Racial and Ethnic Differences in the Association of Metabolic ...

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of Metabolic Syndrome with Prostate-Specific. Antigen Levels in U.S. Men: NHANES 2001–2006. David S. Lopez, DrPH, MPH, MS,1,2 Shailesh Advani, MPH,1,3 ...
JOURNAL OF MEN’S HEALTH Volume 11, Number 4, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jomh.2014.0058

Racial and Ethnic Differences in the Association of Metabolic Syndrome with Prostate-Specific Antigen Levels in U.S. Men: NHANES 2001–2006 David S. Lopez, DrPH, MPH, MS,1,2 Shailesh Advani, MPH,1,3 Konstantinos K. Tsilidis, PhD,4 Mike Hernandez, MS,5 Elaine Symanski, PhD,1 Sara S. Strom, PhD,3 Arup Sinha, MS,6 and Steven Canfield, MD 2

Abstract

Background: The interplay between metabolic syndrome (MetS) and race/ethnicity on prostate specific antigen (PSA) still remains unclear. The three major definitions of MetS (National Cholesterol Education Program [ATP III], International Diabetes Federation [IDF], and World Health Organization [WHO]) differ in number and type of components, which are linked to race/ethnicity. We proposed to investigate the associations of three major definitions of metabolic syndrome with PSA levels, and to determine whether these associations vary by race and ethnicity. Methods: We used measurements of serum PSA levels (ng/mL) in 3528 adult men > 40 years from the National Health and Nutrition Examination Survey 2001–2006. MetS was defined using ATP III, IDF, and WHO criteria. Racial/ethnic groups included non-Hispanic blacks (NHBs), non-Hispanic whites (NHWs), and Mexican Americans (MAs). We computed geometric mean PSA levels from weighted multiple linear regression models. Results: Men classified with MetS-ATP III and MetS-WHO had lower PSA concentrations relative to MetSfree counterparts, 0.77 versus 0.88 ng/mL ( p = 0.01) and 0.79 vs 0.87 ng/mL ( p = 0.03), respectively. Stratifying these associations by race and ethnicity showed that non-Hispanic whites classified with MetS-ATP III (0.76 vs. 0.89 ng/ mL) and MetS-WHO (0.80 vs. 0.88 ng/mL), and Mexican Americans classified with MetS-WHO (0.75 vs. 0.90 ng/ mL) had lower PSA concentrations relative to MetS-free counterparts ( p < 0.01, p = 0.04, and p = 0.02, respectively). Conclusions: MetS was inversely associated with serum PSA levels and this association varied by definition of MetS and race/ethnicity. Fasting glucose of MetS-ATP III was the only component independently associated with PSA, suggesting that all components together have a greater influence on PSA levels than do components by themselves. Our findings highlight the implication when making inferences under the assumption that one definition of MetS fits all men without considering their race and ethnicity. Key words: race/ethnicity; metabolic syndrome; PSA Introduction

T

he United States Preventive Services Task Force recommends against prostate-specific antigen (PSA)based screening for prostate cancer.1 Yet, because of its common use, it is still expected that men will continue asking for it, and physicians will continue offering it.1,2 Previous studies identified factors such as age, race, diabetes, diet, and

obesity as having a potential effect on PSA.3–5 However, it is still unclear whether the combination of these factors can have a greater effect on PSA concentrations than their expected independent effects and to what extent race and ethnicity influence these associations. The metabolic syndrome (MetS) is defined by a clustering of metabolic components, such as glucose levels, insulin resistance, blood pressure, dyslipidemia, triglycerides,

1

Division of Epidemiology, Human Genetics, and Environmental Sciences, 6Division of Biostatistics, University of Texas School of Public Health, Houston, Texas. 4 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. Departments of 5Biostatistics and 3Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas. 2 Division of Urology, University of Texas Medical School, Houston, Texas.

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LOPEZ ET AL.

