Studies of Gene Variants Related to Inflammation, Oxidative Stress, Dyslipidemia, and Obesity: Implications for a Nutrigenetic Approach
Table 2
Summary of studies evaluating interaction between diet and variants of genes involved in lipoprotein metabolism.
Gene
Variant
Population [reference]
Frequency
Design
Main findings
−76G/A (rs 1799837)
97 subjects recruited among students of the University of Cordoba at age-range 18–49 years [107]
G allele: 41,2% A allele: 58,8%
Clinical trial followed by a randomized crossoverThe subjects consumed three diets for four weeks: SFA diet, CHO diet or MUFA diet.
After the participants consumed the CHO diet, there was a decrease in LDL size with respect to high-fat diets in GG homozygotes for the carriers of −76G/A (). LDL size did not differ in GA carriers. Carriers of the A allele for this polymorphism had smaller LDL size as well as increased susceptibility to oxidation after the SFA diet than the GG homozygous ().
Apo A1
−75G/A (rs 670)
1,577 subjects from the Framingham Offspring Study [108]
G allele: 83,5% A allele: 16,5%
Cross-sectional
When PUFA intake was across <4% of energy, the G allele carriers had ~14% higher plasma HDL-c than did carriers of the A allele (). However, when PUFA intake was >8%, HDL-c levels in the A allele carriers were 13% higher than those of G/G subjects (). These interactions were not significant in men
50 subjects voluntaries members of two urban religious communities with 47,1 medium age [109]
G allele: 87% A allele: 13%
Clinical Trial Subjects were first fed a SFA diet for 28 days, followed by a MUFA diet for 35 days and a PUFA diet for 35 days.
The A allele carriers had higher plasma CT, LDL-c, and TG levels than the G homozygous allele (). PUFA diet-induced significantly greater CT ( ,003) and LDL-c decreases ( ,001) in G/A women than in G/G as compared to SFA diet. The variability in LDL-c response from the SFA diet to the PUFA diet in women was associated with LDL-c (55,1%), waist hip ratio (11,4%), and the G/A polymorphism (10%).
In normal glycemia T: 63%, C: 62% In T2DM subjects T: 37%, C: 38%.
Case-control study
Marginally associated with CT levels () and waist-to-hip ratio (). Not associated with T2DM.
Apo A2
−256T/C (rs 5082)
3,462 subjects from Framingham Offspring Study (1,454 Whites), The GOLDN Study (1,078 Whites) and BPR Study (930 Hispanics of Caribbean origin) [111]
CC subjects between Framingham and GOLDN: 15%; in BPR study: 10,5%.
Cross-sectional, follow-up (20 years), and case-control analyses.
No significant association with HDL-c. When SFA intake is low (≤22 g/d), the SNP does not affect BMI. When SFA intake is high (≥22 g/d), SNP is associated with BMI and obesity: a mean increase of 6.2% BMI (). CC genotype was associated with higher obesity prevalence in all populations only in the high-SFA intake stratum.
4,602 subjects from two independent populations: –high–cardiovascular risk Mediterranean –multiethnic Asian population including Chinese, Malays and Asian Indians) [112]
Frequency of CC subjects differed strongly among Chinese, Malays and Asian Indians (1–15%).
Cross-sectional study: analyzed gene-diet interactions between the APOA2 −265T>C and SFA intake on BMI and obesity.
In Mediterranean individuals, the CC genotype was associated with a 6.8% greater BMI in those consuming a high-SFA diet (≥22 g/d), (), but not a low (≤22 g/d), () SFA diet. CC genotype was associated with higher obesity prevalence in Chinese and Asian Indians only with a high-SFA intake ().
Clinical trial: subjects were given a fatty meal containing 1 g fat and 7 mg cholesterol/kg weight and capsules containing 60,000 IU vitamin A. Postprandial lipemia was assessed during the 11 h following the meal.
Carriers of the C allele have significantly lower postprandial increases in plasma total TG and chylomicron TG, suggesting a protective effect against cardiovascular disease.
2,148 subjects from the Framingham Offspring Study with 50,45 medium age [114]
T allele: 86,6% C allele: 13,4% C allele: 88,3% G allele: 11,7%
Cross-sectional
Significant interactions between the −1131T/C and PUFA intake was found () in determining fasting plasma TG, RLP, and particle size. The same results could not be observed in 56 C/G polymorphism. In individuals who consumed a high PUFA diet (6% of the energy), the −1131T/C was associated with higher fasting TG and RLP concentration (). The size of VLDL increases and LDL decreases while PUFA intake increased in the −1131T/C carriers. The PUFA Apo A5 interactions were specific for dietary n-6 fatty acids.
Apo A5
−1131T/C (rs 662799) 56C/G (rs 3135506)
2,280 subjects from the Framingham Offspring Study with 54,2 medium age [115]
T allele: 87,15% C allele: 12,85% C allele: 88,95% G allele: 11,05%
Cross-sectional
A significant interaction between −1131T/C and total fat in relation to the BMI ( ,001) was found. The −1131C minor allele carriers had a lower obesity () and overweight () risk when compared with TT subjects in the high fat intake group, but not when fat intake was low (). The monounsaturated fatty acids intake showed the highest statistical significance for these interactions.
