Genetic Association Analyses Highlight IL6 , ALPL , and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis

Abstract

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

Phenome-wide analyses establish a specific association between aortic valve PALMD expression and calcific aortic valve stenosis

“…The stronger effect of predicted PALMD expression in the aortic valve on CAVS observed in women compared to men is consistent with the results reported for the lead variant rs6702619 in a recent GWAS meta-analysis 21 . Whether this phenomenon is due to sex-specific pathophysiological mechanisms remains unknown and needs further exploration.…”

“…The lead PALMD CAVS risk variant has also been associated with the presence of aortic stenosis in patients with a bicuspid aortic valve (BAV), a congenital anomaly more frequent in men 24 in which the aortic valve has two cusps instead of three, and with aortic root diameter in patients with a tricuspid valve 8 . We showed previously a similar effect on the risk of CAVS when restricting to patients with a tricuspid or a bicuspid valve 21 , suggesting that the risk is not mediated through BAV.…”

“…The underlying process explaining tissue-type specificity with CAVS despite a wide expression of PALMD is likely multifactorial and could involve tissue-specific regulation by transcription factors, tissue-restricted post-transcriptional processes, tissue-specific networks and redundancy of biological function by paralogues 20 . Our previous analysis has identified rs6702619, located 65 kb from the transcriptional start site of PALMD , as the most likely causal variant at this locus 21 . Loss-of-function coding variants in PALMD are rare (all frequencies <1 × 10 −4 ).…”

“…Samples with call rate <95%, outlier heterozygosity rate, gender mismatch, non-white British ancestry, related samples (second degree or closer), samples with excess third-degree relatives (>10), or not used for relatedness calculation were excluded. CAVS diagnosis was determined using diagnoses and procedure codes as previously described 21 . Briefly, CAVS was defined as ICD10 code number I35.0 or I35.2.…”

“…To evaluate the effect of the PALMD genetically-determined expression in the aortic valve, we performed a phenome-wide association study (pheWAS) in 353,378 European individuals from the UK Biobank, as preformed previously 21 . Briefly, we selected 852 phenotypes, including anthropometric traits, health questionnaires, International Classification of Diseases 10th Revision (ICD10) diagnostic codes, Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, 4th Revision (OPCS-4) procedure codes, diagnostic procedure codes and laboratory markers (Supplementary Data 2 ).…”