high-density lipoprotein (HDL) cholesterol, microalbuminuria, and anthropometry measurements (body mass index [BMI] or waist circumference [WC]). The combination of these components depends on the definition of metabolic syndrome used, National Cholesterol Education Program (ATP III), International Diabetes Federation (IDF), and World Health Organization (WHO) (Table 1).6–8 Since 1980, there has been a significant increase in the prevalence of MetS and its association with prostate cancer.9,10 Yet, little is known about the sequelae of MetS on PSA levels. Due to differences in the inclusion of metabolic components (i.e., BMI vs. WC), number of components (i.e., ‡ 3 vs. all 5 together), or racial/ethnic specific thresholds (i.e., WC 102 cm vs. 90 cm), the prevalence of MetS varies with different criteria—25% for ATP III, 39% for IDF, and 20% for WHO (numbers derived from Table 2). Previous studies have identified significant associations between MetS, and its independent components, with PSA levels5,11–13 and metabolism of testosterone.14–16 However, most of these studies defined MetS using the ATP III criteria, which, compared with the MetS-IDF and -WHO definitions, has different defined levels for fasting plasma glucose, no racial/ethnic–specific WC thresholds, no inclusion of overall obesity17 (BMI ‡ 30kg/m2), and direct assessment of insulin resistance (homeostasis model assessment algorithm). A body of literature has already established the association of PSA and metabolic syndrome, or its independent components, with prostate cancer.9,10,18–20 Therefore, the scope of this study is to focus on the interplay between PSA, metabolic syndrome, and race/ethnicity. Our specific study objectives are to investigate the association of MetS (ATP III, IDF, and WHO), and their components, with PSA levels and to determine whether these associations vary by race and ethnicity.

Material and Methods Study population

The National Health and Nutrition Examination Survey (NHANES) is a program of studies undertaken by the National Center for Health Statistics of the U.S. Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States. Continuous NHANES used a multistage, stratified and clustered probability sampling to ensure adequate samples sizes and to represent the total U.S. civilian, noninstitutionalized population. The details of the procedures involved in data collection were published elsewhere.21 For the purpose of this study, we combined data from continuous NHANES waves 2001–2002, 2003–2004. and 2005–2006, as these NHANES waves were stated in our research question before initiation of any data collection and analyses. Assessment of prostate-specific antigen

Serum PSA concentrations (ng/mL) were estimated from blood samples collected in the Mobile Examination Center exam (MEC), and the methods for handling PSA samples have previously been published.22 In NHANES, men older than 40 years were eligible for PSA testing. Men were excluded from this study if they had the following conditions or medical history, as they could influence PSA concentrations:5,17 men who underwent a recent rectal digital examination (in the past week; n = 58), prostate biopsy (n = 45), cystoscopy (in the last 4 weeks; n = 16), surgery (n = 83), medication (n = 58) or radiation treatment (n = 83) for prostate cancer, or were diagnosed with prostate cancer (n = 85) or with current

Table 1. Definitions of Metabolic Syndrome by the National Cholesterol Education Program, International Diabetes Federation, and World Health Organization ATP III6,8 Any three or more of the following criteria: Waist circumference Men: ‡ 102 cm Blood pressurea SBP ‡ 130 mmHg or DBP ‡ 85 mmHg HDL cholesterol Men: < 40 mg/dL Serum triglycerides ‡ 150 mg/dL Fasting plasma glucose ‡ 110 mg/dL

a

IDF7

WHO6,8

Central obesity (defined as waist circumference) plus any two of the following four criteria:

Insulin resistanced or diabetese and at least two of the following criteria:

Central obesity, waist circumference White men: ‡ 94 cm Black men: ‡ 94 cm Mexican-American men: ‡ 90 cm Blood pressureb SBP ‡ 130 mmHg or DBP ‡ 85 mmHg HDL cholesterol Men: < 40 mg/dL Serum triglycerides ‡ 150 mg/dL Fasting plasma glucosec ‡ 100 mg/dL

Body mass index ‡ 30 kg/m2 and/or Waist-to-hip ratio Men: ‡ 0.90 Blood pressuref ‡ 140/90 mmHg or DBP ‡ 90 mmHg HDL cholesterol Men: < 35 mg/dL and/or Serum triglycerides ‡ 150 mg/dL Albumin-to-creatinine ratio ‡ 30 mg/g

Modified blood pressure: ‡ 130/85 mmHg, hypertension diagnosis, or medication. Blood pressure: ‡ 130/85 mmHg, hypertension diagnosis, or medication. Modified fasting plasma glucose ‡ 100 mg/dL, self-reported diabetes, or diabetes medication. d Homeostasis model assessment algorithm ‡ 2.68. e Modified type 2 diabetes: self-reported diabetes, diabetes medication, or ‡ 126 mg/dL of fasting glucose. f Modified blood pressure: ‡ 140/90 mmHg, hypertension diagnosis, or medication. ATP III, National Cholesterol Education Program (Adult Treatment Panel III); IDF, International Diabetes Federation; WHO, World Health Organization; DBP, diastolic blood pressure; HDL, high-density lipoprotein; SBP, systolic blood pressure. b c

