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From genotype to phenotype in human atherosclerosis--recent findings.

Holdt LM, Teupser D - Curr. Opin. Lipidol. (2013)

Bottom Line: The vast majority of the remaining 35 loci (60%) are at genomic regions where the mechanism in atherogenesis is unclear.Loci most frequently found in independent GWAS were at Chr9p21.3 (ANRIL/CDKN2B-AS1), Chr6p24.1 (PHACTR1), and Chr1p13.3 (CELSR2, PSRC1, MYBPHL, SORT1).Recent work suggests that Chr9p21.3 exerts its effects through epigenetic regulation of target genes, whereas mechanisms at Chr6p24.1 remain obscure, and Chr1p13.3 affects plasma LDL cholesterol.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Medicine, University Hospital Munich-LMU and Ludwig-Maximilians-University Munich, Munich, Germany.

ABSTRACT

Purpose of review: Since 2007, genome-wide association studies (GWAS) have led to the identification of numerous loci of atherosclerotic cardiovascular disease. The majority of these loci harbor genes previously not known to be involved in atherogenesis. In this review, we summarize the recent progress in understanding the pathophysiology of genetic variants in atherosclerosis.

Recent findings: Fifty-eight loci with P < 10⁻⁷ have been identified in GWAS for coronary heart disease and myocardial infarction. Of these, 23 loci (40%) overlap with GWAS loci of classical risk factors such as lipids, blood pressure, and diabetes mellitus, suggesting a potential causal relation. The vast majority of the remaining 35 loci (60%) are at genomic regions where the mechanism in atherogenesis is unclear. Loci most frequently found in independent GWAS were at Chr9p21.3 (ANRIL/CDKN2B-AS1), Chr6p24.1 (PHACTR1), and Chr1p13.3 (CELSR2, PSRC1, MYBPHL, SORT1). Recent work suggests that Chr9p21.3 exerts its effects through epigenetic regulation of target genes, whereas mechanisms at Chr6p24.1 remain obscure, and Chr1p13.3 affects plasma LDL cholesterol.

Summary: Novel GWAS loci indicate that our understanding of atherosclerosis is limited and implicate a role of hitherto unknown mechanisms, such as epigenetic gene regulation in atherogenesis.

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Related in: MedlinePlus

Haplotype analysis (HapMap CEU) and annotated genes at the three most frequently identified loci for coronary heart disease (CHD) and myocardial infarction (MI). Single-nucleotide polymorphisms with strongest signals of the respective phenotype and corresponding references are given. (a) Chr9p21.3 CHD and MI locus and adjacent hits for cancer, diabetes, and other traits. (b) Chr6p24.1 CHD and MI locus overlapping with migraine. Significance of pulse pressure and femoral neck width loci is unclear. (c) Chr1p13.3 CHD and MI locus co-segregating with genome-wide association studies (GWAS) hits for lipids.
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Figure 2: Haplotype analysis (HapMap CEU) and annotated genes at the three most frequently identified loci for coronary heart disease (CHD) and myocardial infarction (MI). Single-nucleotide polymorphisms with strongest signals of the respective phenotype and corresponding references are given. (a) Chr9p21.3 CHD and MI locus and adjacent hits for cancer, diabetes, and other traits. (b) Chr6p24.1 CHD and MI locus overlapping with migraine. Significance of pulse pressure and femoral neck width loci is unclear. (c) Chr1p13.3 CHD and MI locus co-segregating with genome-wide association studies (GWAS) hits for lipids.

Mentions: Chr9p21.3 is the most replicated locus of human atherosclerosis (reviewed in [30,31]). The locus lacks associations with common cardiovascular risk factors suggesting that it exerts its effect through an alternative mechanism. The core risk haplotype spans approximately 50 kb [10▪▪,19,22,32–47] (Fig. 2a) and does not contain protein-coding genes but the 3′end of the long ncRNA antisense noncoding RNA in the INK4 locus (ANRIL). The synonyms CDKN2B antisense RNA 1 (CDKN2B-AS1) and CDKN2BAS are used for ANRIL and refer to its antisense orientation to cyclin-dependent kinase inhibitor 2B (CDKN2B), which is located proximal to the core CHD region. Together with CDKN2A, which is located further proximal of ANRIL, this region depicts a GWAS hotspot for different tumor entities [30,34–37] and other phenotypes [32,33], which is in line with loss of function of these genes in many human cancers (Fig. 2a) [48]. In an adjacent haplotype block, an independent locus for diabetes was identified [41]. Despite their expression in human plaques [49], several lines of evidence argue against a role of CDKN2A and CDKN2B as major Chr9p21.3 effector genes. First, SNPs within these genes are not in linkage disequilibrium with the lead CHD SNPs (Fig. 2a). Second, cis-regulation of these genes is lacking in the majority of human studies (reviewed in [30]). Third, mouse models speak against a causal role of CDKN2B in atherogenesis [50▪,51] and yielded conflicting results for CDKN2A[50▪,52–54].


