Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes. Issue 3 (4th January 2023)

• Record Type: Journal Article
• Authors: Aherrahrou, Rédouane; Lue, Dillon; Perry, R. Noah; Aberra, Yonathan Tamrat; Khan, Mohammad Daud; Soh, Joon Yuhl; Örd, Tiit; Singha, Prosanta; Yang, Qianyi; Gilani, Huda; Benavente, Ernest Diez; Wong, Doris; Hinkle, Jameson; Ma, Lijiang; Sheynkman, Gloria M.; den Ruijter, Hester M.; Miller, Clint L.; Björkegren, Johan L.M.; Kaikkonen, Minna U.; Civelek, Mete
• Is Part Of: Circulation research. Volume 132:Issue 3(2023)
• Page Start: 323
• Page End: 338
• Publication Date: 2023-01-04
• Subjects: atherosclerosis -- coronary artery disease -- expression and splice quantitative trait loci -- gene expression -- smooth muscle cell; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.122.321586
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD loci associated with the regulation of transcription in distinct SMC phenotypes. Methods: We measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single-nucleotide polymorphism markers across the genome. Results: We identified 4910 expression and 4412 splicing quantitative trait loci (sQTLs) representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait loci (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC-specific and sex-biased, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 sQTL that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with a sex-specific eQTL ( TERF2IP ), and another locus colocalized with SMC-specific eQTL ( ALKBH8 ). The most significantly associated CAD locus, 9p21, was an sQTL for the long noncoding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. Conclusions: Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes.