Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women

Original Article doi: 10.1111/j.1365-2796.2007.01778.x Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women M. B. Snijder 1,2, P. Lips 2,3, J. C. Seidell 1,2, M. Visser 1,2, D. J. H. Deeg 2, J. M. Dekker 2 & R. M. van Dam 1,4 1 Institute of Health Sciences, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam; 2 EMGO Institute, VU University Medical Center; 3 Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands, and 4 Department of Nutrition, Harvard School of Public Health, Boston, MA, USA Abstract. Snijder MB, Lips P, Seidell JC, Visser M, Deeg DJH, Dekker JM, van Dam RM (Vrije Universiteit Amsterdam; EMGO Institute, VU University Medical Center, Amsterdam, The Netherlands; and Harvard School of Public Health, Boston, MA, USA). Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med 2007; 261: 558 565. Background. Evidence is accumulating that the vitamin D endocrine system has physiological functions beyond bone health including a role in the regulation of blood pressure. Effects of poor vitamin D status on blood pressure may be mediated by elevated parathyroid hormone (PTH) levels. Aim. To evaluate whether serum 25-hydroxyvitamin D [25(OH)D] and PTH levels are independently associated with blood pressure in a population-based study of older men and women. Methods. Subjects were participants of the Longitudinal Aging Study Amsterdam, aged 65 years and older. In 1205 participants, serum 25(OH)D and PTH levels were determined and diastolic and systolic blood pressure were measured. Linear and logistic regression analyses were performed with adjustments for age, sex, region, season, lifestyle factors (physical activity, smoking, alcohol intake), and waist circumference. Results. Serum 25(OH)D was not significantly associated with diastolic (beta 0.00, P ¼ 0.98) or systolic (beta 0.06, P ¼ 0.11) blood pressure. In contrast, higher ln-pth levels were significantly associated with higher diastolic (beta 1.93, P ¼ 0.03) and systolic (beta 4.67, P ¼ 0.01) blood pressure. Higher PTH levels were associated with a substantially higher prevalence of hypertension (OR 2.00, 95% CI 1.31 3.06 for the highest versus the lowest quartile), whereas 25(OH)D showed no significant association (OR 0.89, 95% CI 0.47 1.69 for the lowest versus the highest 25(OH)D category). Conclusion. These results indicate that PTH is a potentially modifiable determinant of blood pressure in the general elderly population. Serum 25(OH)D, however, was not associated with blood pressure, possibly due to the relatively high levels in our population. Keywords: blood pressure, elderly, epidemiology, 25- hydroxyvitamin D, parathyroid hormone, vitamin D. Introduction Vitamin D in the body is derived from vitamin D intake and from endogenous production of vitamin D in the skin under the influence of sunlight [1]. In the liver 25-hydroxyvitamin D [25(OH)D] is formed from vitamin D, and serum 25(OH)D is considered the best marker of the vitamin D status. If serum 558 ª 2007 Blackwell Publishing Ltd

calcium concentrations decrease, serum parathyroid hormone (PTH) levels will increase and stimulate the conversion of 25(OH)D into 1,25-dihydroxyvitamin D [1,25(OH) 2 D] in the kidneys. 1,25(OH) 2 Dis the most metabolically active form of vitamin D and plays a key role in the regulation of extracellular calcium concentrations and bone metabolism. Recently, it has become increasingly clear that the vitamin D endocrine system has physiological functions beyond bone health [2]. Poor vitamin D status has been associated with inflammation, autoimmune disorders and several types of cancer [2]. In addition, an association between a poor vitamin D status and components of the metabolic syndrome, including hypertension, has been suggested [3]. An association between poor vitamin D status and hypertension could potentially be mediated by elevated PTH levels. Elevated PTH levels were associated with high blood pressure and hypertension in several studies [4 9]. High levels of 1,25(OH) 2 D (which can be due to high PTH) were also associated with high blood pressure or hypertension in most studies [4, 5, 10 13], but not in all [6, 14, 15]. Serum 25(OH)D (a negative determinant of PTH levels) showed a weak inverse association with hypertension [16] or blood pressure [17], but this association disappeared after adjustment for confounding factors [17]. Most studies found no association [8, 15, 18, 19], whereas some studies even showed a positive association [5, 12, 19]. Results on the association between vitamin D status and blood pressure, however, may have been inconsistent due to small sample sizes [4 8, 12 15], heterogeneity between study populations and differences in methodology. If poor vitamin D status or elevated PTH levels affect blood pressure, interventions aimed at reducing blood pressure could consider targeting these modifiable risk factors. The prevalence of vitamin D deficiency and hypertension is particularly high among older persons. Therefore, our objective was to investigate whether serum 25(OH)D and PTH levels were associated with blood pressure, in a large population-based study of older men and women. Methods Study population The Longitudinal Aging Study Amsterdam (LASA) is an ongoing cohort study on predictors and consequences of changes in autonomy and well-being in an ageing population in the Netherlands (predominantly Caucasian). The sampling and data collection procedures have been described in detail elsewhere [20]. Briefly, a random sample of older men and women (aged 55 85 years), stratified by age, sex, urbanization and expected 5-year mortality, was drawn from the population registers of 11 municipalities in the areas in the west (Amsterdam and its vicinity), north-east (Zwolle and vicinity) and south (Oss and vicinity) of the Netherlands. In total, 3107 persons (81.7% of those invited) participated in the baseline examination (1992/93). The study sample for the present study included cross-sectional data of persons who participated in the second examination (1995/96) and were aged 65 years and older on January 1, 1996. After a medical interview at home (n ¼ 1509; 87.8% of eligible respondents), participants were invited to the VU University Medical Center (respondents living in or around Amsterdam) or a health care center (respondents living in or around Zwolle or Oss), where blood samples were obtained (n ¼ 1321). All interviews were conducted by specially trained and intensively supervised interviewers, and were tape-recorded in order to monitor the quality of the data. Informed consent was obtained from all respondents. The study was approved by the Medical Ethics Committee of the VU University Medical Center. Of the 1321 participants for whom blood samples were collected, serum 25(OH)D and PTH concentrations were available for 1320 participants. We excluded persons with missing values for body mass index (BMI) (n ¼ 6), waist circumference (n ¼ 62), blood pressure (n ¼ 16) and/or physical activity (n ¼ 51). As a result, our final study sample consisted of 1205 participants. ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565 559

Measurement of vitamin D and parathyroid hormone concentrations Blood samples were obtained and centrifuged in the morning. Subjects were allowed to have tea and toast, but no dairy products before blood sampling. The serum samples were stored at )20 C. PTH (pmol L )1 ) was measured by means of immunoradiometric assay (Incstar Corp., Stillwater, MN, USA) and 25(OH)D (nmol L )1 ) was determined according to a competitive binding protein assay (Nichols Diagnostics, San Juan Capistrano, CA, USA). The inter-assay coefficients of variation were 12% and 10%, respectively. The analyses were carried out at the Endocrine Laboratory of the VU University Medical Center. Measurement of blood pressure Blood pressure (mmhg) was measured after 5 min of rest at the upper left arm with subjects in a seated position, using an oscillometric blood pressure monitor (model HEM-706; Omron Corporation, Tokyo, Japan). Hypertension was defined as systolic blood pressure >140 mmhg and/or diastolic blood pressure >90 mmhg and/or use of anti-hypertensive medication. To obtain information on medication use, the participants had to show all the drugs he/she used