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.

Angiopoietin-2 gene polymorphisms are biomarkers for the development and progression of colorectal cancer in Han Chinese

“…An American study that evaluated genetic associations between 17 candidate genes, including Angpt2, and the development of lymphedema following treatment for breast cancer concluded that Ang2 rs1823375 has no significant involvement in lymphangiogenesis or angiogenesis [18]. Previous studies have reported that Angpt2 gene polymorphisms are associated with sleep-disordered breathing [25] and lung injury syndrome [13,26,27], indicating that Angpt2 could be a biomarker for lung disease. Another study, in an African American cohort, has reported that two SNPs in Angpt2 (rs1868554 and rs2442598) are significantly associated with acute lung injury pathogenesis and susceptibility [13].…”

Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

“…Treatment options, however, are limited by a lack of knowledge of molecular pathways, including those that may be "druggable". Recent analyses of SDB traits have focused on common variants and identified several preliminary genome-level significant associations using GWAS, admixture mapping, and linkage approaches [ [11][12][13][14][15] ], but did not address gene-based or rare variant effects. Ten studies and over 21,000 individuals of multiple ancestries with WGS data at unprecedented resolution from the NHLBI TOPMed program combined with densely imputed data from other sources contributed to these results.…”

“…Therefore, there is a critical need to identify molecular pathways that could provide specific therapeutic targets. The need for overnight studies to phenotype SDB traits has limited the available sample size for genetic analyses, and only several common-frequency genome-wide analysis studies have been reported [11][12][13][14][15]. Increased statistical power may increase the genetic resolution of regions that may not be adequately tagged by current genotyping arrays due to population differences and/or reduced linkage disequilibrium with biologically relevant regions [ 16 ].…”

Update in Sleep-disordered Breathing 2016

“…The same group of authors used linkage analysis in the Cleveland Family Study to identify a strong association between polymorphism in the angiopoietin-2 gene (ANGPT2), an endothelial factor modulating vascular and inflammatory responses, and mean nocturnal Sa O 2 (9). Future large genetic studies are needed to replicate these findings (6).…”