X-linked genetic associations in sporadic thoracic aortic dissection

Area of Science:

• Genetics
• Cardiovascular Diseases
• Human Genetics

Background:

• Male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests a potential role for X-linked genetic factors.
• Previous research has not comprehensively tested the association between X-chromosome variations and sporadic TAD.
• Understanding genetic contributions to TAD is crucial for developing targeted prevention and treatment strategies.

Purpose of the Study:

• To investigate the association between common and rare X-linked genetic variations and sporadic thoracic aortic aneurysm and dissection (TAD).
• To analyze genetic data from three independent cohorts of European descent to ensure robust findings.
• To identify specific X-linked genes or variants contributing to the risk of developing sporadic TAD.

Main Methods:

• Utilized sex-stratified logistic regression for common variants (minor allele frequency [MAF] ≥0.01) and a sex-stratified optimized sequence kernel association test for rare variants (MAF <0.01).
• Analyzed data from three cohorts: Discovery (364 cases, 874 controls), Replication (516 cases, 440,131 controls), and Atherosclerosis Risk in Communities (ARIC) study (753 cases, 2247 controls).
• Performed meta-analyses of sex-specific odds ratios for common variants and overlapping variants between Discovery and Replication cohorts.

Main Results:

• No statistically significant associations were found for common variants in the Discovery cohort.
• A common intergenic variant near SPANXN1 reached statistical significance in the Replication cohort (p=1.81×10⁻⁸).
• A ZNF182 intronic common variant showed the highest signal in the meta-analysis of Discovery and Replication cohorts (p=3.5×10⁻⁶), and the rare variant RTL9 reached statistical significance (p=5.15×10⁻⁵).

Conclusions:

• This comprehensive analysis represents the most extensive investigation of X-chromosome associations with sporadic TAD to date.
• While most results were not statistically significant, potential associations with variants near SPANXN1, ZNF182, and RTL9 warrant further research.
• The findings suggest a possible, albeit complex, role for X-linked genetic factors in the etiology of sporadic thoracic aortic aneurysm and dissection.