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medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 Pathway-specific Polygenic Risk Scores (PRS) identify OSA-related pathways 2 differentially moderating genetic susceptibility to CAD 3 Goodman: Pathway-specific effects of OSA on genetic CAD risk 4 Matthew O Goodman,1,2,3 Brian E Cade,1,2,3 Neomi Shah,4 Tianyi Huang,2,5 Hassan S Dashti,3,6,7 5 Richa Saxena,1,2,3,6,7 Martin K Rutter,8,9 Peter Libby,10 Tamar Sofer,1,2 Susan Redline1,2 6 Affiliations: 7 1Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard 8 Medical School, Boston, MA 9 2Division of Sleep Medicine, Harvard Medical School, Boston, MA 10 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA 11 4Icahn School of Medicine at Mount Sinai, New York, NY 12 5Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical 13 School, Boston, MA 14 6Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA 15 7Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital 16 and Harvard Medical School, Boston, MA, USA 17 8Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, 18 Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic 19 Health Science Centre, Manchester, United Kingdom 20 9Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation 21 Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom 22 10Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's 23 Hospital, Harvard Medical School, Boston, MA, USA. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 Corresponding Author: 2 Matthew Goodman 3 Brigham and Women’s Hospital 4 221 Longwood Avenue 5 Boston, MA 02115 6 (617) 525-9767 7 [email protected] 8 9 Total word count: 8867 (including the title page, abstract, text, references, tables, and figures 10 legends) medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 ABSTRACT 2 Background— 3 Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia (IH), may 4 differentially affect specific molecular pathways and processes in the pathogenesis of coronary 5 artery disease (CAD) and influence the subsequent risk and severity of CAD events. In 6 particular, competing adverse (e.g. inflammatory) and protective (e.g. increased coronary 7 collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize 8 that common genetic variation in selected molecular pathways influences the likelihood of CAD 9 events differently in individuals with and without OSA, in a pathway-dependent manner. 10 Methods— 11 We selected a cross-sectional sample of 471,877 participants from the UK Biobank, 12 among whom we ascertained 4,974 to have OSA, 25,988 to have CAD, and 711 to have both. 13 We calculated pathway-specific polygenic risk scores (PS-PRS) for CAD, based on 6.6 million 14 common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study 15 (GWAS), annotated to specific genes and pathways using functional genomics databases. Based 16 on prior evidence of involvement with IH and CAD, we tested PS-PRS for the HIF-1, VEGF, 17 NFkB and TNF signaling pathways. 18 Results— 19 In a multivariable-adjusted logistic generalized additive model, elevated PS-PRSs for the 20 KEGG VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds 21 ratio 0.86, p = 6E-04). By contrast, the genome-wide CAD PRS did not show evidence of 22 statistical interaction with OSA. 23 Conclusions— medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 2 We find evidence that pathway-specific genetic risk of CAD differs between individuals with 3 and without OSA in a qualitatively pathway-dependent manner, consistent with the previously 4 studied phenomena whereby features of OSA may have both positive and negative effects on 5 CAD. These results provide evidence that gene-by-environment interaction influences CAD risk 6 in certain pathways among people with OSA, an effect that is not well-captured by the genome- 7 wide PRS. These results can be followed up to study how OSA interacts with genetic risk at the 8 molecular level, and potentially to personalize OSA treatment and reduce CAD risk according to 9 individual pathway-specific genetic risk profiles. 10 medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 INTRODUCTION 2 Obstructive sleep apnea (OSA) is a common disorder characterized by recurrent episodes 3 of hypoxemia during sleep, sleep fragmentation, and activation of the sympathetic nervous 4 system, potentially stimulating pro-inflammatory and pro-thrombotic pathways that drive 5 atherosclerosis [1]. Epidemiological studies implicate OSA as a potentially modifiable risk factor 6 for cardiovascular disease (CVD), stimulating research aimed at quantifying the impact of OSA 7 and its treatment on both coronary artery disease (CAD) and cerebrovascular disease [2]. While 8 OSA increases the incidence of cerebrovascular disease, weaker and less consistent associations 9 support associations between OSA and incident CAD [3]. Moreover, large clinical trials of the 10 effect of positive airway pressure (PAP) treatment of OSA on composite CVD outcomes have 11 provided equivocal results, in some cases with point estimates in the direction of increased risk 12 in the treatment group [4-7]. 13 Potential explanations for disappointing results of PAP RCTs include treatment non- 14 adherence, non-optimal trial participant selection (e.g. advanced CVD at baseline) and limited 15 statistical power [8, 9]. Another possibility is that putative CVD benefits of OSA treatment may 16 vary across individuals, influenced by factors related to characteristics of OSA-related stress not 17 captured by the traditional metric of OSA severity (apnea hypopnea index, AHI), as well as by 18 underlying host characteristics [10, 11], including genetic predisposition to CVD and genetic 19 variation within known OSA pathways [12, 13]. Moreover, some features of OSA might even 20 prove protective for CVD in some individuals, and therefore treatment of OSA with PAP could 21 increase CVD risk among those individuals [14]. This hypothesis derives support from human 22 and animal studies showing that exposure to intermittent hypoxemia - a cardinal feature of OSA 1 medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21255520; this version posted April 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 - can promote collateral blood flow, reflective of well-known effects of ischemic preconditioning 2 [15]. 3 The need to develop a precision medicine-informed approach to CVD risk stratification 4 in OSA agrees with data indicating that OSA-related CVD risk varies across subgroups defined 5 by clusters of phenotypic traits [16]. A central question, and the one that we address here, is 6 whether genetic variation in CAD risk interacts with OSA features to modulate CAD risk in a 7 pathway-dependent manner. We conceptualize repeated intermittent hypoxia (IH) and 8 reoxygenation as a modifying environment for preexisting genetic risk for CAD, locating our 9 analysis within a gene-by-environment (GxE) interaction paradigm. Our pathway-level GxE 10 approach provides a new scale on which to study the genetic architecture of CAD susceptibility 11 and its modification by OSA. 12 We build on prior work that (1) identified genetic markers for CAD risk involved in 13 atherosclerosis, small vessel disease, inflammatory pathways, and angiogenesis, with evidence 14 from genome-wide association studies (GWAS), expression studies, animal experiments and 15 clinical trials [17-19]; and (2) showed the influence of IH on a variety of pathways (in positive 16 and negative directions) relevant to CAD, including redox, inflammatory and angiogenic 17 pathways [20]. 18 Our approach considers effect modification of genetic risk, aggregated to the pathway 19 level, and investigates pathway-specific polygenic risk scores (PS-PRS) for CAD.
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