Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

Heming Wang; Bärian E. Cade; Han Chen; Kevin J. Gleason; Richa Saxena; Tao Feng; Emma K. Larkin; Ramachandran S. Vasan; Honghuang Lin; Sanjay R. Patel; Russell P. Tracy; Yongmei Liu; Daniel J. Gottlieb; Jennifer E. Below; Craig L. Hanis; Lauren E. Petty; Shamil R. Sunyaev; Alexis C. Frazier-Wood; Jerome I. Rotter; Wendy Post; Xihong Lin; Susan Redline; Xiaofeng Zhu

doi:10.1093/hmg/ddw324

Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

Heming Wang, Bärian E. Cade, Han Chen, Kevin J. Gleason, Richa Saxena, Tao Feng, Emma K. Larkin, Ramachandran S. Vasan, Honghuang Lin, Sanjay R. Patel, Russell P. Tracy, Yongmei Liu, Daniel J. Gottlieb, Jennifer E. Below, Craig L. Hanis, Lauren E. Petty, Shamil R. Sunyaev, Alexis C. Frazier-Wood, Jerome I. Rotter, Wendy PostXihong Lin, Susan Redline, Xiaofeng Zhu

School of Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO₂) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO₂ is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD=4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO₂ (P=8×10^-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO₂. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P=1.29×10^-4), which was associated with SaO₂ (P=0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO₂, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.

Original language	English (US)
Pages (from-to)	5244-5253
Number of pages	10
Journal	Human molecular genetics
Volume	25
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddw324
State	Published - 2016

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddw324

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Wang, H., Cade, B. E., Chen, H., Gleason, K. J., Saxena, R., Feng, T., Larkin, E. K., Vasan, R. S., Lin, H., Patel, S. R., Tracy, R. P., Liu, Y., Gottlieb, D. J., Below, J. E., Hanis, C. L., Petty, L. E., Sunyaev, S. R., Frazier-Wood, A. C., Rotter, J. I., ... Zhu, X. (2016). Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level. Human molecular genetics, 25(23), 5244-5253. https://doi.org/10.1093/hmg/ddw324

Wang, H, Cade, BE, Chen, H, Gleason, KJ, Saxena, R, Feng, T, Larkin, EK, Vasan, RS, Lin, H, Patel, SR, Tracy, RP, Liu, Y, Gottlieb, DJ, Below, JE, Hanis, CL, Petty, LE, Sunyaev, SR, Frazier-Wood, AC, Rotter, JI, Post, W, Lin, X, Redline, S & Zhu, X 2016, 'Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level', Human molecular genetics, vol. 25, no. 23, pp. 5244-5253. https://doi.org/10.1093/hmg/ddw324

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title = "Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level",

abstract = "Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD=4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P=8×10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P=1.29×10-4), which was associated with SaO2 (P=0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.",

author = "Heming Wang and Cade, {B{\"a}rian E.} and Han Chen and Gleason, {Kevin J.} and Richa Saxena and Tao Feng and Larkin, {Emma K.} and Vasan, {Ramachandran S.} and Honghuang Lin and Patel, {Sanjay R.} and Tracy, {Russell P.} and Yongmei Liu and Gottlieb, {Daniel J.} and Below, {Jennifer E.} and Hanis, {Craig L.} and Petty, {Lauren E.} and Sunyaev, {Shamil R.} and Frazier-Wood, {Alexis C.} and Rotter, {Jerome I.} and Wendy Post and Xihong Lin and Susan Redline and Xiaofeng Zhu",

year = "2016",

doi = "10.1093/hmg/ddw324",

language = "English (US)",

volume = "25",

pages = "5244--5253",

journal = "Human molecular genetics",

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T1 - Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

AU - Wang, Heming

AU - Cade, Bärian E.

AU - Chen, Han

AU - Gleason, Kevin J.

AU - Saxena, Richa

AU - Feng, Tao

AU - Larkin, Emma K.

AU - Vasan, Ramachandran S.

AU - Lin, Honghuang

AU - Patel, Sanjay R.

AU - Tracy, Russell P.

AU - Liu, Yongmei

AU - Gottlieb, Daniel J.

AU - Below, Jennifer E.

AU - Hanis, Craig L.

AU - Petty, Lauren E.

AU - Sunyaev, Shamil R.

AU - Frazier-Wood, Alexis C.

AU - Rotter, Jerome I.

AU - Post, Wendy

AU - Lin, Xihong

AU - Redline, Susan

AU - Zhu, Xiaofeng

PY - 2016

Y1 - 2016

N2 - Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD=4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P=8×10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P=1.29×10-4), which was associated with SaO2 (P=0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.

AB - Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD=4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P=8×10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P=1.29×10-4), which was associated with SaO2 (P=0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.

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DO - 10.1093/hmg/ddw324

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AN - SCOPUS:85016048358

SN - 0964-6906

VL - 25

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JO - Human molecular genetics

JF - Human molecular genetics

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ER -

Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

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