Genome-wide association study of coronary artery disease in the Japanese

Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
European journal of human genetics: EJHG (Impact Factor: 4.35). 03/2012; 20(3):333-40. DOI: 10.1038/ejhg.2011.184
Source: PubMed


A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 10(-16)). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10(-40)). On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects - population specific and common - on susceptibility to CAD.

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Available from: Eitaro Nakashima
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    • "The marked differences in the allele frequencies between populations of Asian and European descent raise the question whether rs3798220 defines LPA risk alleles in Asian populations. The only genome-wide association study (GWAS) which included direct analysis of rs3798220 in East Asians did not find an association with CAD in Japanese [29]. As the strong linkage disequilibrium (LD) between rs3798220 and the KIV-2 CNV in Europeans could indicate that this haplotype is evolutionary rather young, the mutation possibly has occurred twice after the out of Africa-migration of modern humans, once in Asian populations and once in Europeans. "
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    ABSTRACT: The variant allele of rs3798220 in the apolipoprotein(a) gene (LPA) is used to assess the risk for coronary artery disease (CAD) in Europeans, where it is associated with short alleles of the Kringle IV-2 (KIV-2) copy number variation (CNV) and high lipoprotein(a) (Lp(a)) concentrations. No association of rs3798220 with CAD was detected in a GWAS of East Asians. Our study investigated the association of rs3798220 with Lp(a) concentrations and KIV-2 CNV size in non-European populations to explain the missing association of the variant with CAD in Asians. We screened three populations from Africa and seven from Asia by TaqMan Assay for rs3798220 and determined KIV-2 CNV sizes of LPA alleles by pulsed-field gel electrophoresis (PFGE). Additionally, CAD cases from India were analysed. To investigate the phylogenetic origin of rs3798220, 40 LPA alleles from Chinese individuals were separated by PFGE and haplotyped for further SNPs. The variant was not found in Africans. Allele frequencies in East and Southeast Asians ranged from 2.9% to 11.6%, and were very low (0.15%) in CAD cases and controls from India. The variant was neither associated with short KIV-2 CNV alleles nor elevated Lp(a) concentrations in Asians. Our study shows that rs3798220 is no marker for short KIV-2 CNV alleles and high Lp(a) in East and Southeast Asians, although the haplotype background is shared with Europeans. It appears unlikely that this SNP confers atherogenic potential on its own. Furthermore, this SNP does not explain Lp(a) attributed risk for CAD in Asian Indians. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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    • "Inactivation of CDKN2A, through loss of heterozygosity or hypermethylation of its promoter, has been reported in endometriosis and endometrial cancer (Goumenou et al., 2000; Martini et al., 2002; Guida et al., 2009). SNPs in or near the CDKN2B-AS1 locus have been associated with many other traits and disease (Supplementary data, Table SI), with a number in LD (r2 > 0.2) with the endometriosis SNPs (Fig. 4), including rs1063192 and rs2157719 with glaucoma (Osman et al., 2012; Wiggs et al., 2012), rs4977756 with glioma (Rajaraman et al., 2012), rs10757269 with ankle-brachial index (Murabito et al., 2012), rs6475606 and rs10757272 with intracranial aneurysm (Foroud et al., 2012; Low et al., 2012), rs1537370 with coronary artery calcification (van Setten et al., 2013) and rs7865618, rs10757274, rs1333042 and rs944797 with coronary heart disease (Wild et al., 2011; Lu et al., 2012; Takeuchi et al., 2012; Lee et al., 2013); because of these diverse associations, its function is an area of research for many investigators. "
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    ABSTRACT: BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition.
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    • "Eleven transcripts were validated by both methods and hence show promise for follow-up studies (Additional file 2: Tables S7 and S8). Interestingly, this list included the human leukocyte antigen gene HLA-H, variation in which has been associated with CAD susceptibility [29]. "
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    ABSTRACT: Massively-parallel cDNA sequencing (RNA-Seq) is a new technique that holds great promise for cardiovascular genomics. Here, we used RNA-Seq to study the transcriptomes of matched coronary artery disease cases and controls in the ClinSeq(R) study, using cell lines as tissue surrogates. Lymphoblastoid cell lines (LCLs) from 16 cases and controls representing phenotypic extremes for coronary calcification were cultured and analyzed using RNA-Seq. All cell lines were then independently re-cultured and along with another set of 16 independent cases and controls, were profiled with Affymetrix microarrays to perform a technical validation of the RNA-Seq results. Statistically significant changes (p < 0.05) were detected in 186 transcripts, many of which are expressed at extremely low levels (5-10 copies/cell), which we confirmed through a separate spike-in control RNA-Seq experiment. Next, by fitting a linear model to exon-level RNA-Seq read counts, we detected signals of alternative splicing in 18 transcripts. Finally, we used the RNA-Seq data to identify differential expression (p < 0.0001) in eight previously unannotated regions that may represent novel transcripts. Overall, differentially expressed genes showed strong enrichment (p = 0.0002) for prior association with cardiovascular disease. At the network level, we found evidence for perturbation in pathways involving both cardiovascular system development and function as well as lipid metabolism. We present a pilot study for transcriptome involvement in coronary artery calcification and demonstrate how RNA-Seq analyses using LCLs as a tissue surrogate may yield fruitful results in a clinical sequencing project. In addition to canonical gene expression, we present candidate variants from alternative splicing and novel transcript detection, which have been unexplored in the context of this disease.
    Full-text · Article · Mar 2014 · BMC Genomics
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