Abstract
Background and aim: Growing evidence suggests that some of the effects of diet on cardiovascular disease (CVD) occur through mechanisms involving subclinical inflammation. We assessed the relationship between selected dietary constituents and serum high-sensitivity C-reactive protein (hsCRP) concentration in a population-based sample of United States adults.
Methods: In this cross-sectional analysis, participants were selected from the US National Health and Nutrition Examination Survey (NHANES) and restricted to those with available data on dietary intake, biochemical and anthropometric measurements from 2001 to 2010. All statistical analyses accounted for the survey design and sample weights by using SPSS Complex Samples v22.0 (IBM Corp, Armonk, NY).
Results: Of the 17,689 participants analysed, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample, 44.9 in men and 46.5 in women (p = .047). The age-, race-, sex-, energy intake- and body mass index-adjusted mean dietary intakes of total dietary fibre, polyunsaturated fatty-acids, vitamin E, vitamin A, vitamin B6, total folate, vitamin B family, vitamin C, vitamin K, magnesium, iron, copper and potassium monotonically decreased across increasing hsCRP quarters (p < .001 for all), whereas sugar intake increased (p < .001). In analysis of covariance adjusted for potential confounders (age-, race-, sex-, energy intake- and body weight-) hsCRP levels increased across increasing quarters of sugar intake (p < .001).
Conclusions: This study provides further evidence of an association between dietary sugar, polyunsaturated fatty-acids, fibre and antioxidant intake and hsCRP levels, a subclinical inflammation marker. hsCRP concentrations are likely modulated by dietary intake.
Serum high-sensitivity C-reactive protein (hsCRP) concentration is positively associated with sugar intake, and negatively with the consumption of minerals, vitamins and polyunsaturated fatty-acids (fruit and vegetables).
hsCRP concentrations, and accordingly subclinical inflammation, are likely influenced by dietary intake.
KEY MESSAGES
Introduction
Recent evidence supports a key role of inflammation in all stages of the development of atherosclerosis [Citation1]. Circulating markers of inflammation such as C-reactive protein (CRP), tumour necrosis factor-α and some interleukins (IL-6 and IL-1), are associated with high risk of cardiovascular disease (CVD) [Citation2,Citation3]. There is evidence to suggest that the influence of diet on CVD risk is mediated through mechanisms that include subclinical inflammation [Citation4]. High-sensitivity CRP (hsCRP) is a biomarker of low-grade inflammation, which has been shown to be predictive of the future risk of CVD and type 2 diabetes (DM), although not always above and beyond established risk markers [Citation5].
Although it is not known whether inflammation is a primary event that causes atherosclerosis, DM and perhaps obesity or whether it is a collateral event, it is important to identify environmental and lifestyle factors that modulate sub-clinical inflammation. In a cross-sectional study involving women aged >45 years, it was reported that magnesium intake is inversely associated with systemic inflammation [Citation6]. Cross-sectional [Citation7,Citation8] and longitudinal [Citation9] studies have reported an inverse association between dietary fibre intake and levels of inflammatory markers. Dietary fibre may therefore play an important role in mediating the relation between diet, inflammation and CVD [Citation7]. Moreover, higher intakes of whole grains (source of fibre), fruits and vegetables (source of antioxidants, fibre, potassium, magnesium and other phytochemicals) [Citation10] in adults have been associated with low CRP levels. An observational study has reported that a high glycaemic load (i.e. a high intake of rapidly digested and absorbed carbohydrates), was positively associated with CRP in healthy women [Citation11]; suggesting a pro-inflammatory process that may increase the risk of CVD and DM, and may be exacerbated by a high intake of rapidly digested and absorbed carbohydrates.
To our knowledge, no prior study has comprehensively examined the association of dietary constituents with CRP levels in the US population. We therefore assessed the association between reported dietary constituents and serum CRP concentrations in the NHANES population sample.
