtained by stepwise logistic regression followed by bootstrap aggregation. Variables were ranked using the number of inclusions in iterations and P values. Results The benign neoplasm diagnosis was negatively associated with AAA, a novel finding. Similarly, type 2 diabetes, diastolic blood pressure, weight and myelogenous neoplasms were negatively associated with AAA. Peripheral artery disease, smoking, age, coronary stenosis, systolic blood pressure, age, height, male sex, pulmonary disease and hypertension were associated with an increased risk for AAA. Conclusions This study utilized EMR data, retrospectively, for risk factor assessment of a complex disease. Known risk factors for AAA were replicated in magnitude and direction. A novel negative association of benign neoplasms was identified. EMRs allow researchers to rapidly and inexpensively use clinical data to expand cohort size and derive better risk estimates for AAA as well as other complex diseases. [ABSTRACT FROM AUTHOR]

Background: Yes-associated protein (YAP) is a transcriptional co-activator and regulates cell proliferation and apoptosis. We investigated the clinical and biological significance of YAP in endometrial cancer (EMCA). Methods: YAP expression in 150 primary tumor tissues from patients with EMCA was evaluated by immunohistochemistry and its association with clinicopathological data was assessed. The biological functions of YAP were determined in EMCA cell lines through knockdown/overexpression of YAP. The role of YAP in modulating radiation sensitivity was also investigated in EMCA cells. Results: Increased nuclear YAP expression was significantly associated with higher grade, stage, lympho-vascular space invasion, postoperative recurrence/metastasis and overall survival in estrogen mediated EMCA, called type 1 cancer (p = 0.019,  = 0.028,  = 0.0008,  = 0.046 and  = 0.015, respectively). In multivariate analysis, nuclear YAP expression was confirmed as an independent prognostic factor for overall survival in type 1 EMCA. YAP knockdown by siRNA resulted in a significant decrease in cell proliferation (p<0.05), anchorage-dependent growth (p = 0.015) and migration/invasion (p<0.05), and a significant increase in the number of cells in G0/G1 phase (p = 0.002). Conversely, YAP overexpression promoted cell proliferation. Clonogenic assay demonstrated enhanced radiosensitivity by approximately 36% in YAP inhibited cells. Conclusions: Since YAP functions as a transcriptional co-activator, its differential localization in the nucleus of cancer cells and subsequent impact on cell proliferation could have important consequences with respect to its role as an oncogene in EMCA. Nuclear YAP expression could be useful as a prognostic indicator or therapeutic target and predict radiation sensitivity in patients with EMCA. [ABSTRACT FROM AUTHOR]

Background: The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals. Though some rare variants in MC4R discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects. Subjects/Methods: In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of MC4R. We matched rare variant carriers to patients with the MC4R reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. In vitro, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy. Results: While carrying a rare MC4R allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, V95I, I137T or L250Q, lost less weight after surgery. In vitro, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between in vitro signaling and pre- or post-surgery clinical phenotype. Conclusions: These data suggest that subtle differences in receptor signaling conferred by rare MC4R variants combined with additional factors predispose carriers to obesity. In the absence of complete MC4R deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention. [ABSTRACT FROM AUTHOR]

A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms. [ABSTRACT FROM AUTHOR]

Objective: The aim was to identify differences in microRNA expression between patients with and without preeclampsia. Methods: Microarray-based study was carried out with placental samples. Results: Comparison of eight previous studies with the current study revealed a total of 138 microRNAs; only 20/138 (14%), however, were seen in more than one study and the results agreed in the direction of change. Bioinformatic analysis of these 20 microRNAs identified a wide range of biological functions including apoptosis and cell movement for their mRNA targets. Conclusion-. The associations between miRNA expression and preeclampsia suggest a potential role for microRNAs in preeclampsia pathobiology. [ABSTRACT FROM AUTHOR]

Background: Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA. Methods: To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®. Results: A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells. Conclusions: Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis. [ABSTRACT FROM AUTHOR]

Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m2) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m2, with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m2. Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI. [ABSTRACT FROM AUTHOR]

Background: The infrarenal abdominal aorta exhibits increased disease susceptibility relative to other aortic regions. Allograft studies exchanging thoracic and abdominal segments showed that regional susceptibility is maintained regardless of location, suggesting substantial roles for embryological origin, tissue composition and site-specific gene expression. Results: We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibited spatial expression differences. HOXA4 was chosen for further study, since it had decreased expression in the abdominal compared to the thoracic aorta. Western blot analysis from 24 human aortas demonstrated significantly higher HOXA4 protein levels in thoracic compared to abdominal tissues (P < 0.001). Immunohistochemical staining for HOXA4 showed nuclear and perinuclear staining in endothelial and smooth muscle cells in aorta. The HOXA4 transcript levels were significantly decreased in human abdominal aortic aneurysms (AAAs) compared to age-matched non-aneurysmal controls (P < 0.00004). Cultured human aortic endothelial and smooth muscle cells stimulated with INF-γ (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (P < 0.0007). Conclusions: Our results demonstrated spatial variation in expression of HOXA4 in human aortas that persisted into adulthood and that downregulation of HOXA4 expression was associated with AAAs, an important aortic disease of the ageing population. [ABSTRACT FROM AUTHOR]