at the moment of the medical interview at home. The names, types and doses were noted by the interviewer. All medication was classified according to the internationally accepted ATC-classification. Medications with ATC-code starting with C02 or C07 were classified as anti-hypertensive medication. Information on potential confounders Because vitamin D status is partly dependent on sunlight exposure, we adjusted regression analyses for the season of data collection. Four periods during the year were distinguished: January March, April June, July September and October December. Additionally, we adjusted for the region where the data collection took place (Amsterdam, Zwolle and Oss). Because mild renal impairment could affect PTH and 25(OH)D homeostasis, we also adjusted for serum creatinine (lmol L )1 ; determined by routine laboratory method). Body weight (kg) was measured without upper clothes and shoes using a calibrated balance beam scale. Height (m) was measured using a stadiometer. BMI was calculated by weight divided by height squared (kg m )2 ). Waist circumference (cm) was measured midway between the lower rib margin and the iliac crest following a normal expiration. Smoking status was classified as current smoker or nonsmoker (cigarettes, tobacco, cigar and pipe), and alcohol use was classified as none, light, moderate, excessive, very excessive, adapted from the alcohol index developed by Garretsen [21]. The level of physical activity was estimated by a validated interview-administered questionnaire for older persons [22], covering household activities, sports, walking outdoors and bicycling during the previous 2 weeks (min/day). Statistical analyses All analyses were performed with the use of spss for Windows version 11.0.1 (SPSS Inc., Chicago, IL, USA). Characteristics of the participants are presented according to previously defined cut points for 25(OH)D: less than 25, 25 49.9, 50 74.9 and 75 or more nmol L )1 [1], and according to quartiles of PTH. Multiple linear regression analyses were used to study the associations between 25(OH)D or PTH levels (independent variables) and systolic or diastolic blood pressure (dependent variables). In addition to continuous variables, we used categorical variables for 25(OH)D and PTH to detect possible nonlinear associations. Because the distribution of PTH was skewed, PTH values were logarithmically transformed. Logistic regression analyses were performed to study the associations between 25(OH)D or PTH levels (independent variables) and the presence of hypertension (dependent variable). The highest group of serum 25(OH)D ( 75 nmol L )1 ) and the lowest quartile of PTH were used as the reference groups. We first adjusted for potential confounding by age, sex, season and region of data collection by adding these as independent variables to the regression models. In additional analyses, we also adjusted for lifestyle variables (physical activity, smoking and alcohol consumption), 560 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565

for measures of adiposity (waist circumference or BMI), and for creatinine. We conducted analyses with adjustment for potential confounding by waist circumference or BMI, because adiposity is associated with blood pressure as well as 25(OH)D and PTH levels [23]. It should be noted, however, that adiposity could also partly mediate possible effects of vitamin D status and PTH levels on blood pressure, because effects of vitamin D and PTH on adiposity are plausible [23]. Effect modification by sex was tested by adding product terms of 25(OH)D*sex or PTH*sex to the regression models. The results of the linear regression models are reported as regression coefficients with 95% confidence intervals. Results of the logistic regression analyses are reported as odds ratios with 95% confidence intervals. P-values are two-sided and P < 0.05 was considered statistically significant. Results Characteristics of the study population are shown by 25(OH)D level and by quartiles of PTH in Table 1. Serum 25(OH)D levels < 25 nmol L )1 were found in 126 subjects (10.5%) and serum 25(OH)D levels of 25 50 nmol L )1 in 442 subjects (36.7%). Participants