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Table 2. Selected Characteristics and Prostate-Specific Antigen Concentration of 3528 Adult Men by Three Metabolic Syndrome Definitions, National Cholesterol Education Program, International Diabetes Federation, and World Health Organization in NHANES 2001–2006 MetS-ATP IIIa Characteristic

No

MetS-IDFa Yes

No

No. of participants 2654 874 2169 Age (years), mean – SE 54.46 – 0.32 56.80 – 0.45c 53.99 – 0.35 Race, n (%) 397 (61.08) MA 517 (76.40) 193 (23.6)d NHW 1566 (75.37) 555 (24.63) 1295 (62.93) NHB 571 (83.63) 126 (16.37) 477 (70.98) 1.47 (1.38, 1.55) 1.30 (1.19, 1.42)c 1.38 (1.30, 1.46) Total PSA (ng/mL), mean (95% CI)b PSA mass (lg), 0.17 – 0.00 0.16 – 0.01 0.16 – 0.00 mean – SE Height (cm), mean – SE 176.28 – 0.20 177.07 – 0.37 176.32 – 0.22 Weight (kg), mean – SE 86.023 – 0.38 101.30 – 0.89c 85.27 – 0.39 Smoking status, n (%) 742 (65.03) Never 908 (77.82) 253 (22.18)d Current 880 (71.85) 384 (28.15) 709 (58.90) Former 863 (78.68) 237 (21.32) 717 (66.62) Physical activity status, n (%) Moderate No 1290 (75.50) 429 (24.50) 1041 (62.41) Yes 1287 (76.88) 416 (23.12) 1071 (64.92) Vigorous d 1443 (60.14) No 1786 (73.29) 645 (26.71) Yes 737 (82.36) 174 (17.64) 627 (71.37) Plasma volume (mL), 0.12 – 0.00 0.13 – 0.00c 0.12 – 0.00 mean – SE Metabolic syndrome components 27.72 – 0.12 32.34 – 0.29c 27.40 – 0.13 BMI (kg/m2), mean – SE c Waist circumference 100.73 – 0.33 113.86 – 0.58 99.62 – 0.35 (cm), mean – SE Triglycerides (mg/dL), 125.64 – 2.84 254.45 – 16.44c 116.47 – 3.10 mean – SE c HDL (mg/dL), 50.79 – 0.28 39.26 – 0.45 51.67 – 0.37 mean – SE Systolic BP (mm Hg), 124.73 – 0.53 132.22 – 0.76c 123.63 – 0.55 mean – SE c Diastolic BP (mm Hg), 73.48 – 0.35 76.23 – 0.55 73.33 – 0.37 mean – SE Fasting glucose 98.41 – 0.48 100.40 – 0.57 124.26 – 1.85c (mg/dL), mean – SE Insulin (uU/mL), 9.41 – 0.28 18.60 – 0.61c 8.35 – 0.35 mean – SE HOMA, mean – SE N/Ae N/Ae N/Ae Albumin-to-creatinine ratio Low ( < 30) High ( ‡ 30) N/Ae N/Ae N/Ae Type 2 diabetes, n (%) No 2042 (70.20) Yes N/Ae N/Ae 127 (19.23) a

MetS-WHOa Yes

No

Yes

1359 56.83 – 0.40c

2806 54.49 – 0.32

722 57.34 – 0.5c

313 (38.92)d 548 (80.48) 162 (19.52) 826 (37.07) 1705 (81.38) 416 (18.62) 220 (29.02) 553 (81.23) 144 (18.77) 1.51 (1.39, 1.63) 1.44 (1.35, 1.53) 1.35 (1.19, 1.51) 0.19 – 0.01

0.17 – 0.01

0.17 – 0.01

176.73 – 0.29 97.75 – 0.71c

176.57 – 0.20 86. 80 – 0.36

176.03 – 0.36 102.90 – 1.12c

419 (34.97)d 555 (41.10) 383 (33.38)

961 (84.23) 953 (77.74) 890 (81.61)

200 (15.77)d 311 (22.26) 210 (18.39)

678 (37.59) 632 (35.08)

1368 (80.10) 1368 (82.89)

351 (19.90) 335 (17.11)