From genotype to phenotype in human atherosclerosis--recent findings.

Holdt LM, Teupser D - Curr. Opin. Lipidol. (2013)

Haplotype analysis (HapMap CEU) and annotated genes at the three most frequently identified loci for coronary heart disease (CHD) and myocardial infarction (MI). Single-nucleotide polymorphisms with strongest signals of the respective phenotype and corresponding references are given. (a) Chr9p21.3 CHD and MI locus and adjacent hits for cancer, diabetes, and other traits. (b) Chr6p24.1 CHD and MI locus overlapping with migraine. Significance of pulse pressure and femoral neck width loci is unclear. (c) Chr1p13.3 CHD and MI locus co-segregating with genome-wide association studies (GWAS) hits for lipids.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814939&req=5

Figure 2: Haplotype analysis (HapMap CEU) and annotated genes at the three most frequently identified loci for coronary heart disease (CHD) and myocardial infarction (MI). Single-nucleotide polymorphisms with strongest signals of the respective phenotype and corresponding references are given. (a) Chr9p21.3 CHD and MI locus and adjacent hits for cancer, diabetes, and other traits. (b) Chr6p24.1 CHD and MI locus overlapping with migraine. Significance of pulse pressure and femoral neck width loci is unclear. (c) Chr1p13.3 CHD and MI locus co-segregating with genome-wide association studies (GWAS) hits for lipids.
Mentions: Chr9p21.3 is the most replicated locus of human atherosclerosis (reviewed in [30,31]). The locus lacks associations with common cardiovascular risk factors suggesting that it exerts its effect through an alternative mechanism. The core risk haplotype spans approximately 50 kb [10▪▪,19,22,32–47] (Fig. 2a) and does not contain protein-coding genes but the 3′end of the long ncRNA antisense noncoding RNA in the INK4 locus (ANRIL). The synonyms CDKN2B antisense RNA 1 (CDKN2B-AS1) and CDKN2BAS are used for ANRIL and refer to its antisense orientation to cyclin-dependent kinase inhibitor 2B (CDKN2B), which is located proximal to the core CHD region. Together with CDKN2A, which is located further proximal of ANRIL, this region depicts a GWAS hotspot for different tumor entities [30,34–37] and other phenotypes [32,33], which is in line with loss of function of these genes in many human cancers (Fig. 2a) [48]. In an adjacent haplotype block, an independent locus for diabetes was identified [41]. Despite their expression in human plaques [49], several lines of evidence argue against a role of CDKN2A and CDKN2B as major Chr9p21.3 effector genes. First, SNPs within these genes are not in linkage disequilibrium with the lead CHD SNPs (Fig. 2a). Second, cis-regulation of these genes is lacking in the majority of human studies (reviewed in [30]). Third, mouse models speak against a causal role of CDKN2B in atherogenesis [50▪,51] and yielded conflicting results for CDKN2A[50▪,52–54].

Bottom Line: The vast majority of the remaining 35 loci (60%) are at genomic regions where the mechanism in atherogenesis is unclear.Loci most frequently found in independent GWAS were at Chr9p21.3 (ANRIL/CDKN2B-AS1), Chr6p24.1 (PHACTR1), and Chr1p13.3 (CELSR2, PSRC1, MYBPHL, SORT1).Recent work suggests that Chr9p21.3 exerts its effects through epigenetic regulation of target genes, whereas mechanisms at Chr6p24.1 remain obscure, and Chr1p13.3 affects plasma LDL cholesterol.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Medicine, University Hospital Munich-LMU and Ludwig-Maximilians-University Munich, Munich, Germany.

ABSTRACT

Purpose of review: Since 2007, genome-wide association studies (GWAS) have led to the identification of numerous loci of atherosclerotic cardiovascular disease. The majority of these loci harbor genes previously not known to be involved in atherogenesis. In this review, we summarize the recent progress in understanding the pathophysiology of genetic variants in atherosclerosis.

Recent findings: Fifty-eight loci with P < 10⁻⁷ have been identified in GWAS for coronary heart disease and myocardial infarction. Of these, 23 loci (40%) overlap with GWAS loci of classical risk factors such as lipids, blood pressure, and diabetes mellitus, suggesting a potential causal relation. The vast majority of the remaining 35 loci (60%) are at genomic regions where the mechanism in atherogenesis is unclear. Loci most frequently found in independent GWAS were at Chr9p21.3 (ANRIL/CDKN2B-AS1), Chr6p24.1 (PHACTR1), and Chr1p13.3 (CELSR2, PSRC1, MYBPHL, SORT1). Recent work suggests that Chr9p21.3 exerts its effects through epigenetic regulation of target genes, whereas mechanisms at Chr6p24.1 remain obscure, and Chr1p13.3 affects plasma LDL cholesterol.

Summary: Novel GWAS loci indicate that our understanding of atherosclerosis is limited and implicate a role of hitherto unknown mechanisms, such as epigenetic gene regulation in atherogenesis.

Show MeSH
Related in: MedlinePlus