Dietary factors and hypertension: A Mendelian randomization analysis

Abstract This research explores the causal link between dietary habits and hypertension through Mendelian randomization, providing distinct perspectives on the role of diet in addressing this worldwide health issue. Utilizing instrumental variables, we applied advanced statistical methods, including the weighted median, inverse variance weighted, and MR‐Egger, to evaluate the impact of 17 dietary elements on hypertension. These elements ranged across various food groups, such as fruits, meats, vegetables, and beverages, both alcoholic and nonalcoholic. Our results identified a significant positive association of hypertension with weekly alcohol consumption (OR 1.340 [95%CI 1.0001 to 1.794], p = .0499) and poultry intake (OR 2.569 [95%CI 1.305 to 5.057], p = .00631). Conversely, a negative association was observed with lamb/mutton (OR 0.550 [95%CI 0.343 to 0.881], p = .0129), cheese (OR 0.650 [95%CI 0.519 to 0.813], p = .000159), tea (OR 0.797 [95%CI 0.640 to 0.993], p = .0433), cereal (OR 0.684 [95%CI 0.494 to 0.948], p = .0227), and dried fruit consumption (OR 0.492 [95%CI 0.343 to 0.707], p = .000127). These findings suggest that dietary modifications, such as increasing consumption of specific foods like cheese, lamb/mutton, tea, cereals, and dried fruits, could potentially reduce hypertension risk while reducing intake of alcoholic beverages and poultry might mitigate its increase. No direct causal relationships were established between other dietary factors and hypertension. The study highlights the importance of specific dietary modifications for the prevention and control of hypertension, making a substantial contribution to public health tactics and recommendations.


| INTRODUC TI ON
Hypertension is a global issue that endangers people's health (Zhou et al., 2021).Elevated blood pressure levels can result from heightened cardiac output, increased peripheral vascular resistance, or a combination of both, adversely affecting the average lifespan (Kitt et al., 2019).Familial clustering implies a genetic susceptibility whose interaction with environmental factors (such as salt and calorie consumption) ultimately determines the severity of the rise in blood pressure.Nearly half of the population is endangered by potential hypertension (Williams et al., 2018a).The danger of hypertension is mainly due to heart disease, chronic kidney disease, and cardiovascular and cerebrovascular pathologies (Guo et al., 2020).
Understanding the impact of particular diets on blood pressure readings is crucial from a clinical perspective (Saklayen, 2018).The first thing that people with hypertension take is nonmedication to control their blood pressure, and even after taking medication, they should also maintain good dietary habits.The most important nonpharmaceutical treatment measures are a low-salt diet, adequate potassium consumption, and a healthy balanced diet (Williams et al., 2018b).
An earlier study found that the DASH diet lowered blood pressure (Sacks et al., 2001), numerous dietary recommendations, such as reducing sodium intake, consuming low-fat dairy products, limiting sweets and red meat, and increasing fruit and vegetable consumption, have been shown to effectively lower blood pressure in recent years.Numerous research studies have demonstrated that high carbohydrate consumption appears to exacerbate metabolic syndrome (MS; Taskinen et al., 2019), conversely, carbohydrate-restricted dietary regimens appear to be more effective in controlling the characteristics of MS (Volek et al., 2009).Increasing the intake of fresh fruits and vegetables, rich in potassium, antioxidants, and flavonoids, while reducing dietary sodium, can effectively lower blood pressure across the population (Borgi et al., 2016).People's health comes from changes in long-term dietary habits (Sacks et al., 2001).
Advocating for a healthy DASH eating plan can impact the diverse physiological processes regulating blood pressure, thereby diminishing the risk of cardiovascular disease (Filippou et al., 2022).
Observational research has consistently demonstrated a clear connection between dietary patterns and the prevalence of hypertension (Tseng et al., 2021).Mendelian randomization (MR) uses instrumental variable (IV) consisting of genetic variation and has advantages compared to other study methods.Mendelian randomization (MR) studies investigating the cause-and-effect relationship between dietary factors and hypertension have been relatively scarce.Thus, our research focuses on exploring the causal connection between diet and hypertension through Mendelian randomization.

| ME THODOLOGY
In Mendelian randomization analysis, choosing appropriate instrumental variables is crucial.These variables should be strongly associated with exposure factors but not influenced by confounding TA B L E 1 Information of the exposures and outcome datasets.

| Data sources and the selection of IVs
We obtained summary data from genome-wide association studies (GWAS) of 17 dietary patterns, sourced from the UK Biobank.
This expansive prospective cohort encompasses around 500,000 individuals, providing both genetic and a range of phenotypic details (Sudlow et al., 2015).Abbreviations: CI, confidence interval; NA, not available; OR, odds ratio; SNPs, single-nucleotide polymorphisms. a The results of MR-PRESSO are presented in the form of beta values, and there is a conversion relationship between beta values and OR, specifically beta = log(OR). b We repeated the Mendelian randomization analysis after removing outliers.
| 2505 In conducting this Mendelian randomization (MR) analysis, we exclusively analyzed anonymized databases, thereby ensuring no impact on patients.The study utilized GWAS summary statistics from published studies and publicly accessible summary data available online.Each GWAS included had previously secured ethical approval.The summary statistics used were deidentified, readily downloadable, and available for unrestricted use.

