APOA5 -1131 T>C
Research provides vast ethnic differences in the minor allele (C-allele) frequency of this polymorphism. Frequencies reported in Su et al. (2018) and Son et al. (2015) are 35.3% in Japanese, 30.2% in Koreans, 28.3% and 30.4% in Chinese, 12.8% in Turkish and 9.5% and 7.5% in Caucasian populations.
APOA5 Gene Detail
The apolipoprotein A5 (apoA5) plays an important role in lipid metabolism, specifically in triglyceride (TG) and TG-rich lipoprotein (TRL) metabolism. Several studies have reported an association between apoA5 and TG levels, risk for obesity, dyslipidemia and metabolic syndrome.
The apoA5 -1131 T>C polymorphism has been associated with various conditions such as metabolic syndrome, elevated plasma TG (fasting and post-prandial), elevated total cholesterol, elevated BMI, decreased HDL-C as well as possible involvement in glucose metabolism.
Research suggests that C-allele carriers, although at higher risk for hypertriglyceridemia, may be more responsive to weight loss interventions, especially with the inclusion of MUFA-rich foods. TT homozygotes should limit total fat intake to decrease obesity risk.
APOA5 -1131 T>C
The human apoA5 gene is located on the long arm of chromosome 11 (11q) and was initially thought to express exclusively in the liver. Recent evidence suggests that a small amount of apoA5 is also expressed in the human intestine. The mature apoA5 protein consists of 343 amino acids and is highly hydrophobic.
The apoA5 forms part of the apolipoprotein superfamily and despite its low plasma concentration, is described as a potent regulator of TG metabolism. It has been reported that mice lacking the apoA5 gene presented with four-times greater plasma TG levels than the control group whilst overexpression of the apoA5 gene presented a 66% reduction in plasma TG levels. Similarly, an inherited deficiency of the apoA5 gene in humans has been associated with severe hypertriglyceridemia.
Although the mechanism by which apoA5 influence obesity and metabolic syndrome risk is not fully clear, evidence reports that apoA5 could significantly reduce plasma TG concentrations by stimulating lipoprotein lipase (LPL) activity and inhibiting VLDL-TG production. Also, since adipocytes provide the largest storage depot for TG and play a central role in the development of obesity, Su et al. suggested that apoA5 may act as a unique regulator to control TG storage in adipocytes.
The apoA5 -1131 T>C polymorphism occurs in the promoter region of the apoA5 gene and this mutation is thus thought to modulate the expression of apoA5. The C-allele in this polymorphism is thought to result in an impaired ribosomal translational efficiency that may lead to reduced LPL activity and thus reduced TG uptake into adipocytes.
Cross-sectional and longitudinal analyses from Hsu et al. (2013) found that the C-allele was associated with adverse metabolic profiles in obese but not in non-obese Taiwanese individuals at baseline, including elevated waist-to-hip ratio (WHR), hypertriglyceridemia, low HDL-C and an increased risk for metabolic syndrome. An independent association was found between the -1131 T>C SNP and central obesity in obese male participants. A similar finding was made by Son et al. where Korean men with the -1131 T>C SNP displayed a significant association with elevated TG, reduced HDL-C levels and an increased prevalence of metabolic syndrome. Moroccan subjects with the same SNP also presented a significant association with metabolic syndrome and related parameters such as increased TG levels, waist circumference, fasted glucose and lower HDL in a study from Ajjemami et al (2015).
Following a 6-month weight loss intervention in the Taiwanese men, significant improvements were seen in TG levels for male and female C-allele carriers as well as for WHR in male C-allele carriers, so that WHR were comparable between male C-allele carriers and non-carriers at the end of the study. The authors suggested the presence of a gender-specific association with metabolic parameters as none of these WHR changes were seen at baseline nor post-study in the female participants.
In addition to its association with serum TG, HDL levels and dyslipidemia, Hishida et al. (2012) also found a significant association between the -1131 T>C SNP and the risk of dysglycemia – defined by the authors as a fasting blood sugar level ≥ 6.1 mmol/L (110 mg/dL) – in 2030 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Similarly, a case-control study investigating a group of Romanian subjects with metabolic syndrome found that those homozygous for the C-allele not only presented with lower HDL levels but also higher glucose readings than T-allele carriers.
Son et al. (2015) investigated the association between the -1131 T>C SNP and TG levels in relation to various health-related behaviours such as smoking, alcohol use and physical activity in 1193 Korean men. The authors found no interaction with smoking, whereas minor allele carriers showed significantly increased TG levels in the heavy-drinker group (defined as having more than 2 alcoholic drinks daily or ≥ 196g alcohol per week) and significantly decreased TG levels in the group engaging in high levels of physical activity (using the Korean version of the International Physical Activity Questionnaire scoring protocol).
In terms of gene-diet interaction, most cross-sectional studies performed agreed that this SNP may modulate the effect of fat intake on BMI and obesity risk. It is suggested that a higher MUFA intake in C-allele carriers may be associated with a lower BMI and that C-allele carriers may be able to reduce BMI more efficiently even with a higher fat intake as compared to TT homozygotes.
In a previous report, authors also found that higher n-6 (but not n-3) polyunsaturated fatty acid (PUFA) intake increased fasting triglycerides in C-allele carriers.
Corella et al. (2007) found that minor C-allele carriers only had about one third the risk of obesity compared with TT individuals in the high fat (≥ 30% of total energy) intake group while the minor C-allele was not associated with a lower obesity risk when fat intake was low (< 30% total energy). This association was mainly found for mono-unsaturated fatty acids (MUFA) where C-allele carriers consuming ≥ 11% of total energy from MUFA demonstrated a 38.2% lower obesity risk compared with TT homozygotes. This study concluded that individuals homozygous for the T-allele display a positive association between fat intake and BMI whereas in C-allele carriers, a higher fat intake is not associated with a higher BMI. This is supported by findings from Sánchez-Moreno et al. (2011); their cross-sectional analysis revealed that TT homozygotes displayed a positive association between fat intake and obesity while C-allele carriers and higher fat intake was not associated with higher BMI.
Weight Loss With Total Energy Restriction
In a previous study investigating the effect of a short-term diet, researchers found no differences in BMI at baseline when comparing C-allele carriers and TT homozygotes. After the 3-month intervention with energy restriction, C-allele carriers lost significantly more weight than TT homozygotes. The authors suggested that the reduced LPL-mediated TG uptake into adipocytes may result in a more efficient decrease in BMI in response to fat intake.
Comparable results were found in Hsu et al. (2013) where Taiwanese C-allele carriers achieved a significantly greater BMI reduction at 3-months post-intervention, which initially involved an intensive 6-month weight loss intervention. The authors concluded that weight loss could ameliorate the adverse metabolic profiles in C-allele carriers, especially referring to the management of central obesity in men.
Other Health-Related Behaviours
Based on results from the Son et al. (2015) cross-sectional analysis in Korean men, it may benefit minor allele carriers to maintain high physical activity levels and moderate alcohol use to manage TG levels.
However, considering a study from Jang et al. (2010), it concluded that TT homozygotes may benefit more than C-allele carriers from the Dietary Intervention and Regular Exercise (DIRE) – which entailed replacing a third of their refined rice intake with legumes, increasing vegetable intake and walking regularly for 12 weeks – to lower TG levels and improve HDL concentration.
New insights into apolipoprotein A5 in
controlling lipoprotein metabolism in obesity and the metabolic syndrome patients.
Su et al, 2018.