The present study found that gene-environment interactions between the NOS3 T-786C polymorphism and leisure-time physical activity on serum triglyceride levels were significant, and that both the moderately and very active groups had significantly lower serum triglyceride levels than the sedentary group in the TC + CC genotype group, but not in the TT genotype group. This suggests that the presence of the C allele enhances the beneficial effect of leisure-time physical activity on serum triglyceride levels. An intervention study showed that the presence of the C allele did not affect the beneficial effect of exercise in reducing serum triglyceride levels among postmenopausal women (n = 49), but the sex difference of this effect was unclear in the current study.
The genotype distribution of the current study subjects was very similar to that described previously in 233 Japanese (83.3%, 15.0%, and 1.7% for the TT, TC, and CC genotypes, respectively). Compared with Caucasians, C allele carriers were much less common in Japanese (32.0%, 52.0%, and 16.0% for the TT, TC, and CC genotypes in Caucasians, respectively).
Recently, the role of triglycerides in atherosclerotic diseases was controversial because of the large variation in triglyceride measurements, and the strong inverse relationship between HDL cholesterol and triglycerides. However, large meta-analyses of prospective studies have reported that triglycerides are an independent risk factor for coronary heart disease in the general Western populations, and Asian and Pacific populations[22, 23]. Triglycerides are not directly atherogenic, but represent an important biomarker of cardiovascular disease risk because of their association with atherogenic remnant particles and apolipoprotein C-III, a lipoprotein lipase (LPL) inhibitor. Therapy with fibrates, most selective triglyceride-reducing drugs, was reported to produce a 10% risk reduction for major cardiovascular events and a 13% relative risk reduction for coronary heart disease.
Triglycerides are frequently associated with lifestyle factors, one of which is exercise. Aerobic exercise was reported to cause a 15% to 20% reduction in serum triglycerides when triglyceride levels were over 150 mg/dL. In rats, exercise induces an increase in LPL mass and total and heparin-releasable LPL activity in white skeletal muscle. Interestingly, these beneficial effects of exercise may involve NO. In vitro, shear stress of bovine aortic endothelial cells increased the eNOS transcriptional rate and upregulated eNOS mRNA levels. An experiment using Goto-Kakizaki rats (a model of type 2 diabetes) showed that exercise increased both the total eNOS expression and the dimer:monomer ratio in the left ventricle and induced significant increases in NO production and concomitant decreases in eNOS-dependent superoxide production.
NO can lower serum triglyceride levels by three mechanisms. Firstly, NO can promote triglyceride metabolism through an increase in blood flow and insulin to tissues. Insulin and its counterregulation have been reported to play a central role in triglyceride metabolism by suppression of hepatic production and secretion of triglyceride-rich lipoproteins and stimulation of LPL activity. Secondly, NO can decrease free fatty acid concentration for the synthesis of triglycerides by promoting the formation of new metabolically active mitochondria and activating carnitine palmitoyltransferase 1, an enzyme which transports activated fatty acids into mitochondria for oxidation. Thirdly, NO can suppress the synthesis of triglycerides in liver by inhibiting the de novo fatty acid synthesis through an adenosine monophosphate-activated protein kinase-dependent inhibition of the activity of acetyl-CoA carboxylase, which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, a key substrate in chain elongation during fatty acid biosynthesis.
To date, there has been no experimental study that has shown the difference in responsiveness to exercise in NO production among the T-786C genotypes. It has been reported that a shear stress responsive element is located near the promoter region of NOS3 between nucleotides −1600 and −779, but the question of whether the polymorphism modifies the effect of physical activity on NO production is controversial. An intervention study showed that six months of aerobic exercise increased the bioavailability of NO only in subjects with the C allele. In contrast, another study showed that the increase in NO production in response to six months exercise was greater in women without the C allele as compared with those with it.
In addition to exercise, the polymorphism has been reported to modulate the effect of statins, which are 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors. An in vitro experiment demonstrated that fluvastatin augmented eNOS transcriptional activity in human umbilical vein endothelial cells (HUVECs) containing the CC genotype more powerfully than those with the TT genotype. This effect was due to a decrease in gene expression of replication protein A1 (RPA1). RPA1 specifically binds to the C allele and significantly suppresses the transcriptional activity of NOS3. This finding was supported by an epidemiological study that showed atorvastatin treatment increased whole blood nitrite concentrations and attenuated oxidative stress in the CC genotype group, but not in the TT genotype group. Future studies investigating the effect of exercise on RPA1 expression by the T-786C genotype is eagerly anticipated.
The current study had several limitations. To begin with, the examination was limited to only one NOS3 polymorphism and did not consider combinations with other NOS3 polymorphisms, as well as polymorphisms of other genes that are associated with serum triglyceride levels. Next, there may have been differences among the institutions in measurement methods concerning clinical data. However, such differences may have had a limited impact on data analysis as enrollment area was added to the adjustment factors. Finally, physical activity of subjects was taken into account only during their leisure time, not all the time, and the effect of physical activity outside of leisure time may have been confounding.
In conclusion, the present study suggests that the NOS3 T-786C polymorphism modifies the effect of leisure-time physical activity on serum triglyceride levels. Tailoring prevention of hypertriglyceridemia on the basis of the T-786C genotypes could be achieved, provided that further studies, including cohort and intervention studies, validate the results of this cross-sectional study.