In this study we considered diet interactions across three sub-groups: 1) normal BP, hypertension, and Hcy-related hypertension (H-type); 2) low, normal, and high Hcy levels; and 3) various Hcy-related genotypes. We observed that those with HHcy expressed more favorable energy and macronutrient intake and body composition measures than those with normal and low-Hcy concentrations. However, hyperhomocysteinemic individuals reported noticeably higher alcohol and lower fruit and vegetable intake, possibly contributing to their inadequate vitamin status and higher CVD measures. There were more men than women in the HHcy category and, after accounting for sex, the body composition associations disappeared, although differences in alcohol and diet intake remained noteworthy. Moreover, 9 in 10 of those with HHcy also presented with hypertension (H-type) and when compared with the regular hypertension sub-group, H-type hypertensives recorded higher alcohol intake and lower fruit and vegetable consumption, including lower folate and other B vitamins intake, than those with hypertension alone. To complement our investigation, we report below on specific dietary aspects of BP categories, Hcy categories and Hcy-related genetic characteristics that associate with cardiovascular functional measures and CVD risk in a population already at a high risk.
4.1. Blood pressure categories, dietary intake and cardiovascular function markers
BP measurement, an affordable, non-invasive tool, helps healthcare professionals detect and manage chronic conditions and is a step that could complement personalized nutrition. Yet, guidelines overlook H-type hypertension, which could significantly impact hypertension management and precision nutrition. We advise everyone, particularly individuals with hypertension, to consume adequate vitamin B12. Research on the direct effects of vitamin B12 intake and BP are scarce [21]; the most plausible link is through the Hcy folate–vitamin B12 dependent and independent remethylation metabolism, in which a reduced vitamin B12 intake results in higher Hcy concentrations and thereby raised hypertension and CVD risk.
We also advise individuals with regular and H-type hypertension to monitor their total protein intake, as it may raise PP, especially advising caution with animal protein for those with H-type, given PP's significance in CVD risk [22]. The 10-year Zutphen study on Dutch middle-aged men showed no link between PP and dietary protein intake [22]. Conversely, a study of younger (< 30 years) white and Black South Africans revealed that despite lower total and animal protein intake among Blacks, they had higher serum protein levels [23]. The authors suggested this could stem from heightened protein catabolism or enhanced endogenous amino acid biosynthesis, potentially increasing collagen to mitigate early vascular aging risk. Given our older hypertensive and H-type participants, they might experience elevated PP from higher protein consumption. However, in individuals with normal BP, increased animal protein intake seemingly did not adversely affect arterial function.
MUFA consumption was positively associated with arterial function in all BP sub-groups, particularly in normal and H-type hypertension. The negative correlations between SFA intake and cr-PWV may stem from MUFAs and SFAs collinearity, as adjusting for MUFAs intake weakened these associations. Despite mixed evidence on MUFAs and vascular health, beneficial impacts on serum lipids, BP, and E-selectin suggest a lower CVD risk [24]. Further intervention studies are essential to substantiate MUFA intake recommendations and elucidate underlying mechanisms.
4.2. Hcy categories, daily dietary intake and markers of cardiovascular function
Hcy measurements are more invasive and elective than recording BP but should be regarded as a necessary step in the approach to personalized nutrition, particularly in cardiovascular health. Incorporating Hcy screening into hypertension guidelines could differentiate between regular and H-type hypertension for targeted treatment.
Biotin, known for immunoregulatory properties affecting proinflammatory cytokine expression, which in turn induces ICAM-1 and VCAM-1 expression [25], showed positive correlations with Hcy in CBS T833C minor allele carriers [6]. However, research to confirm a direct relationship between dietary biotin and ICAM-1 remains to be done. We revealed that the positive associations between ICAM-1 and biotin get stronger when accounting for age more so than sugar in those with normal Hcy concentrations. It seems that the association between ICAM-1 and fruit and vegetable intake in the same Hcy group was unaffected by either. Notably, biotin and fruit/vegetable consumers ingested more added sugar and significance diminished after adjusting for sugar interactions.
Fructose induces ICAM-1 expression by diminishing endothelial nitric oxide and depleting adenosine triphosphate, leading to vascular cell inflammation [26]. Habitually high intake of carbohydrates, simple sugars, and fructose in particular, contributes to insulin resistance, weight gain and increased BP [27]. Some studies speculate that insulin resistance also produces a drop in methionine transmethylation, hepatic Hcy trans-sulphuration and Hcy clearance, resulting in raised concentrations of circulating Hcy [28, 29]. In Black South Africans, higher socio-economic status improves micronutrient intake through better access to fruits, vegetables, pulses, nuts, and seeds [11, 30] but also raises added sugar and SFA consumption, heightening non-communicable disease risks like CVD [31]. We, therefore, advise an adequate intake of fruit and vegetables, but caution against the accompanying consumption of added sugar.
4.3. Hcy-related genetic SNPs, daily dietary intake and markers of cardiovascular function and inflammation
Incorporating genomic testing into CVD and hypertension guidelines could enhance personalized nutrition strategies, emphasizing the role of Hcy-related genetic polymorphisms in dietary impacts on cardiovascular health, particularly for H-type hypertension sufferers.
