Susceptibility Locus for Pregnancy-Associated Spontaneous Coronary Artery Dissection.
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ABSTRACT:
SUBMITTER: Turley TN
PROVIDER: S-EPMC8375625 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Susceptibility Locus for Pregnancy-Associated Spontaneous Coronary Artery Dissection.
Turley Tamiel N TN Kosel Matthew L ML Bamlet William R WR Gulati Rajiv R Hayes Sharonne N SN Tweet Marysia S MS Olson Timothy M TM
Circulation. Genomic and precision medicine 20210813 4
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Project description:ImportanceSpontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.ObjectiveTo identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility.Design, setting, and participantsThis single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019.Main outcomes and measuresGenetic loci and positional candidate genes associated with SCAD.ResultsThis study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1).Conclusions and relevanceThis study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
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Project description:ImportanceSpontaneous coronary artery dissection (SCAD) is a notable cause of acute coronary syndrome in women of childbearing age.ObjectiveTo test the hypothesis that pregnancy after SCAD is associated with recurrent SCAD.Design, setting, and participantsThree study designs were implemented: a case series of women with pregnancy after SCAD; a nested case-control study comparing patients with recurrent SCAD to matched controls without recurrent SCAD; and a cohort study. Women with SCAD who were of childbearing potential and enrolled into the Mayo Clinic SCAD Registry from August 30, 2011, to April 4, 2019, were included in the study. Patients with coronary dissections associated with iatrogenesis, trauma, or atherosclerosis were not enrolled.ExposuresPregnancy after SCAD.Main outcomes and measuresThe primary outcome was SCAD recurrence, defined as an acute coronary syndrome or cardiac arrest due to new SCAD. Other demographic measures collected included age, year of SCAD occurrence, and comorbidities.ResultsThe cohort included 636 women of childbearing potential. Twenty-three of those women had a total of 32 pregnancies after SCAD. The median (interquartile range) age of women with pregnancy after SCAD was 38 years (34-40 years), and 20 (87%) were White. In the nested case-control study, 92 cases of recurrent SCAD were matched to 158 controls. There was no significant difference in exposure to subsequent pregnancies in the women with recurrent SCAD as compared with matched controls (2 of 92 [2%] vs 13 of 158 [8%]; P = .06). In the overall cohort of 636 patients, recurrent SCAD was present in 122 patients with a Kaplan-Meier 5-year SCAD recurrence estimate of 14.8%. The Cox analysis showed no significant association between subsequent pregnancy and SCAD recurrence with a nonsignificant hazard ratio of 0.38 (95% CI, 0.09-1.6) when controlling for age at first SCAD, year of first SCAD, and fibromuscular dysplasia.Conclusions and relevanceThis study found that most women tolerated pregnancy and lactation after SCAD without evidence for increased risk of SCAD recurrence when compared with women with a history of SCAD who did not experience pregnancy. Although this study is reassuring and indicates complex contributors to SCAD recurrence, the results need to be interpreted prudently because of study selection bias and the small total number of women who became pregnant after SCAD. The notable hemodynamic changes that occur with pregnancy and severe presentation of pregnancy-associated SCAD are reasons for concern when considering pregnancy after SCAD.
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Project description:BackgroundSpontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.ObjectivesThis study sought to test the association between the rs9349379 genotype and SCAD.MethodsResults from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.ResultsThe previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.ConclusionsThe first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
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