988 (39.86)d 284 (28.63) 0.13 – 0.00 c

1891 (78.80) 784 (87.54) 0.12 – 0.00

540 (21.20)d 127 (12.46) 0.13 – 0.00c

31.31 – 0.21c

27.81 – 0.12

33.20 – 0.32c

111.24 – 0.50c

101.21 – 0.32

115.34 – 0.73c

222.74 – 12.06c

135.27 – 3.11

254.10 – 18.13c

41.71 – 0.48c

49.32 – 0.30

42.49 – 0.53c

131.53 – 0.60c

125.36 – 0.51

131.61 – 0.91c

75.55 – 0.46c

73.98 – 0.36

74.85 – 0.65

118.64 – 1.33c

102.08 – 0.67

124.22 – 1.77c

16.73 – 0.47c

9.13 – 0.25

20.78 – 0.72c

N/Ae

2.22 – 0.09

6.35 – 0.31c

e

2519 (85.21) 266 (46.93)

443 (14.79)d 277 (53.07)

2583 (88.27) 223 (34.57)

326 (11.73)d 396 (65.43)

N/A

867 (29.80)d 492 (80.77)

Sampling weights were applied. Geometric mean based on log-transformed total prostate-specific antigen (PSA). Weighted p < 0.05. d Weighted, Chi-squared, p < 0.05. e Not part of the definition of metabolic syndrome. NHANES, National Health and Nutrition Examination Survey; 95% CI, 95% confidence interval; BMI, body mass index; BP, blood pressure; HOMA, homeostasis model assessment algorithm; MA, Mexican American; MetS, metabolic syndrome; NHB, non-Hispanic black; NHW, non-Hispanic-white; SE, standard error; WHO, World Health Organization. b c

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infection or inflammation in the prostate (n = 39). We also excluded men without PSA data available (n = 524) and those with ethnicity other than non-Hispanic-white (NHW), nonHispanic black (NHB), or Mexican American (MA) (n = 268), leaving a total sample size of 3528 men. Assessment of metabolic syndrome criteria

MetS was defined using the three well-established criteria by the National Cholesterol Education Program’s Third Adult Treatment Panel (ATP III), International Diabetes Federation (IDF), and World Health Organization (WHO) (Table 1).6–8 According to ATP III criteria, a participant has MetS if he has at least three of the components indicated in Table 1;7,8 whereas, the criteria for IDF requires central obesity (defined with racial- and ethnic-specific thresholds for WC), plus any two or more of the four components shown in Table 1.6 On the other hand, WHO criteria require men to have a history of diabetes (self-reported diagnosis, diabetes medication, or ‡ 126 mg/dL of fasting glucose) or insulin resistance (homeostasis model assessment algorithm [HOMA] ‡ 2.68), plus any two or more of the components shown in Table 1.7,8 These three definitions differ with each other on measurements of overall BMI and abdominal obesity (WC), racial and ethnic thresholds, fasting plasma glucose thresholds, and insulin resistance assessment (Table 1). Serum triglycerides and HDL concentrations were estimated from blood samples collected in the MEC exam. Fasting plasma glucose and insulin concentrations were measured in the morning session after an overnight fast of at least 8 hours, and they were used to compute insulin resistance through HOMA.8 As previously described,5 insulin concentrations were assayed with different laboratory methods in different NHANES waves; therefore, we also used the regression coefficients [Y (Tosoh) = (1.0027 · Pharmacia values) - 2.2934] suggested by NHANES to make the values comparable. We used the albumin-to-creatinine ratio ‡ 30 mg/g suggested by the WHO criteria. Details related to the laboratory procedures of the blood test measurements were discussed elsewhere.21 Three readings of systolic and diastolic blood pressure were obtained from participants who attended the mobile examination center. We used the average of those three measurements. We also considered the current use of antihypertensive medication or being ‘‘told by a doctor you had hypertension’’ as an indication of high blood pressure. BMI was calculated from measured weight and height (weight in kilograms divided by height in meters squared). WC was measured at the high point of the iliac crest at minimal respiration to the nearest 0.1 cm. Hip circumference was measured at the maximal extension of the buttocks. Assessment of covariates

Age, race/ethnicity, smoking status, and physical activity during the past 30 days (moderate and vigorous) were selfreported during the NHANES interview. NHANES categorizes race/ethnicity as non-Hispanic white, non-Hispanic black, Mexican American, and other (other Hispanics and all others). However, we restricted our study to Mexican American rather than the less homogenous Hispanic group, as more than 60% of the Hispanic population has Mexican background.23 Vigorous physical activity information was obtained from the questions on whether participants did any activity that caused heavy

LOPEZ ET AL.