The relationship between sugar, SFAs and fruit and vegetable intake could explain the disappearance of the inverse association between added sugar and cr-PWV in variant allele carriers, which was stronger than in those homozygous for the wildtype allele at the 677 locus, after accounting for fruit and vegetable intake. It could also help clarify why, after adjusting for sugar intake, the folate and VCAM-1 relationships disappeared in those carrying the MTR 2756 minor A genotype. The same can be said for positive associations betweenVCAM-1 and MTR 2756 major allele carriers for vitamin B6 intake. Lastly, the intake of thiamine, a precursor of coenzymes in sugar and amino acid catabolism, led to higher cr-PWV in the TT carriers CBS T883C/ins68 with the interactions disappearing after adjusting for added sugar. It seems therefore that an improved micronutrient status should be accompanied by a balanced, prudent diet of lower added sugar and fructose intake.
cr-PWV was inversely associated with lower PUFA intake in those harboring the TT genotype of CBS T883C/ins68. A previous intervention study reported that daily supplementation of 4,000 mg of omega-3 for 12 weeks decreased carotid-femoral PWV in older, but not younger, healthy adults independent of the effects on BP or arterial wave reflections [32]. The mechanism by which omega-3 PUFAs influence endothelial function (PWV) is mediated by their integration into the phospholipids of biological membranes, so affecting their fluidity. This interaction leads omega-3 PUFAs to bring about their beneficial effects such as increased nitric oxide production and reduced expression of proinflammatory mediators [33]. Despite the study population’s unusually low intake of omega-3 PUFAs, the beneficial implications should not be disregarded. A longitudinal PURE-SA study also found an inverse relationship between omega-6 PUFAs, SBP, and DBP [34], suggesting protective effects may highlight omega-6 long-chain products' role in physiological functions among those with limited omega-3 consumption. The inverse association between SFAs intake and cr-PWV in those harboring MTR 2756AA could possibly be explained by the accompanying PUFAs intake.
Energy consumption was positively associated with VCAM-1 in CBS T883C/ins68 minor allele carriers and CBS 9276 homozygote major allele carriers. However, after adjustment for total carbohydrate intake the interaction disappeared, hinting at a potential link between energy from carbohydrates. Data on the relationship between energy intake and VCAM-1 are scarce. The additional adjustment for total carbohydrate intake that negated the interaction could be explained by the release of VCAM-1 in a dose-dependent manner when energy from carbohydrates increased glucose levels, as illustrated in a previous in vitro experiment using different doses of glucose in human umbilical vein endothelial cells (HUVECs) [35].
Positive linear associations between plant protein intake and VCAM-1 were observed in those harboring homozygote major alleles for CBS 9276 and/or MTR 2756, associations that remained after adjustments. However, an inverse relationship was observed for total protein intake and the MTR 2756 major homozygote AA carriers, suggesting a beneficial relationship. This is supported by previous studies that reported on animal and plant protein intake that decreased VCAM-1 expression in both unstimulated and stimulated HUVECs [36] as well as vascular endothelial cells [37]. The type of protein and concomitant nutrients could contribute to some of the different outcomes observed here.
4.4. Recommendations for precision nutrition
International nutrition and hypertension guidelines offer general recommendations to prevent and manage cardiovascular risk [14, 38]. Although most guidelines are proposed for application across the larger population, and do not currently account for Hcy or H-type hypertension, our personalised nutrition approach still supports and fits within the following general guidelines: 1) lowered sugar intake; 2) sufficient intake of fruit and vegetables; 3) moderate intake of animal products; and 4) an adequate intake of healthy fats. We found that added sugar intake should be limited in those with seemingly normal Hcy or those carrying the T allele at MTHFR 677, to avoid possible detrimental associations with vascular activation (ICAM-1) and vascular function (cr-PWV). Reducing energy and sugar intake benefits CBS T883C/ins68 minor allele and CBS 9276 GG homozygote carriers regarding endothelial activation. Our results endorse consuming fruits and vegetables for their vitamin content, highlighting vitamin B12's role in DBP management and meeting the RDA for those with hypertension. Achieving optimal vitamin status, particularly through fruits and vegetables, supports arterial health. Animal products, high in cholesterol and SFAs, should be consumed sparingly to manage SBP and PP, with a particular focus on animal protein for H-type hypertensives. Carriers of the MTR 2756 AA and CBS 9276 GG genotypes, on the other hand, should be sensible when consuming plant protein – lower rather than higher consumption could be beneficial in terms of vascular-related inflammation and atherosclerosis. Lastly, our results support an adequate intake of healthy fats such as PUFAs and MUFAs. Sufficient consumption of PUFAs is advised for carriers of the TT genotype of CBS T883C/ins68, owing to their positive influence on cr-PWV. We encourage also the intake of MUFAs within the normal ranges for all BP groups to ensure optimal cr-PWV and arterial wall function. Furthermore, dietary management is an alternative treatment avenue that could be explored for those who are resistant to traditional hypertensive drugs.
4.5. Limitations and strengths
The study's large population allowed detection of changes in cardiovascular function and gene–diet interactions, but a larger sample could better account for low-frequency SNPs. Due to its cross-sectional design, only associations were observed without causal inference. Recall bias in dietary assessment via the QFFQ may lead to under- or overreporting. For more precise results, we suggest using biochemical vitamin measures to capture absorption, metabolism and bioavailability, which dietary questionnaires overlook. Future research should conduct dietary supplementation trials by genotype and BP sub-groups to test their effectiveness. Additional cardiovascular markers such as carotid-femoral PWV, a “gold standard” measure for arterial stiffness, and intima media thickness should also be included in future research.