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.)

AimsTo evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.Methods and resultsUsing two case–control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11–1.24) and rs10757274 (OR 1.17; 1.09–1.26), MIA3 rs17465637 (OR 1.10; 1.04–1.15), Ch2q36 rs2943634 (OR 1.08; 1.03–1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84–0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15–1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6.ConclusionSeveral SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

FLG and POSTN expression may be downregulated and upregulated, respectively, in the esophageal mucosa of patients with active EoE, and these changes may be restored with treatment in a significant percentage of cases.

All children with EoE and mild symptoms had resolution of symptoms and normal eosinophils in the esophageal mucosa a year after an allergy-driven elimination diet. Patients with moderate/severe EoE symptoms had the same improvement, indicating that an elimination diet is an efficient complementary treatment to corticosteroids.

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A report on the British Atherosclerosis Society autumn meeting 'Genetics of Complex Diseases', Cambridge, UK, 17-18 Septem ber 2009. IntroductionComplex disease genetics is at a critical turning point. Genome-wide association studies (GWASs) have generated an abundance of data, resulting in the use of advanced analytic methods and raising many questions. This common platform has brought together various scientific disciplines, including genetics, epidemiology, bioinformatics, statistics and medicine, reflected in the diverse backgrounds of speakers and delegates at this meeting. Here, we summarize two principal themes that emerged in the meeting: first, the success of GWASs in the discovery of novel disease loci using emerging new analytical methodologies, and second, the current and future translational applications of GWASs. Genome-wide association studiesdiscoveries, limitations and future directionsGWASs enable a hypothesis-free approach to finding novel genes associated with diseases and traits. Facilitated by the HapMap project (http://www.hapmap.org), chips with probes for up to one million single nucleotide polymorphisms (SNPs) can be used to capture variation across the entire human genome. Mark Caulfield (Barts and The London School of Medicine, London, UK), Sekar Kathiresan (Massachusetts General Hospital and Broad Institute, Boston, USA) and Nilesh Samani (University of Leicester, UK) communicated results on novel loci arising from recent GWASs conducted on cardiovascular diseases (CVDs). They also highlighted the importance of collaborative analyses in reliably identifying signals that might otherwise be missed owing to small sample sizes. This was exemplified by the finding of novel genes associated with blood pressure and the discovery of SNPs on chromosome 1 associated with CVD that alter lowdensity lipoprotein (LDL)-cholesterol.Generation of large volumes of data brings with it analytical challenges, resulting in methodological development. Bayesian approaches that enable direct comparison among SNPs both within and between studies were described by David Balding (Imperial College, London, UK). These methods are in contrast to classical ('frequentist') methods, which compute a P-value as evidence for association without incorporating any information about minor allele frequency (MAF) and study size, both factors that affect the power of the test. Hence, the same P-value computed at different SNPs or in different studies may not provide the same level of confidence for true association. To partly avoid this issue, it has become the norm to discard low-MAF SNPs when using classical methods, but this may result in detectable association being discarded. In Bayesian analysis prior knowledge is incorporated into the model. The outcome is the posterior probability of association, which can be directly compared between SNPs and studies and also avoids the problem of multiple testing.John Whittaker (London School of Hygiene and Tropical Medicine, London, UK) further described how the Bayesian ap...

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