Association of gender-specific risk factors in metabolic and cardiovascular diseases: an NHANES-based cross-sectional study =========================================================================================================================== * Xiu-E Zhang * Bei Cheng * Qian Wang * Jing-Jing Wan ## Abstract In the present cross-sectional study, based on National Health and Nutrition Examination Survey (NHANES, 2007–2010) cohorts, various risk factors for metabolic syndrome (MetS) and cardiovascular diseases (CVDs) were analyzed (n=12,153). The variables analyzed include, demographics, comorbidities associated with MetS or CVD, behavioral and dietary factors, while the primary endpoints were the prevalence of MetS and CVD. The prevalence of MetS and CVD was slightly higher in males as compared with females (42.50% and 7.65% vs 41.29% and 4.13%, respectively). After controlling for confounding factors, advanced age, family history of diabetes mellitus (DM), overweight, and obesity were significantly associated with the likelihood of MetS, irrespective of gender differences. In males, the diagnosis of prostate cancer and regular smoking were additional risk factors of MetS, whereas, advanced age, family history of heart attack or angina, health insurance coverage, diagnosis of rheumatoid arthritis or depression, obesity and low calorie intake were identified as risk factors for CVD. In addition to the above risk factors, higher physical activity and vitamin D insufficiency were also found to increase the risk of CVD in females. Furthermore, obesity was a higher risk factor for MetS than CVD. Emerging risk factors for CVD identified in this study has major clinical implications. Of interest is the correlation of higher physical activity and the risk of CVD in women and the role of depression and lower calorie intake in general population. * metabolic syndrome * cardiovascular disease * behavior * diet * risk factors * National Health and Nutrition Examination Survey (NHANES) ### Significance of the study #### What is already known about this subject? * After adjusting for age, the prevalence of metabolic syndrome is similar in men and women (22% and 24%, respectively). * Patients with metabolic syndrome have a greater risk of developing diabetes mellitus and coronary heart disease later in life. * The risk factors underlying metabolic syndrome and cardiovascular diseases are similar, and cardiovascular disease is often preceded by metabolic syndrome. #### What are the new findings? * The present analysis reveals risk factors that are not previously linked to cardiovascular disease, namely, the correlation of higher physical activity in women, and the role of depression and low calorie intake in the general population. * Diagnosis of depression (adj. OR=2.46, 95% CI 1.13 to 5.36), higher physical activity (adj. OR=2.93, 95% CI 1.63 to 5.26), and low total calorie intake (adj. OR=2.40, 95% CI 1.07 to 5.67) were found to be highly associated with the development of cardiovascular disease in females, after controlling for confounding factors. * In males, diagnosis of depression (adj. OR=1.80, 95% CI 1.09 to 2.92) and low total calorie intake (adj. OR=2.20, 95% CI 1.22 to 3.98) was shown to be strongly associated with the development of cardiovascular disease. ### Significance of the study #### How might these results change the focus of research or clinical practice? * Increased total physical activity is thought to be associated with the reduced risk of coronary heart diseases, but in females, intense and strenuous exercise may have adverse effects. * A low-calorie, high-fiber diet is often recommended to reduce the risk of metabolic syndrome and cardiovascular disease, but our results suggest that a low calorie intake may increase the risk. The underlying mechanism needs to be further investigated. * Patients with depression need more support and attention, as it increases their risk in developing metabolic syndrome and cardiovascular disease. ## Introduction Metabolic syndrome (MetS) is an important risk factor for the subsequent development of cardiovascular disease (CVD). MetS is a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose deposition and function.1 Clinical manifestations of MetS include hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C), and abdominal obesity. MetS is a growing health concern globally2–5 and is equally prevalent in men (24%) and women (22%) after adjusting for age.6 However, there are several factors that are unique to women, including pregnancy, use of oral contraceptives, postpartum breast feeding, polycystic ovarian syndrome and so on.7 We hypothesized that these additional factors may increase the risk of CVD in women with MetS and assessed the role of gender in the development of MetS and CVD in the present study. In addition to adipose dysfunction and insulin resistance,8 9 psychological characteristics also play a major role in the development of MetS. Anger, depression, and hostility had been shown to be associated with increased risk for MetS.10 Recent reports indicate that MetS is significantly associated with lifetime major depression and the presence of any anxiety disorder.11 12 Furthermore, there is compelling evidence linking CVD with major depressive disorder and bipolar disorder.13 14 In recent epidemiological studies in the USA, the prevalence of CVD among adults with major depressive disorder was nearly threefold greater than those without