Methods
Population
The National Health and Nutrition Examination Survey (NHANES) is a continuing, repeated set of cross-sectional surveys conducted by the National Center for Health Statistics (NCHS). NHANES uses a multistage probability sampling strategy [Citation12,Citation13]. Approximately 5000 subjects are recruited into NHANES each year, and the data are publicly available in 2-year cycles [Citation12,Citation13]. Demographic, dietary, and behavioural information are gathered through in-home questionnaires, while anthropometric, and biomarker data are collected by trained staff using mobile examination units. The NCHS Research Ethics Review Board approved the underlying protocol, and written informed consent was obtained from all subjects. The interview consists of questions on socio-demographic characteristics and previously diagnosed medical conditions. More detailed information on the NHANES survey design and questionnaires is reported elsewhere [Citation12–14].
The current study is based on analysis of data for two 2-year NHANES survey cycles between 2001 and 2010 using data from the day one dietary recall. Overall response rates for these years ranged from 73 to 84% for interviews and from 70 to 80% for examinations [Citation15,Citation16]. We identified 17,689 eligible participants aged ≥18 years and with non-acute inflammation range CRP levels (i.e. <10 mg/l) for the analyses. Details on NHANES Laboratory/Medical Technologists Procedures and Anthropometry Procedures are described elsewhere [Citation17,Citation18]. Complete laboratory procedures for collection, storage, calibration and quality control of blood samples for determination of hsCRP concentrations are also available elsewhere [Citation19]. DM is defined as a self-reported history of diabetes or fasting plasma glucose ≥126 mg/dl [Citation20].
Dietary intake was assessed via 24 h recall obtained by a trained interviewer during the mobile examination centre visit, with the use of a computer-assisted dietary interview system with standardized probes, i.e. the United States Department of Agriculture Automated Multiple-Pass Method (AMPM) [Citation21,Citation22]. Briefly, the type and quantity of all foods and beverages consumed in a single 24 h period before the dietary interview (from midnight to midnight) were collected with the use of AMPM. AMPM is designed to enhance complete and accurate data collection while reducing respondent burden [Citation22,Citation23]. In the current study, we have included both total folate (umbrella term used to represent the different forms of vitamin B) and vitamin B family (form that occurs naturally in food sources).
Statistical analysis
Analyses were conducted according to the guidelines set by the Centers for Disease Control and Prevention for analysis of the NHANES dataset, accounting for the masked variance and using their suggested weighting methodology [Citation24,Citation25]. Continuous and categorical demographic variables were compared across quarters of hsCRP using analysis of variance (ANOVA) and Chi-square tests, respectively. Age-, sex-, race-, body mass index (BMI)- and energy-adjusted mean intakes of nutrients were compared across quarters of serum hsCRP using analysis of covariance (ANCOVA). Comparison of dietary intakes across quarters of serum hsCRP was conducted using ANCOVA with Bonferroni’s correction. A p < .05 was used to characterize significant results. Data were analysed using SPSS® complex sample module version 22.0 (IBM Corp, Armonk, NY). Sample weights were applied to account for unequal probabilities of selection, nonresponse bias and oversampling.
Results
The weighted distributions of the study population characteristics are shown in . Of the 17,689 eligible participants, 48.3% (n = 8607) were men. The mean age was 45.8 years overall, 44.9 years in men and 46.5 in women (p = .047). The distribution of the clinical, biochemical and anthropometrical characteristics across quarters of serum hsCRP is shown in , with significant differences (all p < .001) in a linear manner (all p < .001 for linear trends). These reflected monotonically increasing trend (decreasing for high-density lipoprotein cholesterol) across increasing quarters of hsCRP level for a variety of measures. Notable findings were positive associations of serum hsCRP levels with BMI, waist circumference and triglycerides. The prevalence of DM, hypertension and metabolic syndrome increased across quarters of hsCRP.
Table 1. Sample size and weighted characteristics of NHANES 2001–2010 adult participants.
Table 2. Clinical and biochemical measures across quartiles of high sensitivity C-reactive protein (hsCRP).
