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Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.

Publication ,  Journal Article
Liang, J; Wang, H; Cade, BE; Kurniansyah, N; He, KY; Lee, J; Sands, SA; A Brody, J; Chen, H; Gottlieb, DJ; Evans, DS; Guo, X; Gharib, SA ...
Published in: Am J Respir Crit Care Med
November 15, 2022

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 × 10-8). These noncoding variants together significantly contributed to the linkage evidence (P < 10-3). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

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Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

November 15, 2022

Volume

206

Issue

10

Start / End Page

1271 / 1280

Location

United States

Related Subject Headings

  • Sleep Apnea, Obstructive
  • Sequence Analysis, DNA
  • Respiratory System
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Caveolin 1
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 11 Medical and Health Sciences
 

Citation

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Liang, J., Wang, H., Cade, B. E., Kurniansyah, N., He, K. Y., Lee, J., … TOPMed Sleep Working Group, . (2022). Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. Am J Respir Crit Care Med, 206(10), 1271–1280. https://doi.org/10.1164/rccm.202203-0618OC
Liang, Jingjing, Heming Wang, Brian E. Cade, Nuzulul Kurniansyah, Karen Y. He, Jiwon Lee, Scott A. Sands, et al. “Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.Am J Respir Crit Care Med 206, no. 10 (November 15, 2022): 1271–80. https://doi.org/10.1164/rccm.202203-0618OC.
Liang J, Wang H, Cade BE, Kurniansyah N, He KY, Lee J, et al. Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2022 Nov 15;206(10):1271–80.
Liang, Jingjing, et al. “Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.Am J Respir Crit Care Med, vol. 206, no. 10, Nov. 2022, pp. 1271–80. Pubmed, doi:10.1164/rccm.202203-0618OC.
Liang J, Wang H, Cade BE, Kurniansyah N, He KY, Lee J, Sands SA, A Brody J, Chen H, Gottlieb DJ, Evans DS, Guo X, Gharib SA, Hale L, Hillman DR, Lutsey PL, Mukherjee S, Ochs-Balcom HM, Palmer LJ, Purcell S, Saxena R, Patel SR, Stone KL, Tranah GJ, Boerwinkle E, Lin X, Liu Y, Psaty BM, Vasan RS, Manichaikul A, Rich SS, Rotter JI, Sofer T, Redline S, Zhu X, TOPMed Sleep Working Group. Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2022 Nov 15;206(10):1271–1280.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

November 15, 2022

Volume

206

Issue

10

Start / End Page

1271 / 1280

Location

United States

Related Subject Headings

  • Sleep Apnea, Obstructive
  • Sequence Analysis, DNA
  • Respiratory System
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Caveolin 1
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 11 Medical and Health Sciences