Objectives-We have investigated the functional significance of conserved sequences within the 9p21.3 risk locus for coronary artery disease (CAD) and determined the relationship of 9p21.3 to expression of ANRIL and to whole genome gene expression. Methods and Results-We demonstrate that a conserved sequence within the 9p21.3 locus has enhancer activity and that the risk variant significantly increases reporter gene expression in primary aortic smooth muscle cells. Whole blood RNA expression of the short variants of ANRIL was increased by 2.2-fold whereas expression of the long ANRIL variant was decreased by 1.2-fold in healthy subjects homozygous for the risk allele. Expression levels of the long and short ANRIL variants were positively correlated with that of the cyclin-dependent kinase inhibitor, CDKN2B (p15) and TDGF1 (Cripto), respectively. Relevant to atherosclerosis, genome-wide expression profiling demonstrated upregulation of gene sets modulating cellular proliferation in carriers of the risk allele. Conclusion-These findings are consistent with the hypothesis that the 9p21.3 risk allele contains a functional enhancer, the activity of which is altered in carriers of the risk allele. 9p21.3 may promote atherosclerosis by regulating expression of ANRIL, which in turn is associated with altered expression of genes controlling cellular proliferation pathways. Key Words: coronary artery disease Ⅲ atherosclerosis Ⅲ 9p21.3 Ⅲ noncoding RNA Ⅲ ANRIL Ⅲ cellular proliferation T he 9p21.3 risk locus, identified in several genome-wide association studies for coronary artery disease (CAD), 1,2 spans 58 kb and encompasses multiple single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium (LD). Approximately 25% of whites carry 2 copies of the risk allele and have a 1.5-fold increased risk for CAD. 2 The increased risk is independent of all known risk factors including plasma lipids, hypertension, diabetes, obesity, and markers of inflammation. This implies a novel biological pathway relevant to atherosclerosis.BLAST searches against the NCBI nucleotide sequence database and inspection of the UCSC Genome Browser revealed no annotated genes within the 58-kb interval. The localization of the risk locus to a region devoid of known protein coding genes implicates a novel gene or regulatory element that promotes atherosclerosis independently of established risk factors. It is notable that the 9p21 risk locus overlaps a newly annotated noncoding RNA (ncRNA), termed ANRIL, recently identified through a deletion analysis of a large French kindred with hereditary melanoma. 3 ANRIL spans 126.3 kb, overlaps at its 5Ј end with CDKN2B (p15), and consists of 20 exons subjected to alternative splicing. Full-length ANRIL (3834 bp), deposited under GenBank accession number DQ485353, encompasses the first 12 exons plus exons 14 to 20. At least 2 shorter variants of ANRIL that end with an alternative exon 13 have been reported, DQ485454 and EU741058. DQ485454 (2659 bp) comprises the first 12 exons and an alternative exon 13,...

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

The presence of acetic acid during industrial alcohol fermentation reduces the yield of fermentation by imposing additional stress on the yeast cells. The biology of cellular responses to stress has been a subject of vigorous investigations. Although much has been learned, details of some of these responses remain poorly understood. Members of heat shock chaperone HSP proteins have been linked to acetic acid and heat shock stress responses in yeast. Both acetic acid and heat shock have been identified to trigger different cellular responses including reduction of global protein synthesis and induction of programmed cell death. Yeast HSC82 and HSP82 code for two important heat shock proteins that together account for 1–2% of total cellular proteins. Both proteins have been linked to responses to acetic acid and heat shock. In contrast to the overall rate of protein synthesis which is reduced, the expression of HSC82 and HSP82 is induced in response to acetic acid stress. In the current study we identified two yeast genes DOM34 and RPL36A that are linked to acetic acid and heat shock sensitivity. We investigated the influence of these genes on the expression of HSP proteins. Our observations suggest that Dom34 and RPL36A influence translation in a CAP-independent manner.