Mean dietary intakes of fibre, vitamin E, vitamin A, riboflavin, niacin, vitamin B6, total folate, folic acid, vitamin B family, vitamin C, vitamin K, magnesium, iron, copper, potassium and poly-unsaturated fatty acids monotonically decreased across hsCRP quarters (p < .001, ).
Table 3. Age-, sex- and race-adjusted mean nutrient intakes across quartiles of high sensitivity C-reactive protein (hsCRP) levels.
In BMI, energy intake, age, race and gender adjusted models, total dietary fibre, vitamin E, vitamin A, vitamin B6, total folate, vitamin B family, vitamin C, vitamin K, magnesium, iron, copper, potassium and poly-unsaturated fatty acids monotonically decreased across hsCRP quarters (Supplemental Table 1, all p < .001), while total sugar increased across hsCRP quarters (all p < .001). Findings were robust in expanded models adjusted for BMI, energy intake, age, race gender and smoking (all p < .001). In ANCOVA adjusted for potential confounding factors (age-, race-, sex-, energy intake- and BMI) analysis, hsCRP concentrations increased across increasing quarters of sugar intake (p < .001).
The ANCOVA adjusted for age-, sex-, race in participants with prevalent DM, revealed that intake of fibre, vitamin E, vitamin A, total folate, vitamin C, vitamin K, magnesium, iron, copper decreased across increasing quarters of hsCRP. After further adjustment for energy intake and BMI, the patterns remained significant for fibre, vitamin E, total folate, vitamin K and iron intake; while there was no significant association between sugar intake and hsCRP in subjects with DM (β = 0.025, p = .326).
Discussion
The main findings of this study were the association of increasing serum hsCRP levels with increasing sugar intake and decreasing dietary fibre, vitamin E, vitamin A and vitamin C; suggesting a relationship between sugar, dietary fibre and antioxidant intake and subclinical inflammation in this population.
In line with our findings, The Nurses’ Health Studies reported a dietary pattern high in sugar, sugar-sweetened soft drinks, and refined grains, to be positively correlated with concentrations of IL-6 and CRP [Citation26,Citation27]. It has been suggested that dietary patterns rich in refined starches, sugars and poor in natural antioxidants and fibre from fruit, vegetables and whole grains may trigger the innate immune system, leading to an excessive synthesis of pro-inflammatory cytokines and a decreased production of anti-inflammatory cytokines [Citation28,Citation29]. Moreover, a recent randomized clinical trial reported that compliance with low-glycaemic index diet may have satisfactory effect on inflammation among overweight and obese adolescent girls [Citation30].
Fruits have many beneficial health effects including providing vitamins, minerals, anti-oxidants and fibres, which are all essential for human’s health [Citation31]. However, consumed in excess (particularly as fruit juice) fruits could be harmful for health. Excessive consumption of fructose, the most abundant sugar in fruits, has been tied to negative health effects [Citation32]. Havel's group recently investigated the effects of 10 weeks of excessive fructose intake compared with glucose consumption in overweight/obese adults and found that the plasma level of serum intercellular adhesion molecule 1 (ICAM-1) increased in individuals consuming fructose but not in those consuming glucose [Citation33]. Interestingly, fructose at physiologic concentration did not induce other pro-inflammatory mediators. Fructose is distinct from other sugars because it can rapidly cause ATP depletion in cells. Unlike the glucose–glucokinase pathway, which is tightly regulated, the phosphorylation of fructose by fructokinase is not effectively regulated, and, thus, rapid ATP depletion can occur [Citation34]. It is important to keep in mind that regular consumption of fruits and vegetables, generally will not result in excess levels of fructose [Citation32].
Consistent with our findings, Miller et al. suggested that increases in dietary fibre play a significant role in lowering inflammation in overweight youth [Citation35]. Furthermore, in a cross-sectional study of 559 normal-weight African-American and Caucasian adolescents, it was found that total fibre intake was negatively associated with CRP and fibrinogen levels [Citation36]. Dietary fibre can be partially or completely fermented to short chain fatty acids (acetate, propionate and butyrate) and studies have shown that propionate decrease the pro-inflammatory cytokines and inflammation process [Citation37].
