Genetically determined dyslipidemia associated with abdominal aortic aneurysm
Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm - A Meta-analysisHarrison SC, Holmes MV, Burgess S, et al. - JAMA Cardiol 2017; published online ahead of print
Guidelines recommend the screening of patients at high risk for abdominal aortic aneurysm (AAA), particularly men aged 65 to 75 years with a history of smoking . Studies suggest that AAA and CHD have some, but not all, risk factors in common . For example, there is a consistent inverse association between HDL-c and AAA risk, but the association with LDL-c is rather unclear, whereas there are no data on the association between TGs and AAA risk .
In this study, the role of lipids in the etiology of AAA was investigated. For this purpose, the association of genetic risk scores (GRS) for lipid traits with AAA were reported in up to 4914 cases and 48002 controls in 5 international AAA genome-wide association studies (GWASs) from January 2015 to December 2016 . In all studies, AAA was defined as an infra-renal aortic diameter of ≥3 cm by ultrasound or CT imaging, unless there was a history of previous AAA rupture or repair.
Single-nucleotide polymorphisms (SNPs) associated with lipids were identified in the Global Lipid Genetics Consortium , using the SNP selection criteria by Do et al. . SNPs were selected in association with at least 1 of the 3 lipid traits (LDL-c, HDL-c, or TG concentrations) at a genome-wide significance level (P < 5 × 10−8). A conventional Mendelian Randomization (MR) analysis was conducted, as well as a multivariable MR, a MR-Egger, and a weighted median MR.
- The LDL-c-lowering alleles of rs6511720 in LDLR (OR per allele: 0.75; 95% CI: 0.67-0.83; P=5.2 × 10−12) and rs646776 in SORT1 (OR per allele: 0.88; 95% CI: 0.82-0.94; P=3.9 × 10−8) were strongly associated with AAA.
- No other SNP from the 180 lipid associated SNPs was individually associated with AAA at conventional levels of genome-wide significance.
- The LDL-GRS was strongly associated with the AAA risk (OR per SD higher level for LDL-c: 1.66; 95% CI: 1.41-1.96; P=1.1 × 10−9). A 1-SD higher HDL-c level was associated with a reduced AAA risk (OR: 0.67; 95% CI: 0.55-0.82; P=8.3 × 10−5), and the TG-GRS was associated with higher AAA risk (OR per 1-SD higher TG level: 1.69; 95% CI: 1.38-2.07; P=5.2 × 10−7).
- None of the sensitivity MR analyses (Multivariable MR, MR-Egger, and Weighted Median MR Approaches) resulted in an important change to the magnitude or to the significance of the estimates.
- The LDL-c–lowering allele of rs12916 (to proxy statin use) was associated with a lower AAA risk in meta-analysis (OR per LDL-c–lowering allele: 0.93; 95% CI: 0.89-0.98; P=0.009).
- Examination of two independent SNPs in PCSK9 showed that the LDL-c–lowering allele of rs2479409 was not associated with AAA risk (OR: 0.97; 95% CI: 0.84-1.02; P=0.28), and the LDL-c–lowering allele of rs11206510 in PCSK9 was weakly associated with AAA risk (OR: 0.94; 95% CI: 0.88-1.00; P=0.04).
- The rs3764261 allele, as a proxy for CETP inhibition, was associated with lower AAA risk (OR per HDL-c–raising allele: 0.89; 95% CI: 0.85-0.94; P=3.7 × 10−7). However, the allele is also associated with lower TG and LDL-c concentrations, and therefore can give insight into the potential associations with CETP inhibition.
In a meta-analysis of 5 GWASs, the genetic elevation of LDL-c and TG levels was associated with an increased risk of AAA, whereas increased HDL-c level was associated with a lower risk of AAA. These results suggest that patients with an AAA have a high burden of genetically determined dyslipidemia; appropriate treatment of this may lower their AAA risk.