with low 25(OH)D levels were older, less physically active, had a higher BMI, and were less likely to be men. Participants with high PTH levels had a higher BMI and waist circumference. These trends remained statistically significant after adjustment for age and sex. Serum 25(OH)D was not statistically significantly associated with either systolic or diastolic blood pressure (Table 2). In contrast, higher PTH levels were associated with higher systolic and diastolic blood pressure, and this association remained statistically significant after adjustment for potential confounders (Table 2). Additional adjustment for anti-hypertensive medication did not change these results. Also adjustment for BMI instead of waist circumference (or for BMI and waist combined), or additional adjustment for creatinine, or exclusion of participants who used anti-hypertensive medication (32.6%), did not materially change the associations. Regression coefficients for ln-pth in relation to systolic blood pressure were 6.22 (P ¼ 0.006) in men and 5.01 (P ¼ 0.057) in women, after adjustment for age, region, season, physical activity, alcohol intake and smoking. For diastolic blood pressure, regression coefficients were 2.79 (P ¼ 0.021) in men and 2.23 (P ¼ 0.080) in women. There was no statistically significant effect modification by sex for the association with systolic (P interaction ¼ 0.733) and diastolic (P interaction ¼ 0.972) blood pressure. Figure 1 shows the adjusted mean systolic (a) and diastolic (b) blood pressure values within quartiles of PTH. A large proportion of our population of older men and women had hypertension (79.5%). Serum 25(OH)D levels were not appreciably associated with the presence of hypertension (Table 3). In contrast, higher PTH levels were associated with a substantially higher prevalence of hypertension. Results were similar if subjects using anti-hypertensive medication were excluded (data not shown). Discussion In this population-based study of 1205 older men and women, higher serum PTH levels were significantly associated with a higher systolic and diastolic blood pressure and a higher prevalence of hypertension. Vitamin D status was not significantly associated with blood pressure. The observed positive association between serum PTH levels and blood pressure is consistent with the results of other populations [4 10]. In addition, PTH infusion increased blood pressure in healthy volunteers [24]. The underlying mechanisms are not completely known, but PTH has a pro-sclerotic effect on vascular smooth muscle cells [25], which may contribute to vessel-wall thickening and consequently to higher blood pressure. In addition, PTH activates renal 1-alpha-hydroxylase which increases 1,25- (OH) 2 -D. It has been suggested that an increase in serum 1,25-(OH) 2 -D stimulates the calcium influx in a variety of cells, including vascular smooth muscle cells, which results in contraction and increased peripheral vascular resistance [26]. On the other hand, ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565 561

Table 1 Characteristics of participants according to vitamin D [25(OH)D] and to quartiles of parathyroid hormone (PTH) levels 25(OH)D (nmol L )1 ) PTH (pmol L )1 ) <25 (n ¼ 126) 25 50 (n ¼ 442) 50 75 (n ¼ 410) >75 (n ¼ 227) p trend <2.45 (n ¼ 300) 2.45 3.13 (n ¼ 303) 3.14 4.25 (n ¼ 301) >4.25 (n ¼ 301) P trend 25(OH)D (nmol L )1 ) 18.4 ± 4.6 38.5 ± 7.0 61.3 ± 7.0 91.7 ± 15.1 64.3 ± 24.7 56.3 ± 21.6 51.6 ± 23.1 44.6 ± 23.3 <0.01 PTH (pmol L )1 ) 4.08 (3.16 5.49) Possible confounders 3.48 (2.66 4.50) 2.91 (2.39 3.73) 2.64 (2.02 3.51) <0.01 1.98 (1.69 2.24) 2.77 (2.62 2.94) 3.63 (3.39 3.87) 5.14 (4.54 6.56) Age (years) 79.8 ± 5.9 76.9 ± 6.5 73.9 ± 5.8 72.2 ± 5.5 <0.01 74.1 ± 6.1 74.3 ± 6.2 75.7 ± 6.5 77.3 ± 6.5 <0.01 Male (%) 36.5 41.2 54.6 64.3 <0.01 51.3 48.5 47.8 50.8 0.87 BMI (kg m )2 ) 26.9 ± 4.8 27.2 ± 4.2 26.8 ± 3.8 25.8 ± 3.3 <0.01 26.1 ± 3.5 26.7 ± 3.8 26.7 ± 3.9 27.6 ± 4.5 <0.01 Waist circumference 95.3 ± 13.1 96.0 ± 11.2 95.8 ± 10.7 94.3 ± 11.3 0.24 93.8 ± 11.2 95.2 ± 11.1 95.6 ± 10.8 97.7 ± 11.6 <0.01 (cm) Season Jan Mar (%) 34.9 34.2 22.2 13.2 <0.01 28.0 26.7 24.9 25.2 0.38 Apr