This study has several strengths. We used a large sample, and accordingly had adequate statistical power to uncover significant associations, if any. The selection of the participants was based on random sampling of the general population and therefore the results obtained from nationally representative samples can be extrapolated to the general population. As the data collection was performed on all days of the week throughout the year in NHANES, the potential for selection bias is low [Citation38,Citation39].
The present study has some limitations. Its cross-sectional nature does not allow inferences about causality. We lacked data on glycaemic index and glycaemic load and could not explore their possible effect. In the current study, a one-day 24 h food record was used, which may not capture long-term diet. Moreover, there is a possibility of over- and underreporting food intake. Analyses in this paper are based on data collected over a 10-year period. It is likely that the diet of American people changed over this period or subsequently, which may to some extent affect the generalizability of the findings. Lastly, the observed associations of minerals and vitamins to some extent could reflect multiple collinearity, considering the well-established association between fruits and vegetables intake (the source of vitamins and minerals) and CRP levels [Citation40,Citation41].
Our study provides a comprehensive snapshot of dietary correlates of hsCRP among Americans. While our findings reinforce the importance of balanced diet, the uncovered links between some of the nutrients and hsCRP may represent novel metabolic pathways and provide basis for further research. Our findings support the evidence for the association between dietary intake and subclinical inflammation as reflected by hsCRP levels. This raises the possibility that hsCRP concentrations could be improved by changes in sugar, polyunsaturated fatty-acids, dietary fibre and antioxidant intake.
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MM was supported by a TWAS studentship of the Chinese Academy of Sciences.
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References
- Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143.
- Mazidi M, Heidari-Bakavoli A, Khayyatzadeh SS, et al. Serum hs-CRP varies with dietary cholesterol, but not dietary fatty acid intake in individuals free of any history of cardiovascular disease. Eur J Clin Nutr. 2016;70:1454–1457.
- Yousuf O, Mohanty BD, Martin SS, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62:397–408.
- van Bussel BC, Henry RM, Ferreira I, et al. A healthy diet is associated with less endothelial dysfunction and less low-grade inflammation over a 7-year period in adults at risk of cardiovascular disease. J Nutr. 2015;145:532–540.
- Kengne AP, Batty GD, Hamer M, et al. Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies. Diabetes Care. 2012;35:396–403.
- Song Y, Ridker PM, Manson JE, et al. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005;28:1438–1444.
- King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol. 2003;92:1335–1339.
- Bo S, Durazzo M, Guidi S, et al. Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr. 2006;84:1062–1069.
- Ma Y, Griffith JA, Chasan-Taber L, et al. Association between dietary fiber and serum C-reactive protein. Am J Clin Nutr. 2006;83:760–766.
- Esmaillzadeh A, Kimiagar M, Mehrabi Y, et al. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr. 2006;84:1489–1497.
- Liu S, Manson JE, Buring JE, et al. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr. 2002;75:492–498.
- Mazidi M, Michos ED, Banach M. The association of telomere length and serum 25-hydroxyvitamin D levels in US adults: the National Health and Nutrition Examination Survey. AOMS. 2017;13:61–65.
- Kalk WJ, Joffe BI. The metabolic syndrome, insulin resistance, and its surrogates in African and white subjects with type 2 diabetes in South Africa. Metab Syndr Relat Disord. 2008;6:247–255.
- Mazidi M, Gao HK, Vatanparast H, et al. Impact of the dietary fatty acid intake on C-reactive protein levels in US adults. Medicine (Baltimore). 2017;96:e5736.
- Alebiosu CO, Odusan BO. Metabolic syndrome in subjects with type-2 diabetes mellitus. J Natl Med Assoc. 2004;96:817–821.