TRPM2 is a Ca2+-permeable channel activated by oxidative stress or TNF-α, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca2+-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H2O2, a model of oxidative stress, or TNF-α results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H2O2 or TNF-α, and these cells exhibited significantly increased intracellular calcium concentration ([Ca2+]i), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca2+]i rise with the intracellular Ca2+ chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca2+]i in mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca2+]i, enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-α, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF-α mediates cell death is activation of TRPM2, resulting in increased [Ca2+]i, followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca2+ chelation antagonizes this important cell death pathway. [ABSTRACT FROM AUTHOR]

Schwann cell myelination requires interactions with the extracellular matrix (ECM) mediated by cell surface receptors. Previously, we identified a typeVcollagen family member, α4(V) collagen, which is expressed by Schwann cells during peripheral nerve differentiation. This collagen binds with high affinity to heparan sulfate through a unique binding motif in the noncollagenous N-terminal domain (NTD). The principal α4(V) collagen-binding protein on the Schwann cell surface is the heparan sulfate proteoglycan glypican-1. We investigated the role of α4(V) collagen and glypican-1 in Schwann cell terminal differentiation in cultures of Schwann cells and dorsal root ganglion neurons. Small interfering RNA-mediated suppression of glypican-1 expression decreased binding of α4(V)-NTD to Schwann cells, adhesion and spreading of Schwann cells on α4(V)-NTD, and incorporation of α4(V) collagen into Schwann cell ECM. In cocultures, α4(V) collagen coassembles with laminin on the surface of polarized Schwann cells to form tube-like ECM structures that are sites of myelination. Suppression of glypican-1 or α4(V) collagen expression significantly inhibited myelination. These results demonstrate an important role for these proteins in peripheral nerve terminal differentiation. [ABSTRACT FROM AUTHOR]

Messenger RNA levels of phospholemman (PLM), a member of the FXYD family of small single-span membrane proteins with putative ion-transport regulatory properties, were increased in postmyocardial infarction (MI) rat myocytes. We tested the hypothesis that the previously observed reduction in Na+-K+-ATPase activity in MI rat myocytes was due to PLM overexpression. In rat hearts harvested 3 and 7 days post-MI, PLM protein expression was increased by two- and fourfold, respectively. To simulate increased PLM expression post-MI, PLM was overexpressed in normal adult rat myocytes by adenovirus-mediated gene transter. PLM overexpression did not affect the relative level of phosphorylation on serine68 of PLM. Na+-K+-ATPase activity was measured as ouabain-sensitive Na+-K+ pump current (Ip). Compared with control myocytes overexpressing green fluorescent protein alone, Ip measured in myocytes overexpressing PLM was significantly (P < 0.0001) lower at similar membrane voltages, pipette Na+ ([Na+]pip) and extracellular K+ ([K+]o) concentrations. From 70 to +60 mV, neither [Na+]pip nor [K+]o required to attain half-maximal Ip was significantly different between control and PLM myocytes. This phenotype of decreased Vmax without appreciable changes in Km for Na+ and K+ in PLM-overexpressed myocytes was similar to that observed in MI rat myocytes. Inhibition of Ip by PLM overexpression was not due to decreased Na+-K+-ATPase expression because there were no changes in either protein or messenger RNA levels of either α1- or α2-isoforms of Na+-K+-ATPase. In native rat cardiac myocytes, PLM coimmuno-precipitated with α-subunits of Na+-K+-ATPase. Inhibition of Na+-K+-ATPase by PLM overexpression, in addition to previously reported decrease in Na+-K+-ATPase expression, may explain altered Vmax but not Km of Na+-K+-ATPase in postinfarction rat myocytes. [ABSTRACT FROM AUTHOR]

Previous studies have shown that overexpression of phospholemman (PLM) affected contractile function and Ca[sup 2+] homeostasis in adult rat myocytes. We tested the hypothesis that PLM modulated Na[sup +]/Ca[sup 2+] exchanger (NCX1) activity. PLM was overexpressed in adult rat myocytes by adenovirus-mediated gene transfer. After 72 h, the half-time of relaxation from caffeine-induced contracture, an estimate of forward NCX1 activity, was prolonged 1.8-fold (P < 0.003) in myocytes overexpressing PLM compared with control myocytes overexpressing green fluorescent protein alone. Reverse NCX1 current (3 Na[sup +] out:1 Ca[sup 2+] in) was significantly (P < 0.0001) lower in PLM myocytes, especially at more positive voltages. Immunofluorescence demonstrated colocalization of PLM and NCX1 to the plasma membrane and t-tubules. Resting membrane potential, action potential amplitude and duration, myocyte size, and NCX1 and calsequestrin protein levels were not affected by PLM overexpression. At 5 mM extracellular [Ca[sup 2+]] ([Ca[sup 2+]][sub o]), the depressed contraction amplitudes in PLM myocytes were increased towards normal by cooverexpression with NCX1. At 0.6 mM [Ca[sup 2+]][sub o], the supranormal contraction amplitudes in PLM myocytes were reduced by cooverexpression with NCX1. We conclude that PLM modulated myocyte contractility partly by inhibiting Na[sup +]/Ca[sup 2+] exchange. [ABSTRACT FROM AUTHOR]