| Statistical analysis
IVW was used for the calculation of causal effects and had the highest utility among all methods for calculating two-sample analysis (Hartwig et al., 2017) 2).
The exclusionary analysis indicated that the causality behind the positive findings was highly robust (Figure 1).The effectiveness of the IVW was confirmed using MR-PRESSO analysis (causal relationships were only shown in alcoholic drinks per week, poultry consumption, lamb/mutton consumption, cheese consumption, tea consumption, cereal consumption, and dried fruit consumption; Table 2).IVs with a strong correlation with dietary factors (F: 17.571-116.369)were used in this study (Table 1).

| DISCUSS ION
The Mendelian randomization study found that alcoholic drinks per week, poultry consumption, dried fruit consumption, lamb/mutton consumption, cheese consumption, and tea consumption contributed to the risk of hypertension.We would exclude outliers before the research analysis.Other factors (oily fish consumption, alcohol consumption frequency, fresh fruit consumption, nonoily fish consumption, pork consumption, bread consumption, cooked vegetable consumption, beef consumption, salad/raw vegetable consumption, and coffee consumption) showed no significant correlation with the emergence of hypertension.There was a large body of previous research describing the relationship between diet and the development of hypertension.Dietary plans such as the DASH and Mediterranean diets emphasize increased consumption of vegetables and fruits, a low-sodium diet, and reduced fat intake to lower the risk of hypertension (Ahmed et al., 2020;Theodoridis et al., 2023).Hypertension affects 40% of the world's population and is an important risk for cardiovascular and cerebral disease in humans.People at risk often prevented and controlled hypertension in the first place by modifying their diet, which was also a long-term approach to nonpharmacological treatment/prevention, and even after increasing medication the same needed to maintain the previous diet structure.Controlled hypertension significantly reduces the risk of various diseases (Thomopoulos et al., 2014).Mendelian randomization studies, with the help of instrumental variables, can exclude reversing causality as well as confounding factors.To verify the accuracy of the MR analysis, sensitivity, and multi-effect analyses were performed.We used exposures and results from different regions to avoid bias.This study can, therefore, provide more authoritative dietary guidelines and provide reasonable and implementable clinical advice for people with hypertension.
Alcohol's impact on the cardiovascular system is multifaceted and dose dependent.It can contribute to an increase in oxygen free radicals and oxidative stress.Additionally, the metabolites of ethanol can influence the altered activation of the neurohormonal system, specifically the renin-angiotensin-aldosterone system (Roerecke, 2021).
Alcohol consumption is a contributing factor to the worldwide burden of disease, injury, and economic costs.The detrimental effects of alcohol use are universal and have a global impact (Kalinowski & Humphreys, 2016).Two recent meta analyses summarize the association between alcohol and the incidence of hypertension (Jung et al., 2020;Liu et al., 2020).Elevated blood pressure increases the risk of cardiovascular disease and people at risk should pay extra attention to blood pressure control (Lewington et al., 2002).Studies show a clear causal relationship between alcohol consumption and hypertension and a clinically significant dose-systolic blood pressure relationship (Roerecke et al., 2017).Alcohol consumption prolongs the QT interval (Kino et al., 1981), has both short-term and long-term effects on hypertension (Fernández-Solà, 2015), and heavy drinkers are often accompanied by other poor lifestyle habits (tobacco; Chan & Anderson, 2014).It has been proposed that moderate alcohol intake may offer some protective benefits for women, whereas in men, there appears to be a linear relationship between the amount of alcohol consumed and blood pressure levels, irrespective of the quantity of alcohol intake (Taylor et al., 2009).If poor health is the reason for reducing the frequency of alcohol consumption, then this would make moderate alcohol consumption appear healthier (less symptomatic of hypertension), which may explain why the frequency of alcohol consumption was not associated with hypertension after excluding outliers in our analysis.
Much cited in previous studies is the DASH diet versus the Mediterranean diet.The Mediterranean diet mainly emphasizes a dietary pattern of grains, fresh fruit and vegetables, legumes, and The results of leave-one-out analyses.The results of Leave-one-out analyses (a) cereal intake, (b) dried fruit intake, (c) cheese intake, (d) lamb/mutton intake, (e) Tea intake, (f) alcoholic drinks per week, (g) poultry intake.