- Mazidi M, Kengne AP. Nutrient patterns and their relationship with general and central obesity in US adults. Eur J Clin Invest. 2017. [Epub ahead of print] doi: 10.1111/eci.12745
- Konnov MV, Dobordzhinidze LM, Deev AD, et al. Waist circumference below metabolic syndrome harmonizing criteria is associated with increased cardiovascular risk. Kardiologiia. 2010;50:23–27.
- Ogbera AO. Prevalence and gender distribution of the metabolic syndrome. Diabetol Metab Syndr. 2010;2:1.
- Available from: http://www.cdc.gov/NCHS/data/nhanes/nhanes_09_10/CRP_F_met.pdf
- Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197.
- Ahluwalia N, Andreeva VA, Kesse-Guyot E, et al. Dietary patterns, inflammation and the metabolic syndrome. Diabetes Metab. 2013;39:99–110.
- Ahluwalia N, Dwyer J, Terry A, et al. Update on NHANES Dietary Data: focus on collection, release, analytical considerations, and uses to inform public policy. Adv Nutr. 2016;7:121–134.
- Moshfegh AJ, Rhodes DG, Baer DJ, et al. The US Department of Agriculture Automated Multiple-Pass Method reduces bias in the collection of energy intakes. Am J Clin Nutr. 2008;88:324–332.
- Statistics. NCfH. Analytic and reporting guidelines. Available from: http://www.cdc.gov/nchs/data/nhanes/nhanes 03 04/nhanes analytic guidelines dec 2005.pdf
- Mazidi M, Kengne AP, Banach M. Mineral and vitamin consumption and telomere length among adults in the United States. Pol Arch Intern Med. 2017;127:87–90.
- Hu FB. Dietary pattern analysis: a new direction in nutritional epidemiology. Curr Opin Lipidol. 2002;13:3–9.
- Steckhan N, Hohmann CD, Kessler C, et al. Effects of different dietary approaches on inflammatory markers in patients with metabolic syndrome: a systematic review and meta-analysis. Nutrition. 2016;32:338–348.
- Mazidi M, Pennathur S, Afshinnia F. Link of dietary patterns with metabolic syndrome: analysis of the National Health and Nutrition Examination Survey. Nutr Diabetes. 2017;7:e255. doi: 10.1038/nutd.2017.11
- Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48:677–685.
- Rouhani M, Kelishadi R, Hashemipour M, et al. The impact of a low glycemic index diet on inflammatory markers and serum adiponectin concentration in adolescent overweight and obese girls: a randomized clinical trial. Horm Metab Res. 2016;48:251–256.
- Klee HJ. Improving the flavor of fresh fruits: genomics, biochemistry, and biotechnology. New Phytol. 2010;187:44–56.
- Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005;10:294–306.
- Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334.
- Maenpaa PH, Raivio KO, Kekomaki MP. Liver adenine nucleotides: fructose-induced depletion and its effect on protein synthesis. Science. 1968;161:1253–1254.
- Miller SJ, Batra A, Shearrer G, et al. Dietary fibre linked to decreased inflammation in overweight minority youth. Pediatr Obes. 2016;11:33–39.
- Parikh S, Pollock NK, Bhagatwala J, et al. Adolescent fiber consumption is associated with visceral fat and inflammatory markers. J Clin Endocrinol Metabol. 2012;97:E1451–E14E7.
- Ren G-Y, Chen C-Y, Chen G-C, et al. Effect of flaxseed intervention on inflammatory marker C-reactive protein: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016;8:136.
- Tooze JA, Midthune D, Dodd KW, et al. A new statistical method for estimating the usual intake of episodically consumed foods with application to their distribution. J Am Diet Assoc. 2006;106:1575–1587.
- Guenther PM, Ding EL, Rimm EB. Alcoholic beverage consumption by adults compared to dietary guidelines: results of the National Health and Nutrition Examination Survey, 2009–2010. J Acad Nutr Diet. 2013;113:546–550.
- Fung TT, McCullough ML, Newby PK, et al. Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr. 2005;82:163–173.
- Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study. J Am Coll Cardiol. 2004;44:152–158.