A nutrient-wide association study on blood pressure

Abstract

Background: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner.

Methods and results: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP.

Conclusions: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

Figure 1

Procedure to systematically associate nutrients with blood pressure

Figure 2

“Volcano plot” graphic showing the nutrient-wide associations with systolic blood pressure levels in INTERMAP training set for nutrients received from foods and urine excretion markers (A) and for nutrients received from foods and supplements (B) Y-axis indicates -log10(p-value) of the adjusted linear regression coefficient for each of the nutrients. Horizontal line represents the level of significance corresponding to FDR less than 5% and the x axis shows the effect sizes (mmHg) per 1SD change in the nutrient variable. Filled marks represent tentatively validated nutrients in the INTERMAP testing set (p<0.05). Analyses are adjusted for age, sex, reported special diet, use of dietary supplements, moderate or heavy physical activity (hours daily), doctor diagnosed cardiovascular disease or diabetes, family history of hypertension, height, weight and total energy intake,.

Figure 2

“Volcano plot” graphic showing the nutrient-wide associations with systolic blood pressure levels in INTERMAP training set for nutrients received from foods and urine excretion markers (A) and for nutrients received from foods and supplements (B) Y-axis indicates -log10(p-value) of the adjusted linear regression coefficient for each of the nutrients. Horizontal line represents the level of significance corresponding to FDR less than 5% and the x axis shows the effect sizes (mmHg) per 1SD change in the nutrient variable. Filled marks represent tentatively validated nutrients in the INTERMAP testing set (p<0.05). Analyses are adjusted for age, sex, reported special diet, use of dietary supplements, moderate or heavy physical activity (hours daily), doctor diagnosed cardiovascular disease or diabetes, family history of hypertension, height, weight and total energy intake,.

Figure 3

“Volcano plot” graphic showing the nutrient-wide associations with diastolic blood pressure levels in INTERMAP training set for nutrient received from foods and urine excretion markers (A) and for nutrients received for foods and supplements (B) Y-axis indicates −log10(p-value) of the adjusted linear regression coefficient for each of the nutrients. Horizontal line represents the level of significance corresponding to FDR less than 5% and the x axis shows the effect sizes (mm Hg) per 1SD change in the nutrient variable. Filled marks represent tentatively validated nutrients in the INTERMAP testing set (p < 0.05). Analyses are adjusted for age, sex, reported special diet, use of dietary supplements, moderate or heavy physical activity (hours daily), doctor diagnosed cardiovascular disease or diabetes, family history of hypertension, height, weight and total energy intake.

Figure 3

“Volcano plot” graphic showing the nutrient-wide associations with diastolic blood pressure levels in INTERMAP training set for nutrient received from foods and urine excretion markers (A) and for nutrients received for foods and supplements (B) Y-axis indicates −log10(p-value) of the adjusted linear regression coefficient for each of the nutrients. Horizontal line represents the level of significance corresponding to FDR less than 5% and the x axis shows the effect sizes (mm Hg) per 1SD change in the nutrient variable. Filled marks represent tentatively validated nutrients in the INTERMAP testing set (p < 0.05). Analyses are adjusted for age, sex, reported special diet, use of dietary supplements, moderate or heavy physical activity (hours daily), doctor diagnosed cardiovascular disease or diabetes, family history of hypertension, height, weight and total energy intake.

Figure 4

Pearson coefficient correlation heatmap showing all nutrients and potential confounders examined in a) INTERMAP total population and b) NHANES total population Nutrients are clustered according to a hierarchical clustering algorithm in INTERMAP, grouping highly correlated factors closer to one another. For NHANES the clustering of INTERMAP samples has been used. Correlation coefficients are adjusted for age, sex and sample (INTERMAP)/ cohort (NHANES).

Figure 4

Pearson coefficient correlation heatmap showing all nutrients and potential confounders examined in a) INTERMAP total population and b) NHANES total population Nutrients are clustered according to a hierarchical clustering algorithm in INTERMAP, grouping highly correlated factors closer to one another. For NHANES the clustering of INTERMAP samples has been used. Correlation coefficients are adjusted for age, sex and sample (INTERMAP)/ cohort (NHANES).