sweating or large increases in breathing or heart rate (e.g., swimming, aerobics, or fast cycling), while moderate physical activity was determined from the questions on whether they did any activities that caused light sweating or a moderate increase in the heart rate (e.g., playing golf, dancing, bicycling for pleasure, or walking). Because hemodilution has been identified as a potential factor influencing PSA levels, we addressed it in this study by estimating plasma volume (PV) and PSA mass using a body surface area (BSA) equation24: BSA = [body weight (kg)0.425 · height (m)0.725 · 0.2025]; PV (L) = [BSA (m2) · 1.670]; and PSA mass (lg) = PSA concentration · PV. Statistical analysis

Estimates were obtained using sampling weights applied to take into account selection probabilities, oversampling, nonresponse, and differences between the sample and the total U.S. population. Geometric means and 95% confidence intervals for PSA concentrations were estimated for each definition of MetS (ATP III, IDF, and WHO) and their independent components. Linear regression models were used to estimate the association between total PSA levels and the dichotomized definitions of MetS (yes/no) and their independent components. Because total PSA levels were not normally distributed, we used natural log–transformed data. We also truncated total PSA values at the 99th percentile for total population (12.9 ng/ mL) analyses and subsequently for each race/ethnic group (NHBs = 36.9 ng/mL; NHWs = 11.7 ng/mL; and MAs = 10.2 ng/mL). In Model 1, we adjusted for age (1-year increments). In Model 2, we included age (continuous); race/ethnicity (NHWs, NHBs and MAs); smoking status (never, current, and former); moderate (yes/no) and vigorous (yes/no) physical activity; and PV (continuous). We subsequently stratified these models by race and ethnicity. Tests for interaction were done by entering into the model a binary variable for MetS, a categorical variable for race and ethnicity, and a term for their product; the coefficient for this latter term was evaluated by the Wald test. All significance tests were two-sided; p < 0.05 was considered to be

Table 3. Multivariable-Adjusted Geometric Mean (95% CI) Concentrations of PSA by MetS Definitions, ATP III, IDF, and WHO, in 3528 Adult Men, NHANES 2001–2006 Model 1a,b MetS definition

Mean (95% CI)

MetS-ATP III No 0.88 Yes 0.76 MetS-IDF No 0.87 Yes 0.83 MetS-WHO No 0.88 Yes 0.76 a

Model 2a,c pValue

Mean (95% CI)

pValue

(0.86,0.92) 0.88 (0.85,0.91) (0.70,0.82) < 0.01 0.77 (0.71,0.83) 0.01 (0.84,0.91) (0.78,0.87)

0.86 (0.82,0.89) 0.12 0.84 (0.80,0.90) 0.70

(0.85,0.91) 0.87 (0.84,0.90) (0.71,0.80) < 0.01 0.79 (0.74,0.85) 0.03

PSA values truncated at the 99th percentile (12.9 ng/mL). Model 1, geometric mean adjusted for age. Model 2, geometric mean adjusted for age, race/ethnicity, smoking, moderate and vigorous physical activity, and plasma volume. b c

RACE/ETHNICITY, PSA, AND METABOLIC SYNDROME

statistically significant. All statistical analyses were performed using STATA version 12.0. Results

The distribution of baseline characteristics in the study population after applying sampling weights is shown in Table 2. The prevalence of MetS-ATP III, MetS-IDF, and MetS-WHO was 25%, 36%, and 20%, respectively. There was a significant difference in the prevalence of MetS among racial and ethnic groups. Total PSA concentrations were lower among men with MetS-ATP III. Weight and PV values were higher among those with MetS (any definition). Among the demographic covariates, men with MetS (any definition) were older, current smokers, and had less vigorous physical activity. In addition, these men had higher mean BMI, WC, triglycerides, systolic and diastolic blood pressure, fasting glucose, insulin levels, insulin resistance (only WHO definition), and higher prevalence of type 2 diabetes (IDF and WHO definitions) and albumin-to-creatinine ratio (WHO), but lower mean HDL levels. In Table 3, after adjusting for age, race/ethnicity, smoking status, moderate and vigorous physical activity, and PV, men

