TY - JOUR
T1 - Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes
AU - Aherrahrou, Rédouane
AU - Lue, Dillon
AU - Perry, R. Noah
AU - Aberra, Yonathan Tamrat
AU - Khan, Mohammad Daud
AU - Soh, Joon Yuhl
AU - Örd, Tiit
AU - Singha, Prosanta
AU - Yang, Qianyi
AU - Gilani, Huda
AU - Benavente, Ernest Diez
AU - Wong, Doris
AU - Hinkle, Jameson
AU - Ma, Lijiang
AU - Sheynkman, Gloria M.
AU - Den Ruijter, Hester M.
AU - Miller, Clint L.
AU - Björkegren, Johan L.M.
AU - Kaikkonen, Minna U.
AU - Civelek, Mete
N1 - Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/2/3
Y1 - 2023/2/3
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - coronary artery disease
KW - expression and splice quantitative trait loci
KW - gene expression
KW - smooth muscle cell
UR - http://www.scopus.com/inward/record.url?scp=85147307414&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.122.321586
DO - 10.1161/CIRCRESAHA.122.321586
M3 - Article
C2 - 36597873
AN - SCOPUS:85147307414
SN - 0009-7330
VL - 132
SP - 323
EP - 338
JO - Circulation Research
JF - Circulation Research
IS - 3
ER -