Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research

Progressive myelopathy, a consequence of intra‑thecal chemotherapy: Case report and review of the literature

Intra‑thecal chemotherapy is a recognized therapy for hematological malignancies such as acute lymphoblastic leukemia (ALL). Despite the advantage of these drugs in treating or preventing central nervous system disease, they are not without complications. The authors describe a 12‑year‑old girl with ALL, who developed progressive myelopathy following intra‑thecal administration of cytosine arabinoside. Initial presentation was urine and fecal retention that progressed to paraplegia, and finally encephalopathy. magnetic resonance imaging of the neuroaxis showed T2‑weighted foci of increased signal intensity within the substance of the cervical cord indicative of myelopathy. Physicians should be wary of this rare complication of intra‑thecal chemotherapy.Key words: Cytosine arabinoside, intra‑thecal, myelopath

Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation

Autoimmune diseases such as multiple sclerosis (MS) result from complex and poorly understood interactions of genetic and environmental factors. A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex (MHC) region and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA). Multiple environmental factors (vitamin D(3) deficiency and metabolism) converge with multiple genetic variants (IL-7RA, IL-2RA, MGAT1 and CTLA-4) to dysregulate Golgi N-glycosylation in MS, resulting in T cell hyper-activity, loss of self-tolerance and in mice, a spontaneous MS-like disease with neurodegeneration. Here we review the genetic and biological interactions that regulate MS pathogenesis through dysregulation of N-glycosylation and how this may enable individualized therapeutic approaches