1,020 of the Boston Puerto Rican Health Study at age 45–75 [115]
The pairwise LD coefficient between the APOA5 −1131T/C and 56C/G was 0,016
Cross-sectional
The 56C/G polymorphism was associated with HDL-c (). The minor allele carriers had lower HDL-c than those with common variant (). Both polymorphisms were associated with TG or other lipids. Associations of the −1131T/C with total fat energy intake was observed for TG () and CT ().
−1131T/C (rs 662799)
49 male subjects at age 28–55 years were recruited from volunteers who responded to an advertisement for a nutrition study conducted by the Clinical Nutrition Research Team at Yonsei University [116]
TT: 46,9% TC: 36,8% CC: 16,3%
Clinical Trial The subjects were randomly assigned to consume one of two types of experimental enteral formulae (LF versus HF) with a seven-day interval.
Fasting total TG were higher in TC+CC men than TT men, but fasting chylomicron TG were not significantly different between TT men and C carriers. TT subject had no significant difference in postprandial responses of total TG and chylomicron TG between LF and HF meal. C carriers had delayed peak time of total TG compared to TT subject and higher postprandial response at HF meal when compared to LF meal.
299 healthy male at age 20–75 of the 5th Framework Program, [117]
TT: 84,51% TC: 15,16% CC: 0,34%
Cross-sectional
Individual who had the C allele presented higher plasma TG, VLDL-C, and LDL-c levels. Plasma α-tocopherol was increased in C allele carriers compared with homozygote T allele carriers ().
Apo E
Apo E2 rs429358 (T) + rs7412 (T) Apo E3 rs429358 (T) + rs7412 (C) Apo E4 rs429358 (C) + rs7412 (C)
22,915 subjects at age 45–75 years from Norfolk arm of the European Prospective Investigation of Cancer (EPIC) [118]
Individuals who have ε4/ε4 genotype presented the highest serum CT and LDL-c and lowest HDL-c and TG (). There were positive associations between total and saturated fat from usual diet and serum total and LDL-c, and an inverse associations () between polyunsaturated fat, dietary fiber, and lipid fractions overall. Associations were in the same direction for ε2, ε3, and ε4 expressing individuals with no significant interactions between diet and genotype group on blood lipids, except in those who expressed ε2/ε43% ().
84 subjects from students at the University of Cordoba at age 21–55 years [119]
9,5% ε4/ε3 78,6% ε3/ε3 11,9% ε3/ε2
Clinical trial: subjects consumed for 28 days a SFA-rich diet. After this, they were randomly assigned to one of two diet sequences: the first one received a MUFA-rich diet for 28 days, followed for more 28 days with CHO-rich diet. The other group consumed CHO diet before the MUFA diet.
Apo ε2 carriers presented the highest Apo E plasma levels, while Apo ε4 individuals showed the lowest concentration after the SFA, CHO, and MUFA diets ( for men and for women). The Apo E was higher in women () when compared with men after they consumed the SFA diet. In Apo ε3/ε2 and Apo ε3/ε3 carriers, the shift from the SFA to CHO or MUFA-rich diets decreased the Apo E concentration in women (). Sex and Apo E genotype determine the Apo E and plasma levels, but this effect is dependent on dietary fat.
Apo E2 rs429358 (T) + rs7412 (T) Apo E3 rs429358 (T) + rs7412 (C) Apo E4 rs429358 (C) + rs7412 (C)
132 clinically healthy Caucasians subjects at age 40–69 years [120]
A significant correlation between CT and energy intake derived from total () and saturated fat () was observed. Carriers of the Apo ε3/ε4 genotype displayed a stronger positive correlation between serum LDL-c level and percentage of energy derived from intake of saturated fat (). The individuals who carried the Apo ε2 allele demonstrated a positive correlation between alcohol consumption and serum HDL-c level ().
121 subjects recruited by advertising in Gothenburg's major newspaper at age-range 30–65 years [121]
Clinical Trial: the subjects were submitted to a four intervention periods: 1 and 3 a coffee free period of three weeks, 2 and 4 600 mL coffee/day for four weeks.
The ApoE ε2 allele showed an inverse association with serum CT concentration (), but the Apo E polymorphisms do not influence the cholesterol-raising effect of coffee.
BMI: body mass index; BPR: Boston-Puerto Rican Study; CHO: carbohydrate; CT: total cholesterol; GOLDN Study: Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study; HDL-c: High density lipoprotein-cholesterol; HF: High fat; LDL-c: Low density lipoprotein-cholesterol; LF: Low fat; MUFA: Monounsaturated fatty acids; PUFA: Polyunsaturated fatty acids; RLP: Remnant-like particle; SFA: saturated fatty acids; SNP: single nucleotide polymorphism; T2DM: type 2 diabetes mellitus; TG: triglycerides; VLDL-c: Very low density lipoprotein-cholesterol.