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with MetS-ATP III had lower PSA concentrations compared with those without MetS (0.77 vs. 0.88 ng/mL; p = 0.01). Similar findings were observed among men with MetS-WHO definition (0.79 vs. 0.87 ng/mL; p = 0.03). However, no PSA concentration differences were identified among men with MetS-IDF definition. In Table 4, we stratified the associations of the three definitions of MetS with PSA levels by race and ethnicity. MA men classified with MetS-WHO had lower PSA concentrations compared with those men without MetS-WHO (0.75 vs. 0.90 ng/mL; p = 0.02). Among NHW men, those classified with MetS-ATP (0.76 vs. 0.89 ng/mL; p £ 0.01) and -WHO (0.80 vs. 0.88 ng/mL; p = 0.04) definitions had lower PSA levels than those without MetS-ATP and –WHO, respectively. Unexpectedly, among NHB men we did not find PSA concentration differences in any of the three MetS definitions. In addition, none of the interactions between MetS-ATP III, -IDF, and -WHO and race/ethnicity was statistically significant ( p = 0.17, p = 0.24, and p = 0.18, respectively). We further analyzed PSA concentration differences within each component of the three definitions of MetS (Table 5). When controlling for age, race/ethnicity, smoking status,

Table 4. Multivariable-Adjusted Geometric Mean (95% CI) Concentrations of PSA by MetS Definitions (ATP III, IDF, and WHO) and Race and Ethnicity in 3528 Adult Men, NHANES 2001–2006 Race/ethnicity and MetS-definition Mexican American MetS-ATP III No Yes MetS-IDF No Yes MetS-WHO No Yes Non-Hispanic white MetS-ATP III No Yes MetS-IDF No Yes MetS-WHO No Yes Non-Hispanic black MetS-ATP III No Yes MetS-IDF No Yes MetS-WHO No Yes

Model 1a,b

Model 2a,c

Mean (95% CI)

p-Value

Mean (95% CI)

p-Value

0.91 (0.82,1.01) 0.85 (0.73,0.98)

0.44

0.86 (0.75,0.97) 0.85 (0.74,0.98)

0.95

0.94 (0.83,1.06) 0.84 (0.76,0.92)

0.09

0.89 (0.78,1.02) 0.82 (0.74,0.90)

0.23

0.94 (0.85,1.03) 0.75 (0.65,0.86)

< 0.01

0.90 (0.81,1.00) 0.75 (0.65,0.86)

0.02

0.90 (0.86,0.94) 0.76 (0.70,0.82)

< 0.01

0.89 (0.86,0.93) 0.76 (0.70,0.83)

< 0.01

0.88 (0.84,0.92) 0.83 (0.78,0.88)

0.14

0.87 (0.83,0.91) 0.85 (0.79,0.91)

0.56

0.89 (0.85,0.92) 0.76 (0.72,0.81)

< 0.01

0.88 (0.84,0.91) 0.80 (0.74,0.86)

0.04

0.90 (0.80,1.01) 0.91 (0.74,1.13)

0.88

0.88 (0.79,0.98) 0.97 (0.77,1.23)

0.45

0.89 (0.79,1.00) 0.92 (0.78,1.10)

0.69

0.87 (0.77,0.97) 0.97 (0.81,1.18)

0.26

0.92 (0.81,1.04) 0.83 (0.70,0.97)

0.28

0.90 (0.80,1.01) 0.88 (0.74,1.04)

0.77

a PSA values truncated for each race and ethnicity group at the 99th percentile: NHBs = 36.9 ng/mL; NHWs = 11.7 ng/mL; and MAs = 10.2 ng/mL. b Model 1, geometric mean adjusted for age. c Model 2, geometric mean adjusted for age, smoking, moderate and vigorous physical activity, and plasma volume.

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moderate and vigorous physical activity, and PV, we found men with ‡ 110 mg/dL of fasting glucose (component of MetS-ATP III) to have lower PSA levels than those with < 110 mg/dL of fasting glucose (0.76 vs 0.91 ng/mL; p < 0.01). None of the other components of the MetS-IDF and

MetS-WHO definitions had significant PSA concentration differences. We further investigated PSA level differences by each component of the three definitions of MetS among NHW, NHB, and MA men. These results are presented in an

Table 5. Multivariable-Adjusted Geometric Mean (95% CI) Concentrations of PSA by Each Component of Metabolic Syndrome (ATP III, IDF and WHO) in 3528 Adult Men, NHANES 2001–2006 Model 1a MetS definition

Mean (95% CI)