mood disorders.15 The association of traditional risk factors like family history, poor dietary habits, sleep disorders, and inadequate physical activity in the development of MetS and CVD had been well established. However, recent reports indicate that new risk factors that were not previously associated with CVDs are becoming apparent with drastic changes in lifestyle and dietary habits among the general population across the globe. In light of this, we undertook a cross-sectional analysis of the population by utilizing the National Health and Nutrition Examination Survey (NHANES) database of Centers for Disease Control and Prevention (CDC) in the USA. We believed that modern lifestyle and dietary habits may lead to an increased risk of MetS and CHD. Furthermore, though the risk factors underlying the MetS and CVD are similar, CVD is tightly associated with a variety of other behavioral and genetic factors. The present study was undertaken to analyze the risk factors for both diseases separately in order to delineate the commonalities and differences in the behavioral and dietary factors leading to the emergence of one or the other. Recognizing the underlying risk factors may help healthcare providers in identifying individuals prone to CVD at routine clinic visits and to further improve the public health policy. ## Methods ### Design, subjects, and endpoints This cross-sectional study was performed using data stored in the NHANES, CDC, National Center for Health Statistics (NCHS), and the US Department of Health and Human Services ([http://www.cdc.gov/nchs/nhanes/](http://www.cdc.gov/nchs/nhanes/)) (year 2007~2010 cycles). All data from NHANES database were deidentified and hence, analysis of the data did not require Institutional Review Board approval or informed consent by subjects. The present study sample consisted of NHANES participants above 20 years old (n=12,153). Subjects who were more than 80 years old was recorded as 80. Subjects with complete data for coronary heart disease, angina/angina pectoris, or heart attack were included in the analysis of CVDs (n=12,054). Individuals who did not participate in the fasting subsample were excluded from the analysis of the MetS (n=4920). The endpoints of the present study were the prevalence of MetS and CVDs. Criteria of MetS was based on guidelines developed by the 2001 National Cholesterol Education Program Adult Treatment Panel III (ATP III). ATP III MetS criteria were updated in 2005 in a statement from the American Heart Association/National Heart, Lung, and Blood Institute. Prevalence of CVDs included self-reported coronary heart disease, angina/angina pectoris, and heart attack in the questionnaire of ‘Medical condition’ section. ### Study variables The variables obtained for each disease group were patient demographics (age, gender, race/ethnicity, and marital status), family history (diabetes and heart attack/angina), socioeconomic status (education level, ratio of family income to poverty, and health insurance status), behavioral factors (body mass index (BMI), smoking history, alcohol use, physical activity, sleeping hours, postpartum breast feeding, and last childbearing age), dietary factors (vitamin D insufficiency, total daily calorie consumption, and total daily sugar consumption), and disease association (self-reported medical condition of rheumatoid arthritis, depression, asthma, osteoporosis, and prostate cancer). Details of each variable is discussed below. ### Metabolic syndrome Current ATP III criteria16 define MetS as the presence of any **three** of the following five traits: 1. abdominal obesity, defined as a waist circumference in men ≥102 cm (40 in) and in women ≥88 cm (35 in). 2. serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides. 3. serum HDL-C <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) ,in women or drug treatment for low HDL-C. 4. blood pressure ≥130/85 mm Hg or drug treatment for elevated blood pressure. 5. fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose. ### Demographic data Subjects were administered the Family and Sample Person Demographics questionnaires at home by trained interviewers using a Computer-Assisted Personal Interviewing (CAPI) system. The CAPI system is programmed with built-in consistency checks to reduce data entry errors. CAPI also uses online help screens to assist interviewers in defining key terms used in the questionnaire.17 * Age, gender, race/ethnicity and marital status from the ‘Demographic variables and sample weights’ in the NHANES database were recorded. * We separated the subjects by their gender into two categories, so as to identify the unique risk factors for each gender. * Race/ethnicity was self-reported as Mexican American, other Hispanic, non-Hispanic white, non-Hispanic black, and other race, including multiracial. We further stratified them into three racial groups: non-Hispanic white, Hispanic, non-Hispanic black, and others (including Mexican American and other races). ### Family history * Family history of diabetes and heart attack/angina were self-reported using interviewer-administered questionnaires (medical conditions) from NHANES database. ### Socioeconomic status * Education level, ratio of family income to poverty, and health insurance status were recorded using interviewer-administered questionnaires (demographic variables and sample weights) from NHANES database. * Ratio of family income to poverty refers to the ratio of family