Jun (%) 22.2 26.7 27.8 30.4 0.11 21.7 26.7 31.6 29.2 0.02 Jul Sept (%) 7.9 12.9 21.2 20.3 <0.01 16.0 17.2 17.3 15.9 0.99 Oct Dec (%) 34.9 26.2 28.8 36.1 0.23 34.3 29.4 26.2 29.6 0.14 Physical activity 134.1 ± 99.1 143.9 ± 92.6 160.5 ± 101.5 149.9 ± 91.3 0.03 148.4 ± 98.9 157.8 ± 93.2 152.7 ± 98.1 139.7 ± 95.1 0.21 (min/day) Alcohol No (%) 31.7 30.1 20.2 12.3 <0.01 20.7 24.1 24.6 24.9 0.23 Light (%) 54.0 48.2 51.0 51.5 0.84 53.3 49.2 47.5 51.5 0.58 Moderate (%) 13.5 16.1 21.5 28.2 <0.01 19.7 20.8 22.3 16.9 0.51 (Very) excessive (%) 0.8 5.6 7.3 8.0 0.01 6.3 5.9 5.6 6.7 0.92 Smoking (%) 23.8 18.6 15.6 17.6 0.13 21.0 18.5 16.9 15.3 0.06 Study outcomes Systolic BP (mmhg) 154.3 ± 27.0 154.3 ± 26.5 151.3 ± 25.4 153.7 ± 24.8 0.42 150.1 ± 26.1 151.7 ± 24.8 154.7 ± 24.6 156.2 ± 27.6 <0.01 Diastolic BP (mmhg) 84.1 ± 13.6 82.6 ± 13.7 83.2 ± 12.9 84.4 ± 12.8 0.41 82.5 ± 13.0 82.6 ± 13.4 84.3 ± 13.6 83.9 ± 13.0 0.09 Use of anti-hyper-tensive 38.9 35.1 32.0 25.6 <0.01 24.3 31.4 31.9 42.9 <0.01 medication (%) Hypertension (%) 82.5 80.1 77.6 80.2 0.49 69.7 81.2 82.7 84.4 <0.01 Data are mean ± standard deviation, median (interquartile range), or percentages. P trend: by linear or logistic regression analyses using categories of 25(OH)D or PTH as continuous independent variable. BMI, body mass index; BP, blood pressure. 562 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565

Table 2 Associations of 25-hydroxyvitamin D [25(OH)D, nmol L )1 ] and ln-transformed parathyroid hormone (PTH, pmol L )1 ) concentrations with systolic and diastolic blood pressure in 1205 older Dutch men and women 25(OH)D (nmol L )1 ) Ln[PTH(pmol L )1 )] RC (95% CI) P RC (95% CI) P Systolic blood pressure (mmhg) Model 1 )0.015 ()0.076 to 0.046) 0.643 6.465 (3.204 to 9.726) 0.000 Model 2 0.042 ()0.027 to 0.111) 0.221 5.536 (2.182 to 8.890) 0.001 Model 3 0.042 ()0.027 to 0.111) 0.238 5.481 (2.118 to 8.844) 0.001 Model 4 0.041 ()0.028 to 0.110) 0.241 5.663 (2.254 to 9.071) 0.001 Model 5 0.055 ()0.014 to 0.124) 0.120 4.986 (1.589 to 8.383) 0.004 Diastolic blood pressure (mmhg) Model 1 0.020 ()0.011 to 0.051) 0.215 1.731 (0.055 to 3.407) 0.043 Model 2 )0.003 ()0.038 to 0.032) 0.848 2.409 (0.698 to 4.120) 0.006 Model 3 )0.007 ()0.042 to 0.028) 0.708 2.350 (0.633 to 4.067) 0.007 Model 4 )0.008 ()0.043 to 0.027) 0.676 2.514 (0.775 to 4.253) 0.005 Model 5 )0.001 ()0.036 to 0.034) 0.964 2.156 (0.423 to 3.889) 0.015 Model 1: crude model. Model 2: model 1 adjusted for age (years), sex, region and season. Model 3: model 2 additionally adjusted for physical activity (min/day), alcohol intake and smoking. Model 4: model 3 additionally adjusted for anti-hypertensive medication use. Model 5: model 4 additionally adjusted for waist circumference (cm). RC, regression coefficient; 95% CI, 95% confidence interval. serum 1,25-(OH) 2 -D has been shown to play a role in the regulation of the renin angiotensin system, which is an important regulator of blood pressure, as a suppressor of renin synthesis [27]. Inappropriate stimulation of the renin angiotensin system has been associated with hypertension [28]. The lack of association between vitamin D status and blood pressure in the present study agrees with findings in previous observational studies [8, 17 19]. In contrast, supplementation with vitamin D and calcium reduced blood pressure and PTH levels more than calcium supplementation alone in an intervention study in older women with vitamin D insufficiency [25(OH)D < 50 nmol L )1 ] [29]. In another intervention study, ultraviolet B radiation, which stimulated the endogenous production of vitamin D, reduced blood pressure in untreated mild essential hypertensive subjects [30]. Most subjects in that study had serum 25(OH)D levels well below 50 nmol L )1. Possibly, 25(OH)D only affects blood pressure at lower levels, whereas only a limited proportion of our population was vitamin D deficient (10.5%). Although vitamin D status is a determinant of PTH levels, this did not translate into significant association between 25(OH)D concentrations and blood pressure in our study population. The reason for this may be that PTH levels can be substantially influenced by factors