ATP III Components Waist circumference < 102 cm 0.91 (0.87,0.95) ‡ 102 cm 0.81 (0.78,0.84) Blood pressurec < 130/85 mmHg 0.87 (0.83,0.91) ‡ 130/85 mmHg 0.84 (0.81,0.88) HDL cholesterol ‡ 40 mg/dL 0.87 (0.84,0.90) < 40 mg/dL 0.82 (0.77,0.87) Serum triglycerides < 150 mg/dL 0.89 (0.83,0.95) ‡ 150 mg/dL 0.84 (0.77,0.91) Fasting glucose < 110 mg/dL 0.91 (0.86,0.96) ‡ 110 mg/dL 0.75 (0.68,0.82) IDF components Waist circumference (race/ethnicity)d < 94/94/90 cm 0.90 (0.85,0.96) ‡ 94/94/90 cm 0.84 (0.81,0.87) Blood pressurec < 130/85 mmHg 0.87 (0.83,0.91) ‡ 130/85 mmHg 0.84 (0.81,0.88) HDL cholesterol ‡ 40 mg/dL 0.87 (0.84,0.90) < 40 mg/dL 0.82 (0.77,0.87) Serum triglycerides < 150 mg/dL 0.89 (0.83,0.95) ‡ 150 mg/dL 0.84 (0.77,0.91) Fasting glucosee < 100 mg/dL 0.88 (0.85,0.91) ‡ 100 mg/dL 0.80 (0.75,0.86) WHO components Body mass indexf < 30 kg/m2 0.88 (0.85,0.92) 0.79 (0.75,0.83) ‡ 30 kg/m2 Blood pressure < 140/90 mmHg 0.87 (0.83,0.90) ‡ 140/90 mmHg 0.84 (0.80,0.88) HDL or triglyceridesg ‡ 35 mg/dL 0.86 (0.82,0.90) < 35 mg/dL 0.84 (0.79,0.90) Albumin:creatinine ratio < 30 mg/g 0.85 (0.82,0.88) ‡ 30 mg/g 0.84 (0.76,0.92) Insulin resistance (HOMA) < 2.68 0.93 (0.87,0.99) ‡ 2.68 0.76 (0.73,0.85) a

Model 2b P value

Mean (95% CI)

P value

< 0.01

0.89 (0.83,0.95) 0.82 (0.78,0.86)

0.14

0.38

0.86 (0.82,0.90) 0.85 (0.81,0.89)

0.83

0.15

0.86 (0.83,0.89) 0.83 (0.77,0.88)

0.31

0.34

0.89 (0.81,0.95) 0.84 (0.76,0.91)

0.38

< 0.01

0.91 (0.86,0.95) 0.76 (0.70,0.84)

< 0.01

0.06

0.84 (0.78,0.92) 0.86 (0.82,0.89)

0.81

0.38

0.86 (0.82,0.90) 0.85 (0.81,0.89)

0.83

0.15

0.86 (0.83,0.89) 0.83 (0.77,0.88)

0.31

0.34

0.89 (0.93,0.95) 0.84 (0.78,0.91)

0.38

0.04

0.87 (0.83,0.90) 0.82 (0.77,0.88)

0.24

< 0.01

0.87 (0.83,0.91) 0.82 (0.77,0.87)

0.15

0.36

0.85 (0.82,0.89) 0.85 (0.80,0.90)

0.91

0.67

0.86 (0.82,0.89) 0.85 (0.79,0.91)

0.83

0.72

0.85 (0.82,0.88) 0.86 (0.78,0.95)

0.78

< 0.01

0.90 (0.84,0.96) 0.83 (0.76,0.90)

0.20

Model 1, geometric mean adjusted for age. Model 2, geometric mean adjusted for age, race/ethnicity, smoking, moderate and vigorous physical activity, and plasma volume. Blood pressure ‡ 130/85 mmHg, hypertension diagnosis or medication. d Waist circumference ethnicity-specific values for men: NHW ‡ 94 cm, NHB ‡ 94 cm, and MA ‡ 90 cm. e Fasting glucose ‡ 100 mg/dL, self-reported diabetes or diabetes medication. f BMI ‡ 30 kg/m2 and/or waist-to-hip ratio ‡ 90. g HDL < 35 mg/dL or triglycerides ‡ 150 mg/dL. b c

RACE/ETHNICITY, PSA, AND METABOLIC SYNDROME

(Supplementary Tables S1, S2, and S3; Supplementary Data are available online at www.liebertpub.com/jomh). The main finding from these analyses was that the PSA concentration difference among NHW men with ‡ 110 mg/dL of fasting glucose (component of MetS-ATP III) those with < 110 mg/dL of fasting glucose (0.76 vs. 0.91 ng/mL; p < 0.01). None of these interactions reached statistical significance (data not shown). Discussion