nuts.This dietary approach also encompasses the inclusion of fish and seafood, low-fat dairy products, poultry, and eggs.It advocates for a reduction in the consumption of red meat and sweets or sugary beverages while increasing the proportion of fats in the total daily caloric intake (Davis et al., 2015).Study shows a U-shaped association between poultry consumption, cereal consumption, and new-onset hypertension (Zhou et al., 2022).The consumption of poultry has been associated with an increased risk of developing hypertension (Zhang & Zhang, 2018).The hypertension risk linked to poultry and red meat intake in our study may relate to Maillard reaction products (MRPs) like heterocyclic amines and advanced glycoxidation end-products (AGEs) formed during cooking.These compounds enhance oxidative stress and inflammation, potentially impacting hypertension.Moreover, L-carnitine in red meat, metabolized into trimethylamine-N-oxide (TMAO), is associated with cardiovascular risks, including hypertension (Borgi et al., 2015).The grading of evidence levels indicates a potentially negative correlation, suggesting that higher intake of fruits, whole grains, fish, legumes, nuts, and dietary fiber might be correlated with a decreased chance of developing hypertension (Jabbari et al., 2022).This link could be due to the existence of particular bioactive components in these food items.For example, fruits and vegetables are rich in potassium, which helps regulate blood pressure.Whole grains and dietary fiber can improve blood lipid profiles and reduce arterial pressure.Omega-3 fatty acids, prevalent in fish, are known for their anti-inflammatory effects and ability to improve endothelial function.Legumes and nuts contain various phytochemicals and antioxidants that contribute to cardiovascular health.These compounds collectively work to modulate blood pressure, thereby reducing hypertension risk (Hosseinpour-Niazi et al., 2022;Shridhar et al., 2018).A study finds no correlation between cheese consumption and high blood pressure (Hu et al., 2022).A combined higher intake of yogurt along with a higher score on the DASH ("Dietary Approaches to Stop Hypertension") diet scale has been linked to a decreased occurrence of hypertension (Buendia et al., 2018).Research has suggested that due to its high antioxidant content, coffee consumption may be inversely related to the probability of elevated blood pressure (Ding et al., 2014).The Singapore Chinese Health Study has found that coffee consumption is associated with a reduced risk of developing high blood pressure, but coffee may be responsible for increased risk in daily tea drinkers (Chei et al., 2018).Contrary to some findings, this study did not observe a significant association between coffee consumption and the risk of hypertension.
However, a study by Chieng & Kistler (2022) indicated that coffee intake may lower the risk of cardiovascular diseases, and consuming tea could potentially help in preventing metabolic syndrome, this is consistent with the risk of hypertension being reduced by tea drinking in this study.A separate study focusing on elderly Chinese individuals who have lived long lives revealed that daily consumption of green tea increased the risk of high blood pressure by approximately 38% in men, while it showed no significant effect in women (Peng et al., 2021).Currently, there is a scarcity of research investigating the relationship between the consumption of mutton or lamb and the development of hypertension.
Diet may indirectly influence the development of hypertension through the gut microflora and the level of hormones in the blood.Hypertension may develop from ectopic fat stores (Montani et al., 2004), and sodium in food can directly increase systolic blood pressure (He et al., 2020).Maintaining normal blood pressure through a regular diet is a virtuous habit for today's generation, and controlling blood pressure levels is not just for people with hypertension (Lackland & Egan, 2007).Whereas past RCT studies have tended to study hypertension separately from diet and alcohol consumption to avoid interaction, Mendelian randomization trials are not so troubled.
The following limitations exist in this study: Long-term eating habits rather than short periods could affect the risk of hypertension.There is also variation in the impact of different ethnic areas, and the combined effect of multiple factors may also lead to biased Future studies are anticipated to delve deeper into multimodal predictive models for hypertension, incorporating these varied factors.

| CON CLUS ION
This research revealed associations between the consumption of lamb/mutton, cheese, tea, cereals, and dried fruits with a lowered incidence of hypertension, and the consumption of alcoholic beverages on a weekly basis and the intake of poultry have been linked to the onset of hypertension.At the same time, alcohol consumption frequency, oily fish consumption, fresh fruit consumption, nonoily fish consumption, pork consumption, bread consumption, cooked vegetable consumption, beef consumption, coffee consumption, and salad/ raw vegetable consumption were not associated with hypertension.
findings.Mendelian randomization is limited in its ability to analyze causality across different ages and sexes, indicating potential complexity in the mechanisms linking exposure and outcome.The F statistic, which assesses the correlation between intermediate variables and exposure factors, could potentially compromise the study's accuracy if it registers below 100.Moreover, this study falls short in offering a detailed examination of diverse diet mixes or a thorough comparative analysis of various diet plans.It is also crucial to recognize that hypertension is influenced by a multitude of factors, including physical activity, body composition, and genetics.

Used SNPs Inverse variance weighted method (Wald ratio) Weighted median method MR-Egger method Cochrane's Q test Pleiotropy MR-PRESSO a OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value Q p-value MR-Egger intercept SE p-value Raw
The results of Mendelian randomization analyses.