income to poverty threshold. Range of values include 0–5. Value of 5 and greater were recorded as 5. ### Behavioral factors #### Body mass index * BMI data were recorded based on ‘Body Measures’ of NHANES Examination Protocol.18 The body measurement data were collected, in the Mobile Examination Center (MEC), by trained health technicians. * We further categorized data based on WHO criteria into: underweight (BMI <18.5 kg/m2), normal (BMI=18.5~24.9 kg/m2), overweight (BMI=25~29.9 kg/m2), and obese (BMI ≥30.0 kg/m2). #### Smoking history * Smoking status was recorded using interviewer-administered questionnaires (smoking – cigarettes use) from NHANES database. * We further categorized the subjects into current regular smoker and never regular smoker. #### Risky alcohol use * The National Institute on Alcohol Abuse and Alcoholism in the USA has estimated the amount of alcohol consumption that can increase health risks.19 For men under the age of 65: * More than 14 standard drinks per week on average. * More than four drinks on any day. Women and adults 65 years and older: * More than seven standard drinks per week on average. * More than three drinks on any day. #### Physical activity: metabolic equivalent of task (MET) score * MET score20 was calculated from the provided data using the *interviewer-administered questionnaires (physical activity) from NHANES database.* * MET score at 600 MET-min/week is considered having a moderate intensity of physical activity based on WHO recommendation, and we set this as the cut-off value in our study. #### Sleep duration * Participants were asked using the CAPI system at the comfort of their home, ‘How much sleep do you usually get at night on weekdays or workdays?’ The numbers of hours of sleep were recorded. * National Sleep Foundation has updated their recommendations for daily sleep amounts across the lifespan, clarifying that the average recommended amount of hours ‘may be appropriate,’ but varies significantly among subjects, and new ranges for each age group were given.21 * Based on the National Sleep Foundation recommendation, we further categorized data into normal sleep duration, short sleep duration, and long sleep duration. #### Postpartum breast feeding * These questions were administered at the MEC, by trained interviewers, using the CAPI system as a part of the MEC interview. * Participants were asked, ‘Did you breast feed your child or any of your children for at least one month?’ in the questionnaire, and an answer of yes or no was obtained. #### Last childbearing age * These questions were administered at the MEC, by trained interviewers, using the CAPI system as a part of the MEC interview. * Participants were asked, ‘How old were you at the time of your last live birth?’ in the questionnaire, and the range of age was recorded. * We categorized the age range into 20s, 30s, and more than 40s. ### Dietary factors #### Vitamin D insufficiency * Serum 25-hydroxyvitamin D (25 (OH)D) data were extracted based on ‘Vitamin D’ from NHANES Examination Protocol. * There is no definite consensus on the value of vitamin D deficiency. After careful evaluation of literature, we set our cut-off value at <40 nmol/L.22 * The most widely used indicator of vitamin D status is the measurement of 25(OH)D in either serum or plasma. The National Institute of Standards and Technology (NIST) along with the National Institutes of Health’s Office of Dietary Supplements developed a standard reference material for circulating vitamin D analysis and have suggested the use of liquid chromatographycoupled with tandem mass spectrometry (LC-MS/MS) measurement procedure developed by NIST.23 24 #### Total daily calorie and sugar consumption * The in-person interview was conducted in a private room in the NHANES MEC. A set of measuring guides (various glasses, bowls, mugs, drink boxes and bottles, household spoons, measuring cups and spoons, a ruler, thickness sticks, bean bags, and circles) was available in the MEC dietary interview room for the participant to use for reporting the amounts of foods. * NHANES collected data on study participants’ use of dietary supplements for 30 days during the Dietary Supplements Section in the household interview. In 2007–2008, additional information on supplement and antacid use for the previous 24 hours was collected to provide data of the same timeframe as the food and beverage intake. With a similar protocol, the 24-hour dietary supplement interview was collected following the 24-hour dietary recall. All NHANES examinees responding to the dietary recall interview were eligible for the dietary supplement and antacid use questions. Information was obtained on all vitamins, minerals, herbals, and other dietary supplements that were consumed during a 24-hour time period (midnight to midnight), including the name and the amount of dietary supplement taken.25 * Data of total daily calorie and total daily sugar consumption were extracted. * Based on the dietary guidelines for Americans in 2010,26 we categorized data into recommended intake, higher intake, and lower intake based on age and gender differences. ### Diseases association * Different medical conditions were self-reported using the interviewer-administered questionnaires (medical conditions) from NHANES database. * For identification of depression, we used ‘Patient Health Questionnaire’27 as our screener. Patient with score of 5 and greater is considered mild depression, while score of