In this cross-sectional study of U.S. men, we found lower PSA concentrations among men classified with MetS-ATP III and MetS-WHO than those without MetS. When these associations were stratified by race and ethnicity, MA men classified with MetS-WHO and NHW men classified with MetS-ATP III and MetS-WHO had lower PSA levels than those without MetS. Interestingly, only fasting plasma glucose—from MetS-ATP III definition—was inversely associated with PSA levels. Unexpectedly, among NHB men we did not find strong significant PSA concentration differences with MetS definitions. Our results agree with those previous studies that show lower PSA concentrations among men with MetS using the ATP III definition;5,12,24,25 however, findings from these studies did not reach statistical significance in multivariable analyses. It is important to note that most of these studies were conducted among Asian men, who in general have a lower prevalence of MetS.12,24,25 Parekh et al.5 conducted a study among U.S. men (n = 1,200) from the NHANES 2001–2004 as well, but no PSA concentration differences were found among men classified with MetS-ATP III. On the other hand, we found PSA concentration differences among men with MetS-ATP III. Yet, our study included one more survey wave from NHANES (2005–2006) and multivariable models were further adjusted with PV, a well-established confounder24,26 that takes into account hemodilution and its related components (body weight, height, and PSA mass). In contrast to the inverse association between MetS and PSA levels we found, other studies have shown higher levels of PSA among men with MetS. Yet, it seems these studies did not conduct multivariable analyses; therefore, they may be confounded by PV.27,28 Previous studies found racial and ethnic differences in PSA concentrations;4,17,29 thus, we stratified our MetS-PSA relationships by race and ethnicity. To the best of our knowledge, variation in PSA concentrations among men classified with three well-established MetS definitions (ATP III, IDF, and WHO), and subsequently stratifying by race and ethnicity, has not been previously investigated in a sample of noninstitutionalized U.S. men. Based on our findings, it is still unclear the underlying biological mechanism(s) that influenced the different significant associations between MetS and PSA levels among NHW and MA men, and no significant associations were found among NHB men, who have the highest incidence and mortality rates of prostate cancer. Components of MetS and their relationships with PSA have been previously investigated. Our findings with fasting plasma glucose (ATP III) and its inverse relationship with PSA concurred with previous studies.12,25,27 However, a small study showed a positive relationship between fasting glucose and PSA,28 but this association was not fully explored in multivariable analyses. It is possible that the small sample size and uncontrolled confounders played a role in

169

those results. Fasting plasma glucose is also one of the components of the IDF definition; however, in our study we did not find any PSA concentration difference, yet our definition for fasting plasma glucose was more robust [threshold of ‡ 100 mg/dL (IDF definition), or defined with self-reported diabetes or diabetes medication). Because we used diabetes and hypertension medication to define presence of diabetes and hypertension, we did not adjust for these medications. We were aware that in 2009 the Joint Scientific Statement reported the harmonization of the MetS definition,30 which is a more robust definition compared with the MetS-ATP III because racial and ethnic specific thresholds for abdominal obesity are considered. We decided not to include specific analyses of the 2009 MetS definition in this study, as this definition includes similar components to the MetS-ATP III and MetSWHO. Yet we conducted multivariable regression analyses to examine the association of the 2009 MetS definition with PSA and whether this association varied by race and ethnicity, but no significant associations were found (data not shown). The strength of our study is the size and availability of information in NHANES to use different definitions of MetS, exclusion of men with medical conditions that affect PSA levels, the homogenous racial and ethnic groups, and the adjustment for PV as an important confounding factor. A possible limitation of this study is the cross-sectional design of NHANES, as the collection of the components of MetS and PSA were collected at the same time; therefore, it is difficult to make causal inferences or discuss possible clinical implications. We excluded several factors that may have influenced PSA concentrations, and there may be undetected ones that we were not able to adjust for or for which we did not have the data (e.g., prostate volume). In addition, we cannot rule out that these findings may be due to chance. Conclusions

In this representative sample of U.S. men, those classified by MetS-ATP III, MetS-WHO, and fasting plasma glucose (MetS-ATP III) had lower PSA concentrations, and these associations differed by race and ethnicity. This study highlights the implications when making inferences on the relationship of a single definition of MetS with PSA and the extent to which this relationship can be influenced by race and ethnicity. Acknowledgments

Dr. David S. Lopez was supported by the The University of Texas Medical School at Houston, Division of Urology, and by a National Cancer Institute grant award U54CA153505. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Author Disclosure Statement

No competing financial interests exist. References

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Address correspondence to: David S. Lopez, DrPH, MPH, MS Division of Epidemiology, Human Genetics, and Environmental Sciences University of Texas School of Public Health 1200 Pressler Street Suite E-629 Houston, TX 77030 E-mail: [email protected]