We have investigated the presence of hydrophobic membrane-associated heparan sulfate proteoglycans (HSPG) on the cell surface of differentiated skeletal muscle cells. A HSPG releasable by incubation with a phosphatidylinositol-specific phospholipase c (PtdIns-PLC) was obtained HSPG were also isolated from Triton X-100 extracts of the cells. The hydrodynamic characteristics of the PtdIns-PLC-releasable and detergent-extracted HSPG were indistinguishable. SDS/PAGE analysis of the PtdIns-PLC-releasable HSPG indicated a molecular mass of 250 kDa. Analysis of proteins immunoprecipitated by specific antibodies against a HSPG isolated from Schwann cells demonstrated that the antisera precipitated an intact HSPG that was present in the pool of proteins released by PtdIns-PLC and by Triton X-100 from [35S]sulfate labeled cells. Nitrous acid degradation of the immunoprecipitated proteins released by PtdIns-PLC from [35S]methionine labeled cells produced a single 67-kDa core protein. Analysis of hydrophobicity of the purified HSPG revealed that only the HSPG obtained from the detergent extract were able to be incorporated into the liposomes whereas the PtdIns-PLC-released HSPG was not. Immunocytolocalization analysis of the differentiated cells indicated that the PtdIns-PLC-releasable HSPG was located on the cell surface. Prior incubation of the cells with PtdIns-PLC significantly reduced the surface staining. Analysis of skeletal-muscle sections of adult rat skeletal muscles indicated that this HSPG localized exclusively at the endomysium. The Localization suggest that these HSPG may be acting as a cell receptor for extracellular-matrix (ECM) components. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition.Methods: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI).Results: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10- 20). This effect was consistent in both pediatric (p = 9.92 × 10- 6) and adult (p = 9.73 × 10- 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10- 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10- 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10- 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10- 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.Conclusions: In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings. [ABSTRACT FROM AUTHOR]

Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes attributed to a highly penetrant variant in one of several genes, including GCK. GCK-MODY rarely requires pharmacotherapy, however, the clinical management of pregnant mothers depends on whether the fetus inherited the GCK variant. The classic GCK-MODY phenotype is young (diagnosed before 25 years), lean (BMI < 25 mg/kg2), with stable, mild hyperglycemia (Hba1c 5.8-7.6%). We hypothesized that strict application of these guidelines has led to under-reporting of GCK-MODY (prevalence 1.1 per 1000). In a cohort of 92,412 individuals from the DiscovEHR study, we identified 252 heterozygous carriers of 88 rare GCK variants (minor allele frequency < 0.02%). None had an existing diagnosis of monogenic diabetes. The median BMI of GCK carriers was 35 mg/kg2, compared to 31 mg/kg2 for nondiabetic noncarriers and 38 mg/kg2 for noncarriers with type 2 diabetes (T2D). Excluding variants with no evidence of hyperglycemia in 50% of the carriers resulted in 70 variants in 213 individuals. GCK-MODY variant carriers had mean HbA1c, fasting blood glucose (FBG), and random glucose measurements that were greater than nondiabetic non-carriers but less than those with T2D. Kaplan-Meier analysis adjusted for left-truncation bias showed that the age at which 50% of GCK-MODY subjects diagnosed with impaired fasting glucose and diabetes is 35 and 55 years, respectively, compared to 60 and 65 years in non-carriers with T2D (p< 2e-16). Within-individual variability of lifetime FBG measurements of GCK-MODY carriers was less than noncarriers with T2D (GCK-MODY, 7.9 ± 2.0 mg/dL; T2D, 17.6 ± 0.03 mg/dl, p <1e-4). The odds ratios [95% confidence intervals] for diabetes in GCK-MODY carriers was 4.0 [3.1 - 5.2], p<0.0001. We estimate a GCK-MODY prevalence of 1 per 508 individuals and 1 per 59 individuals with gestational diabetes. GCK variant carriers in this study had a broader spectrum of clinical characteristics compared to the classic GCK phenotype. Disclosure: U.L. Mirshahi: None. J.M. Goehringer: None. Y. Hu: None. A.H. Wardeh: None. J. Williams: None. C.B. Manney: None. J.C. Staples: Employee; Self; Regeneron Pharmaceuticals. J.B. Leader: None. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. T.I. Pollin: Other Relationship; Self; Regeneron Genetics Center. D.J. Carey: None. [ABSTRACT FROM AUTHOR]

Following publication of the original article [1], the authors reported that Fig. 1 was not correctly processed during the production process. The correct Fig. 1 is given below. [ABSTRACT FROM AUTHOR]