other than 25(OH)D, for example calcium, sodium and phosphate intakes [31 34]. Higher calcium intake can decrease intracellular calcium (through decreasing PTH and serum 1,25- (OH) 2 -D), and may therefore decrease peripheral vascular resistance and blood pressure [26]. Due to the tight relation between sodium and calcium excretion [26], an increase in dietary sodium can increase urinary calcium excretion, which results in an increase in PTH and serum 1,25-(OH) 2 -D. Therefore, sodium intake may also be an important determinant of PTH levels. High phosphorus intake may cause secondary hyperparathyroidism [34]. Unfortunately, dietary intake of these factors was not estimated. Another limitation of the present study was its crosssectional design that did not allow us to establish the order of events. In addition, despite our detailed adjustment for confounding we cannot completely ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565 563

Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) (a) 161 159 157 155 153 151 149 147 145 1.0 2.0 3.0 4.0 5.0 6.0 Median PTH within quartiles of PTH (pmol/l) (b) 91 89 87 85 83 81 79 77 75 1.0 2.0 3.0 4.0 5.0 6.0 Median PTH within quartiles of PTH (pmol/l) Fig. 1 Mean (with 95% confidence interval) systolic (a) and diastolic (b) blood pressure, adjusted for age (year), sex, region and season, according to the median of each quartile of parathyroid hormone (PTH). exclude residual confounding as an explanation of the findings because our study was not randomized. However, our findings for PTH were consistent with the reduction in blood pressure after interventions that reduced PTH levels. We used only a single measurement of blood pressure, which may have resulted in nondifferential measurement error and an underestimation of the strength of the true associations. Finally, we did not measure 1,25-(OH) 2 -D levels, the most biologically active form of vitamin D, which may have given us more precise information on the biological pathway for putative effects of PTH on blood pressure. In conclusion, the results of the present populationbased study suggest that PTH is a potentially modifiable determinant of blood pressure in the general elderly population. Future studies should evaluate the importance of vitamin D status as determinant of blood pressure in populations with higher prevalence of vitamin D deficiency and in other ethnic groups. Interventions aimed at reducing blood pressure should consider PTH levels and its possible population-specific determinants, such as sodium intake, calcium intake and vitamin D status. Conflict of interest statement All authors declare that they have no conflict of interest. Acknowledgements This study is based on data collected in the context of the Longitudinal Aging Study Amsterdam (LASA), which is largely funded by the Ministry of Health, Welfare, and Sports of the Netherlands. RM van Dam was supported by the Netherlands Organization for Scientific Research (ZonMw VENI grant no. 916.46.077). Table 3 Associations (ORs with 95% CI) of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations with the presence of hypertension in 1205 older Dutch men and women 25(OH)D (nmol L )1 ) PTH (pmol L )1 ) <25 25 50 50 75 >75 <2.45 2.45 3.13 3.14 4.25 >4.25 Model 1 1.17 (0.67 2.05) 1.00 (0.67 1.49) 0.86 (0.57 1.28) 1.0 1.0 1.88 (1.29 2.75) 2.09 (1.42 3.07) 2.35 (1.58 3.50) Model 2 1.00 (0.54 1.86) 0.94 (0.61 1.46) 0.84 (0.56 1.27) 1.0 1.0 2.03 (1.38 2.99) 2.15 (1.44 3.22) 2.32 (1.54 3.51) Model 3 1.01 (0.54 1.90) 0.94 (0.60 1.46) 0.84 (0.56 1.27) 1.0 1.0 2.03 (1.37 2.99) 2.15 (1.44 3.21) 2.31 (1.53 3.50) Model 4 0.89 (0.47 1.69) 0.79 (0.50 1.25) 0.75 (0.49 1.15) 1.0 1.0 1.93 (1.30 2.86) 2.00 (1.33 3.02) 2.00 (1.31 3.06) Model 1: crude model. Model 2: model 1 adjusted for age (years), sex, region and season. Model 3: model 2 additionally adjusted for physical activity (min/day), alcohol intake and smoking. Model 4: model 3 additionally adjusted for waist circumference (cm). OR, odds ratio; 95% CI, 95% confidence interval. 564 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 261; 558 565

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