👤 Nitin Sukumar

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

It was observed that many people in the western coastal belt were found to have a high HDL cholesterol, the cause of which was not known. This study was done to learn about the factors contributing to the high HDL cholesterol in these patients and its effect on ASCVD risk. In this prospective, case control study, 150 patients were recruited, of which 63 were cases (patients with high HDL cholesterol), and 87 were controls (patients with normal HDL cholesterol). Details regarding their diet, sea-food consumption, habits, comorbidities, daily activity (using GPAQ questionnaire), and blood reports were collected. ASCVD risk score was calculated using an online ASCVD risk estimator. Blood samples of 96 patients (cases 40, controls 56) was tested for cholesterol esterase transfer protein (CETP) levels using ELISA, and the results were compared. Patients with high HDL cholesterol were found to be physically more active and had median metabolic equivalent (METs) of 4680 (1200, 8580) compared with controls with median METs of 1680 (720, 5580), P-0.013. Cases had a lower mean BMI 23.09(SD-3.69), than in patients with normal HDL cholesterol with a mean of 24.41(SD-4.01), P-0.04. Cases also had a lower triglyceride level (91(69,118) in cases vs 121 (80,151) in controls, P-0.002. Alcohol and sea food consumption had no role on HDL levels in this study. The median CETP level was lower in patients with high HDL levels, 0.336(0.08, 0.336) versus 1.435(0.061, 2.893) in the control group although not statistically significant. Patients with high HDL cholesterol were found to have a significantly lower median 10-year ASCVD risk score 3.05 (0.6, 8.95), compared with patients with normal HDL 6.45 (2.7,14.2). Patients with high HDL cholesterol were found to be physically more active, had a lower BMI, a lower triglyceride level, and a lower ASCVD risk compared with controls. They also had a lower CETP level. Further research will be required to determine the normal CETP level in Indian population, their genetic makeup, and whether it has a role in cardiovascular protection. Show less

Symptoms from overactive bladder (OAB) and cystitis secondary to urinary tract infection (UTI) can be similar in post-menopausal women. Effects of ovariectomy (OVX) on voiding behavior after lipopolysaccharide (LPS) intravesical exposure (surrogate for cystitis) in mice were measured. Urothelial genes associated with micturition changes were identified. Female C57BL6/J mice underwent OVX or sham surgeries (n = 10 for each). Voiding spot assays (VSA) were performed prior to surgery, 4 weeks post-surgery, and each time after 3 consecutive days of transurethral instillation of LPS. In another experiment, mice underwent either sham (n = 9) or OVX (n = 9) surgeries. Urothelial RNAs were collected 4 weeks post-surgery, day 1 and day 3 after LPS instillation. Mouse Gene 2.0 ST Arrays (entire 34 K transcripts) were used for microarray hybridization. A set of criteria was utilized to identify gene expression changes that mimicked voiding behavior changes. Three days after LPS exposure, OVX mice persisted with overactive whereas sham mice normalized voiding behavior. Nine urothelial paralleling voiding behavior changes were identified: IL6 (interleukin 6), IL6rα (Interleukin 6 receptor α), Ptgs2 (Prostaglandin-endoperoxide synthase 2 or COX-2), Ereg (epiregulin), Dusp6 (dual specificity phosphatase 6), Zfp948 (zinc finger protein 948), Zfp52 (Zinc finger protein 52), Gch1 (GTP cyclohydrolase 1), and Amd (S-adenosylmethionine decarboxylase). Three other genes, coding unknown proteins, were also identified: GM12840, GM23134, and GM26809. OVX mice persisted with increased voiding frequency after LPS. Urothelial genes that could mediate this voiding behavior include IL6, COX-2, and S-adenosylmethionine decarboxylase. Show less

GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of T Show less