Dataset Information

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

ABSTRACT:

Aims

Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

Methods and results

We tested for epistatic interactions in 10 CAD case-control studies and UK Biobank with focus on 8068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD [odds ratio (OR) = 1.37, P = 1.07 × 10-11], peripheral arterial disease (OR = 1.22, P = 2.32 × 10-4), aortic stenosis (OR = 1.47, P = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, P = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, P = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, P = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

Conclusions

These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

SUBMITTER: Zeng L

PROVIDER: S-EPMC8930071 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Zeng Lingyao L Moser Sylvain S Mirza-Schreiber Nazanin N Lamina Claudia C Coassin Stefan S Nelson Christopher P CP Annilo Tarmo T Franzén Oscar O Kleber Marcus E ME Mack Salome S Andlauer Till F M TFM Jiang Beibei B Stiller Barbara B Li Ling L Willenborg Christina C Munz Matthias M Kessler Thorsten T Kastrati Adnan A Laugwitz Karl-Ludwig KL Erdmann Jeanette J Moebus Susanne S Nöthen Markus M MM Peters Annette A Strauch Konstantin K Müller-Nurasyid Martina M Gieger Christian C Meitinger Thomas T Steinhagen-Thiessen Elisabeth E März Winfried W Metspalu Andres A Björkegren Johan L M JLM Samani Nilesh J NJ Kronenberg Florian F Müller-Myhsok Bertram B Schunkert Heribert H

Cardiovascular research 20220301 4

<h4>Aims</h4>Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.<h4>Methods and results</h4>We tested fo ...[more]

PMID: 33878186

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Project description:BackgroundCoronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown.MethodsWe performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus.ResultsThe meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes.ConclusionsGenetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Project description:Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention. To determine whether a genetic risk score (GRS) comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement. The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, an LPA GRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020. Measured lipoprotein(a) and LPA GRS. We estimated the associations between measured lipoprotein(a) and LPA GRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) and LPA GRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively). The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). The LPA GRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) and LPA GRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33; P < .001). The association between LPA GRS and ASCVD was substantially attenuated after adjusting for measured lipoprotein(a). Adding measured lipoprotein(a) or LPA GRS to QRISK3 provided modest improvements to the risk discrimination of incident ASCVD events (area under the receiver operating curve, 0.640; 95% CI, 0.633-0.647 vs 0.642; 95% CI, 0.635-0.649 for both; P = .005 and P = .01, respectively). When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.

Project description:The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease, accounting for ~10-15% of disease among non-African populations. The ~60kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Genetic studies implicate the 9p21.3 locus and other risk genes to effects in the vascular wall. Here, we use genome editing to delete the entire risk on non-risk haplotype from the genomes of human iPSCs and perform genomewide transcriptional profiling along the timecourse of their differentiation into vascular smooth muscle cells (VSMCs). These studies identify a network of ~3000 genes governed by the risk haplotype in VSMCs that predict deficits in cell division, adhesion and contraction, which we confirmufunctionally. Remarkably, deleting the risk haplotype reverts VSMCs to resemble the non-risk VSMCs, suggesting that the risk region drives a cell state transition. transcriptionally and functionally. . Deleting the risk haplotype reverts these cells to reverted to the non-risk of iPSCs we show that the non-risk haplotype has little effect on locus we produce iPSCs from risk and non-risk individuals, delete each haplotype using genome editing and generate vascular smooth muscle cells (VSMCs). We show that risk VSMCs exhibit aberrant adhesion and contraction, concomitant with dramatically altered global transcriptional changes that are enriched in previously identified cardiovascular disease genes and pathways. Unexpectedly, deleting the risk haplotype rescues VSMC transcriptional identity and function, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This studies shows that the risk haplotype dominantly predisposes VSMCs to adopt perturbed phenotypes associated with cardiovascular disease and establishes haplotype-edited iPSCs as powerful tools for functionally annotating human-specific variation in non-coding genomic regions.

Project description:Background and aimsOne of the most common causes of death worldwide is cardiovascular diseases (CVDs). This study evaluated the prevalence of CVDs risk factors (RFs) and their constellation electively among the Jordanian population and, assessing the most prevalent RF interplay with the rest of CVDs RFs as well as the impact of age and gender dimorphism on the frequencies of coexistence of multiple CVDs risk factors (RFs) among the Jordanian population.Methods and resultsIn this observational multicenter study, a total of 1449 subjects were enrolled. The mean age (±SD) was 44.35 ± 14.46 years; 796 (54.9%) of them were females and 801 (55.28%) of the whole study pool had no family history of premature CVDs. Only 5.9% of the population did not have any of these RFs. The prevalence of CVDs MRFs within-affected subjects was as follows: there were 1081 (74.6%) subjects with overall dyslipidemia, 471 (32.51%) with obesity, 456 (31.47%) were smokers, and at the first diagnostic encounter 541 (37.47%) were with elevated blood pressure and, 310 (21.51%) were with elevated random blood sugar. The coexistence of ≥ two, ≥ three and, ≥ four RFs was observed in 75.7%, 44.4%, and 21.4% of the subjects, respectively. The constellation of multiple RFs was more frequent in men than that in women, where the presence of ≥ two RFs for men was at 86.18% vs. 67.09% for women. Similarly, the appearance of multiple RFs increases with age, starting from the existence of ≥ three, and four RFs respectively. Most notably the clustering of ≥ five RFs in the age group of 45-59 years showed the greatest frequency vs. any other age group.ConclusionsCVDs risk factors (RFs) and clusters of them are extremely prevalent in the Jordanian population. Overall dyslipidemia is the most prevalent MRF and the most favors clustering with other CVDs RFs. Combined two RFs had the highest proportional frequency between all six RFs clusters. The constellation of at least two, three, and four CVDs RFs presented at almost three-fourth, half, and around one-fourth; respectively, Middle-aged males presented significantly higher rates of ≥ five RFs occurrences than females.

Project description:Susceptibility loci identified by GWAS generally account for a limited fraction of heritability. Predictive models based on identified loci also have modest success in risk assessment and therefore are of limited practical use. Many methods have been developed to overcome these limitations by incorporating prior biological knowledge. However, most of the information utilized by these methods is at the level of genes, limiting analyses to variants that are in or proximate to coding regions. We propose a new method that integrates protein protein interaction (PPI) as well as expression quantitative trait loci (eQTL) data to identify sets of functionally related loci that are collectively associated with a trait of interest. We call such sets of loci "population covering locus sets" (PoCos). The contributions of the proposed approach are three-fold: 1) We consider all possible genotype models for each locus, thereby enabling identification of combinatorial relationships between multiple loci. 2) We develop a framework for the integration of PPI and eQTL into a heterogenous network model, enabling efficient identification of functionally related variants that are associated with the disease. 3) We develop a novel method to integrate the genotypes of multiple loci in a PoCo into a representative genotype to be used in risk assessment. We test the proposed framework in the context of risk assessment for seven complex diseases, type 1 diabetes (T1D), type 2 diabetes (T2D), psoriasis (PS), bipolar disorder (BD), coronary artery disease (CAD), hypertension (HT), and multiple sclerosis (MS). Our results show that the proposed method significantly outperforms individual variant based risk assessment models as well as the state-of-the-art polygenic score. We also show that incorporation of eQTL data improves the performance of identified POCOs in risk assessment. We also assess the biological relevance of PoCos for three diseases that have similar biological mechanisms and identify novel candidate genes. The resulting software is publicly available at http://compbio.Caseedu/pocos/.

Dataset Information

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Aims

Methods and results

Conclusions

Publications

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Similar Datasets

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