Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

<p>Abstract</p> <p>Background</p> <p>Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population.</p> <p>Methods</p> <p>We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, <it>NOD2</it>, <it>IL23R</it>, <it>IRGM</it>, <it>ATG16L1</it>, <it>PTGER4</it>, <it>NKX2-3</it>, <it>IL12B</it>, <it>PTPN2</it>, <it>TNFSF15 </it>and <it>STAT3</it>, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value.</p> <p>Results</p> <p>Three <it>NOD2 </it>SNPs, two <it>IL23R </it>SNPs, and one SNP each at <it>IRGM </it>and <it>PTGER4 </it>were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16).</p> <p>Conclusions</p> <p>CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.</p

A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim

Genetic variation associated with circulating monocyte count in the eMERGE Network

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count

Evolution of cardiac pathology in classic fabry disease. progressive cardiomyocyte enlargement leads to increased cell death and fibrosis, and correlates with severity of ventricular hypertrophy

BACKGROUND: Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galactosidase A (α-GalA) activity and the systemic accumulation of α-galactosyl-terminated glycosphingolipids. Two major phenotypes, "Classic" and "Later-Onset", lead to renal failure, and/or cardiac disease, and early demise. To date, the evolution and progression of the cardiac pathology and resultant clinical manifestations in family members of phenotype have not been well characterized. METHODS AND RESULTS: In a Classic family with nine affected members (GLA mutation c.983delG), cardiac imaging, angiography, and cardiac biopsies were performed in four males and two heterozygous females. Tissues were examined histologically, ultrastructurally, and myocardial necrosis and apoptosis were evaluated by in situ ligation with hairpin probes. Increasing cardiac pathology correlated with ECG and cardiac magnetic resonance findings. Young affected males with "pre-hypertrophy" had 18-20μm cardiomyocyte diameters, &lt;30% vacuolar areas in myocytes, and normal levels of necrosis and apoptosis. Patients with "moderate hypertrophy" (maximal wall thickness (MWT) ≤16mm) had 30-35μm cardiomyocyte diameters, ~45% vacuolar areas, and moderate levels of necrosis and apoptosis. In contrast, the oldest male with severe hypertrophy (MWT=21mm) had 38-40μm cell diameters, &gt;60% vacuolar areas, and marked necrosis and apoptosis. CONCLUSION: Progressive gender-specific cardiac pathology and clinical manifestations were documented in affected Classic family members. Increasing cardiomyocyte diameter was correlated with disease severity, age, and gender. Fibrosis was presumably caused by cell death of enlarged, substrate-engorged cardiomyocytes. These results support early enzyme therapy in Classic males to prevent/minimize irreversible cardiac damage

Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: a genome-wide association study.

Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV-controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women's Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10(-4)), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10(-7) vs. P<5.0x10(-8)) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10(-5)); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10(-5)); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies