High-Saturated-Fat Diet Increases Circulating Angiotensin-Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient-Dependent Increases of Blood Pressure

Rita Schüler, Martin A Osterhoff, Turid Frahnow, Anne-Cathrin Seltmann, Andreas Busjahn, Stefan Kabisch, Li Xu, Alexander S Mosig, Joachim Spranger, Matthias Möhlig, Silke Hornemann, Michael Kruse, Andreas F H Pfeiffer, Rita Schüler, Martin A Osterhoff, Turid Frahnow, Anne-Cathrin Seltmann, Andreas Busjahn, Stefan Kabisch, Li Xu, Alexander S Mosig, Joachim Spranger, Matthias Möhlig, Silke Hornemann, Michael Kruse, Andreas F H Pfeiffer

Abstract

Background: Angiotensin-converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high-saturated-fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study.

Methods and results: Forty-six healthy and nonobese twin pairs initially consumed a carbohydrate-rich, low-fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6×10-30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8×10-6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5×10-8) and additionally showed a 2-fold increase in ACE concentrations in response to the HF diet as compared to non- or heterozygous carriers (AA/AG, P=2×10-6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene-diet interaction was confirmed in a second independent, cross-sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study.

Conclusions: The HF-diet-induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high-saturated-fat diets.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123.

Keywords: angiotensin‐converting enzyme; blood pressure; diet; gene‐diet interaction; nutrigenomics genetics.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
CONSORT flow diagram of the NUGAT study. NUGAT indicates NUtriGenomic Analysis in Twins; HF, high‐saturated‐fat diet; LF, low‐fat diet.
Figure 2
Figure 2
Time line of the NUGAT (NUtriGenomic Analysis in Twins) intervention study. For 1 week prior to each particular investigation day (hatched areas, weeks 6, 7, and 12) most of the food was provided to ensure standardized dietary patterns for all participants. HF1 indicates investigation day after 1 week of the high‐saturated‐fat diet; HF6, investigation day after 6 weeks of the high‐saturated‐fat diet; LF6, investigation day after 6 weeks of the low‐fat diet.
Figure 3
Figure 3
ACE serum concentrations at LF6, HF1, and HF6 (mean±SD; ***P<0.001). ACE indicates angiotensin‐converting enzyme; LF6, investigation day after 6 weeks of the low‐fat diet; HF1, investigation day after 1 week of the high‐saturated‐fat diet; HF6, investigation day after 6 weeks of the high‐saturated‐fat diet.
Figure 4
Figure 4
Results of ACE gene expression in subcutaneous adipose tissue by (A) microarray analysis and (B) quantitative real‐time PCR. A, Values are presented as fold changes (HF1 vs LF6 and HF6 vs LF6). P‐values are shown after Benjamini‐Hochberg correction (*P<0.05, **P<0.01). B, Values are shown as mean±SD. Bonferroni post hoc test was used to compare main effects (HF6 vs LF6, P=0.010) of repeated‐measures ANOVA (P=0.005). ACE indicates angiotensin‐converting enzyme; LF6, investigation day after 6 weeks of the low‐fat diet; HF1, investigation day after 1 week of the high‐saturated‐fat diet; HF6, investigation day after 6 weeks of the high‐saturated‐fat diet.
Figure 5
Figure 5
Intrapair correlation of ACE serum concentrations in monozygotic (A) and dizygotic (B) twins (**P<0.01). Estimated heritability (C) for ACE serum concentrations in comparison with estimates for bone mineral content (BMC) and height: “A” additive genetic effects, “C” common environmental influences, and “E” unique environmental influences. ACE indicates angiotensin‐converting enzyme.
Figure 6
Figure 6
A, ACE serum concentrations at LF6, HF1, and HF6 stratified for ACE rs4343 genotype and (B) ∆ACE (HF6–LF6) stratified for ACE rs4343 genotype (mean±SD; ***P<0.001). ACE indicates angiotensin‐converting enzyme; LF6, investigation day after 6 weeks of the low‐fat diet; HF1, investigation day after 1 week of the high‐saturated‐fat diet; HF6, investigation day after 6 weeks of the high‐saturated‐fat diet.

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