Abstract 10884: X-Linked Genetic Associations in Sporadic Thoracic Aortic Aneurysm and Dissection

Introduction: The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) and the high prevalence of TAD in Turner syndrome patients suggest the contribution of X chromosome genes to TAD. However, such role has not been explored. Methods: We investigated whether X-linked variation, both common (Minor Allele Frequency (MAF) ≥0.01) and rare (MAF <0.01), was associated with sporadic TAD in three datasets of European descent (dataset-1: 753 cases, 2247 controls; dataset-2: 253 cases, 282 controls; dataset-3: 364 cases, 874 controls). All cases were obtained from McGovern School of Medicine and Baylor College of Medicine; however, controls were obtained from the Atherosclerosis Risk in Communities study (dataset-1), the University of Washington Center for Mendelian Genomics (dataset-2), and the National Institute of Neurological Disorders and Stroke Repository (dataset-3). We applied a sex-stratified logistic regression model, followed by a meta-analysis of sex specific odds ratios for common variants, and an optimized sequence kernel association test model for rare variants. For top (P≤1x10 -3 ) common X-linked variants from the three datasets, we performed tissue enrichment analysis using a hypergeometric test. Results: The majority of cases (75%) were males. In dataset-2, common variant, rs55936630, in IGSF1 (P meta-analysis: 2.43x10 -7 ), reached X chromosome-wide significance. An additional 125 variants were suggestive of an association (P meta-analysis ≤1x10 -3 ) in at least one of the three datasets. Tissue enrichment identified a set of 12 X-linked genes that was significantly enriched in blood vessels (P: 3x10 -2 ). RTL9 (P: 5.15x10 -5 ; dataset-1) reached X chromosome-wide significance in rare variants analyses. Conclusions: This is the most comprehensive X-chromosome association analysis of TAD to date. Although most of our common variants did not reach X chromosome-wide significance, collectively testing these variants in tissue enrichment analysis identified a set of 12 X-linked genes that was significantly enriched in blood vessels. Among these 12 X-linked genes were C1GALT1C1 and DMD which were previously associated with vasculitis and arterial stiffness, respectively, both of which are risk factors for TAD.