Abstract 18143: Impact of FMO3 Gene Loss-of-Function Variants on Coronary Artery Disease in Japanese
High-fat foods are rich in the lipid phosphatidylcholine, which is converted to trimethylamine by intestinal bacteria and then processed to harmful metabolite, trimethylamine N-oxide (TMAO), by key enzyme flavin containing monooxygenase 3 (FMO3) in the liver. TMAO has been liked to heart disease in human metabolomic studies, and accelerates foam cell formation and atherosclerosis in animal models. We hypothesize that loss-of-function variants of FMO3 can be atheroprotective in coronary artery disease (CAD) high-risk population.
Methods: Coding regions of FMO3 gene were analyzed with high-resolution melting method followed by direct sequencing in total of 506 patients (255 males, mean age of 58 ± 13) suspected CAD in our lipid clinic including 191 patients with genetically confirmed heterozygous familial hypercholesterolemia (FH). Coronary stenosis index (CSI) was estimated with angiography in 203 patients (118 males, mean age of 59 ± 12) including 61 patients with FH. Fasting lipid profiles without lipid-lowering drugs by ultracentrifugation, 75gOGTT, eGFR, and other conventional coronary risk factors were analyzed.
Results: In FMO3 gene, 6% (29 patients) were heterozygotes of loss-of-function (LOF) variants (p.C197X, p.R205C, and p.R500X) that showed no activity or reduced activity with in vitro study. LOF carriers showed no differences in age, sex, BMI, glucose tolerance, smoking, blood pressure, eGFR, except for lower HDL-C (50 ± 16 vs. 43 ± 12 mg/dL, p<0.05). In angiography, LOF carriers showed lower CSI (14.8 ± 11 vs. 7.3 ± 6, p<0.05). In subgroup, CSI was lower in non-FH group (14.0 ± 11 vs. 5.8 ± 5, p<0.05) even with lower HDL-C (51 ± 17 vs. 42 ± 11, p<0.05), but not significant in FH group. As HDL-C showed significant negative correlation with CSI in total study group, we speculated that FMO3 gene LOF variants should be atheroprotective in CAD high-risk group. Relatively high-rate of LOF variants in FMO3 gene can be a part of background of low rate of CAD deaths in Japanese.
Conclusion: FMO3 gene LOF variant carriers showed less coronary atherosclerosis in CAD high-risk group. FMO3 can be a new candidate to fight against atherosclerosis.
Author Disclosures: A. Nohara: None. S. Okazaki: None. M. Yoshida: None. M. Mori: None. C. Nakanishi: None. H. Tada: None. M. Kawashiri: None. K. Yagi: None. A. Inazu: None. M. Yamagishi: None. H. Mabuchi: None.
- © 2014 by American Heart Association, Inc.