Abstract 1807: Biliverdin Reductase Genetic Polymorphisms are Associated with Early-Onset Coronary Artery Disease in Two Datasets
Background: Bilirubin is a known antioxidant with roles including inhibition of lipid peroxidation. Studies have shown that higher serum bilirubin levels correlate with decreased CAD risk. Biliverdin reductase (BLVRA) is a key enzyme involved in the metabolism of heme to bilirubin. We have previously shown modest linkage to early-onset CAD on chromosome 7p in the region of the BLVRA gene. Hence, we hypothesized that BLVRA genetic variants are associated with atherosclerosis.
Methods: Ten tagging BLVRA single nucleotide polymorphisms (SNPs) were genotyped and assessed for association in 3 datasets:
GENECARD study of early-onset CAD (n=420 families, 1129 individuals);
CATHGEN study of non-familial CAD (n=901 cases, 397 controls); and
Aortas (N=78) from human heart donors with varying degrees of atherosclerosis by Sudan IV staining.
In GENECARD, Association in the Presence of Linkage (APL) was used for association. In CATHGEN, logistic regression models adjusting for sex, race and CAD risk factors were constructed. In aortas, mixed models were used to test for association of SNPs with atherosclerosis.
Results: One synonymous coding BLVRA SNP (rs1131372) was associated in GENECARD (APL p=0.0012). In CATHGEN, the same SNP was associated with CAD (genotype OR 1.82, p=0.0005) with minimal attenuation after adjustment for CAD risk factors (genotype OR 1.81, p=0.001). An additional synonymous coding SNP (rs9632617) in linkage disequilibrium with rs1131372 (r2=0.86) was also associated with CAD in CATHGEN (genotype OR 1.86, p=0.0001; adjusted genotype OR 1.93, p=0.0001). These results survived adjustment for multiple comparisons (Bonferroni p=0.005). In aortas, rs9632617 was associated with atherosclerosis (p=0.008). However, BLVRA SNPs were not associated with differential serum total bilirubin levels.
Conclusions: We report a novel finding of BLVRA as a strong atherosclerosis susceptibility gene. Given previous studies showing that higher bilirubin levels are associated with decreased CAD risk, this is also a biologically plausible candidate gene. Further functional studies are necessary.