What is the clinical evidence from this study?

Study design: Case-Control. Population: Calcific aortic valve stenosis (n=2026). Intervention: PALMD risk variant rs6702619 vs. Reference allele. Primary outcome: Risk of calcific aortic valve stenosis (OR 1.29, 95% CI 1.14-1.46, p=6.12e-05).

March 1, 2018Open Access

A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis

STSébastien ThériaultStructural Heart Disease NGNathalie GaudreaultInstitut Universitaire de Cardiologie et de Pneumologie de Québec MLMaxime LamontagneBrigham and Women's Hospital

Key Result

The PALMD risk variant rs6702619 was significantly associated with an increased risk of calcific aortic valve stenosis (OR 1.29) and decreased mRNA expression levels of PALMD in valve tissues.

Study Design

Type

Case-Control (n=2,026)

Multicenter

Yes

Structured PICO

Are genetic variants in PALMD associated with susceptibility to calcific aortic valve stenosis?

Population

2,026 patients (1,009 with severe calcific aortic valve stenosis and 1,017 controls without CAVS) from Canada, with replication in the UK Biobank.

Comparator

Controls without calcific aortic valve stenosis

Outcome

Genetic susceptibility to calcific aortic valve stenosis (CAVS)surrogate

The identification of PALMD as a susceptibility gene for calcific aortic valve stenosis provides new insights into the genetic etiology of the disease.

Main Result

Odds Ratio: 1.29 (95% CI 1.14–1.46)

p-value: p=6.12e-05

Limitations

Only individuals of European ancestry were included, limiting generalizability to other ethnic groups.
Power in the GWAS analysis was limited by the number of available samples.
Aortic valve tissue was only available in stenotic valves, so patterns of expression in normal valves might differ.

Abstract

Abstract Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues ( n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS ( P = 1.53 × 10 −10 ) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options.

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Cite This Study

Thériault et al. (Thu,) conducted a case-control in Calcific aortic valve stenosis (n=2,026). PALMD risk variant rs6702619 vs. Reference allele was evaluated on Risk of calcific aortic valve stenosis (OR 1.29, 95% CI 1.14-1.46, p=6.12e-05). The PALMD risk variant rs6702619 was significantly associated with an increased risk of calcific aortic valve stenosis (OR 1.29) and decreased mRNA expression levels of PALMD in valve tissues.

synapsesocial.com/papers/6a5ac571375350ccdbf699f2 https://doi.org/https://doi.org/10.1038/s41467-018-03260-6

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