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Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.

ABSTRACT: Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

SUBMITTER: de Vries PS

PROVIDER: S-EPMC11138106 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.

de Vries Paul S PS Conomos Matthew P MP Singh Kuldeep K Nicholson Christopher J CJ Jain Deepti D Hasbani Natalie R NR Jiang Wanlin W Lee Sujin S Lino Cardenas Christian L CL Lutz Sharon M SM Wong Doris D Guo Xiuqing X Yao Jie J Young Erica P EP Tcheandjieu Catherine C Hilliard Austin T AT Bis Joshua C JC Bielak Lawrence F LF Brown Michael R MR Musharoff Shaila S Clarke Shoa L SL Terry James G JG Palmer Nicholette D ND Yanek Lisa R LR Xu Huichun H Heard-Costa Nancy N Wessel Jennifer J Selvaraj Margaret Sunitha MS Li Rebecca H RH Sun Xiao X Turner Adam W AW Stilp Adrienne M AM Khan Alyna A Newman Anne B AB Rasheed Asif A Freedman Barry I BI Kral Brian G BG McHugh Caitlin P CP Hodonsky Chani C Saleheen Danish D Herrington David M DM Jacobs David R DR Nickerson Deborah A DA Boerwinkle Eric E Wang Fei Fei FF Heiss Gerardo G Jun Goo G Kinney Greg L GL Sigurslid Haakon H HH Doddapaneni HarshaVardhan H Hall Ira M IM Bensenor Isabela M IM Broome Jai J Crapo James D JD Wilson James G JG Smith Jennifer A JA Blangero John J Vargas Jose D JD Mosquera Jose Verdezoto JV Smith Joshua D JD Viaud-Martinez Karine A KA Ryan Kathleen A KA Young Kendra A KA Taylor Kent D KD Lange Leslie A LA Emery Leslie S LS Bittencourt Marcio S MS Budoff Matthew J MJ Montasser May E ME Yu Miao M Mahaney Michael C MC Mahamdeh Mohammed S MS Fornage Myriam M Franceschini Nora N Lotufo Paulo A PA Natarajan Pradeep P Wong Quenna Q Mathias Rasika A RA Gibbs Richard A RA Do Ron R Mehran Roxana R Tracy Russell P RP Kim Ryan W RW Nelson Sarah C SC Damrauer Scott M SM Kardia Sharon L R SLR Rich Stephen S SS Fuster Valentin V Napolioni Valerio V Zhao Wei W Tian Wenjie W Yin Xianyong X Min Yuan-I YI Manning Alisa K AK Peloso Gina G Kelly Tanika N TN O'Donnell Christopher J CJ Morrison Alanna C AC Curran Joanne E JE Zapol Warren M WM Bowden Donald W DW Becker Lewis C LC Correa Adolfo A Mitchell Braxton D BD Psaty Bruce M BM Carr John Jeffrey JJ Pereira Alexandre C AC Assimes Themistocles L TL Stitziel Nathan O NO Hokanson John E JE Laurie Cecelia A CA Rotter Jerome I JI Vasan Ramachandran S RS Post Wendy S WS Peyser Patricia A PA Miller Clint L CL Malhotra Rajeev R

Nature cardiovascular research 20231204 12

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (<i>ARSE</i> and <i>MMP16</i>), with evidence of significant associations in replication analyses for both novel loci. Functional assays o ...[more]

PMID: 38817323

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Project description:BackgroundVascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models.Study designCohort analysis of clinical trial participants.Setting & participants112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m2) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification.PredictorSerum deoxycholic acid concentration.OutcomesBaseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months.MeasurementsDeoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density.ResultsHigher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (β=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (β = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (β=0.06; 95% CI, -0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered.LimitationsThe use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time.ConclusionsAmong patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD.

Project description:BackgroundGenome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.ObjectivesThis study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.MethodsIn discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.ResultsWe identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits.ConclusionsWe identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Dataset Information

Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.

Publications

Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.

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