Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

Background-Preeclampsia is a life-threatening pregnancy syndrome of uncertain origin. To elucidate the pathogenesis, we evaluated the temporal relationships between changes in vascular function and circulating biomarkers of angiogenic activity before and after the onset of preeclampsia and gestational hypertension. Methods and Results-Maternal mean arterial pressure, uterine artery pulsatility index, brachial artery flow-mediated dilatation, and serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin were prospectively measured in 159 women from 10 weeks gestation until 12 weeks postpartum. At 10 to 17 weeks, women who developed preterm preeclampsia had lower serum PlGF (Pϭ0. Pϭ0.03). Flow-mediated dilatation was higher during a pregnancy with gestational hypertension compared with preeclampsia (Pϭ0.001). Twelve weeks postpartum, serum PlGF was higher in women who had a hypertensive pregnancy compared with a normotensive pregnancy (PϽ0.001). Conclusions-These observations support a role for placenta-derived angiogenic biomarkers in the control of maternal vascular resistance of preeclampsia. Gestational hypertension develops differently, with a hyperdynamic circulation and angiogenic biomarker profile similar to normotensive pregnancy. Larger studies of unselected women are needed to ascertain whether measures of these angiogenic biomarkers assist with the prediction and prognosis of preeclampsia and whether postpartum measures of serum PlGF have a role in predicting future cardiovascular disease. (Circulation. 2010;122:478-487.)