Serum uric acid as a predictor for cardiovascular and all-cause mortality in women versus men Yu Yang, Yichuan Fan, Jun Li, Bing Liu, Yang Shao, Hui Cao, Junpeng Wang, Rui Zou, Qiang Zhang, Xinhua Hu PII: DOI: Reference:
S0167-5273(15)00360-5 doi: 10.1016/j.ijcard.2015.03.121 IJCA 19885
To appear in:
International Journal of Cardiology
Received date: Accepted date:
12 December 2014 7 March 2015
Please cite this article as: Yang Yu, Fan Yichuan, Li Jun, Liu Bing, Shao Yang, Cao Hui, Wang Junpeng, Zou Rui, Zhang Qiang, Hu Xinhua, Serum uric acid as a predictor for cardiovascular and all-cause mortality in women versus men, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.03.121
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Serum uric acid as a predictor for cardiovascular and all-cause
T
mortality in women versus men
IP
Yu Yang* , Yichuan Fan, Jun Li, Bing Liu, Yang Shao, Hui Cao, Junpeng Wang, Rui Zou, Qiang
SC R
Zhang, Xinhua Hu*
Department of Vascular and Thyroid Surgery, The First Affiliated Hospital, China Medical
MA
NU
University, Shenyang, 110001, China
*Correspondence to: Mrs. Yu Yang and Prof. Xinhua Hu, Department of Vascular and Thyroid Surgery, the First Affiliated Hospital, China Medical University, Shenyang 110001, China. E-mail:
TE
D
[email protected] and [email protected]. Tel: +86 2483283288; fax: +86243283288.
Keywords: Serum uric acid; mortality; gender difference; meta-analysis
CE P
Acknowledgements: This work was supported by National Nature Science Foundation of China (81070254, 30872527, and 30672048).
AC
Conflict of interest: None
1
ACCEPTED MANUSCRIPT Uric acid is the end product of purine metabolism in humans. Higher levels of serum uric acid (SUA) are confirmed in men than in women at all ages [1]. Many studies [2-5] indicated excess mortality in women than men, but others [6, 7] did not confirm these findings. Most studies on
IP
T
SUA levels and mortality risk were conducted in a single sex populations [8-11] or not conducted gender specific analyses [12]. Therefore, whether SUA confering the same risk of mortality
SC R
between women and men is conflicting. A meta-analysis [13] suggested that elevated SUA increased all-cause mortality risk among men but not in women, and the risk of cardiovascular mortality was more pronounced in women. However,these conclusions were based on the indirect
NU
comparisons. Direct comparisons of the relation between SUA levels and mortality risk in men and women through within-study comparisons could reduce the impact of extraneous
MA
between-study factors. Therefore, we conducted this meta-analysis to investigate SUA levels and risk of cardiovascular or all-cause mortality comparing women with men using the female-to-male
TE
D
ratio of relative risks (RRR).
We searched from PubMed, Embase, and Cochrane Library databases for studies published
CE P
prior to May 2014. Potentially articles were identified by the following words: hyperuricemia, uric acid, mortality, death, prospective, follow-up. Studies were included if: 1) prospective design; 2) participants in the general population;3) providing multiple adjusted risk ratio (RR) with 95%
AC
confidence interval (CI) of cardiovascular or all-cause mortality for the highest versus lowest SUA levels in males and females,respectively. Studies were excluded if they were conducted in a single gender populations. Quality assessment was done using the Newcastle–Ottawa Scale (NOS)[14]. We pooled the sex-specific RR for the highest versus lowest SUA category from each study,and then used the sex-specific multivariate-adjusted RR and 95% CI in the individual study to estimate the female-to-male ratio of RRR. All analyses were carried out with STATA statistical software (version 12.0; Stata Corporation). Our initial search identified 629 articles, six studies [2-7] finally included in this meta-analysis. Characteristics of the individual studies are shown in Table 1. Overall quality of the included studies was good (range from 6 to 8) based on a 9-star NOS scales. Six studies [2-7] reported data on all-cause mortality according to the gender. Compared the highest to lowest SUA category, pooled RR of all-cause mortality was 1.15 (95% CI 0.89–1.49) for women and 1.13 2
ACCEPTED MANUSCRIPT (95% CI 1.05–1.20) for men (Fig.1). Three studies [3, 4, 6] reported data on cardiovascular mortality according to gender. Pooled RR of cardiovascular mortality compared the highest SUA with lowest SUA category was 1.27 (95% CI 0.78–2.07) for women and 1.20 (95% CI 1.00–1.43)
IP
T
for men (Fig.2).
Six studies [2-7] reported data on gender-stratified RR of all-cause mortality. Pooled
SC R
female-to-male RRR of all-cause mortality was 1·06 (95% CI 0.81–1.38) compared the highest with the lowest SUA category (Fig.3). Publication bias was not observed according to Begg’s rank correlation test (P=0.707) or Egger’s linear regression test (P=0.429). Three studies[3, 4, 6]
NU
reported data on gender-stratified RR of cardiovascular mortality. Pooled female-to-male RRR of cardiovascular mortality was 1.08 (95% CI 0.6–1.96) compared the highest with the lowest SUA
MA
category (Fig. 3).Sensitivity analyses indicated that there was little influence in the pooled
D
estimate of RRR and 95% CI when any one study was omitted from the analysis.
TE
To our knowledge, this is the first meta-analysis focusing on sex-specific differences on SUA levels and excess mortality risk. Our study suggests that there is no significant gender
CE P
difference in the relationship between SUA levels and mortality risk. However, elevated SUA levels show some trend to confer excessive risk of cardiovascular or all-cause mortality in women than those in men. The possible mechanisms for gender differences of mortality risk might be
AC
explained by different SUA levels between men and women. Many factors contribute to higher SUA levels with excess risk of mortality in women. SUA levels are influenced by sex, age, alcohol consumption, obesity, use of diuretics, glucose intolerance, hypertension, and dyslipidemia [15]. Higher SUA levels in men than in women might attribute to the gender-related steroids involved in uric acid regulation [16]. Moreover, inflammatory process appeared to have a strongly impact on the relationship between SUA and all-cause mortality and impact might be absent in men [7]. Lack of clear evidence of a sex difference in SUA-related risk of mortality is an intriguing finding. Despite our finding did not confirm the gender differences of higher SUA levels conferring greater risk of mortality, different participants’ characters and wide range of age across the included studies might partly account for the negative findings. Given the evidence of obvious differences in SUA levels between men and women, more studies focusing on gender and age-specific analysis are warranted. 3
ACCEPTED MANUSCRIPT Several limitations should be acknowledged. First, few studies reported gender-specific stratification of SUA levels and mortality risk which prevent us to conduct subgroup analysis. Second, genetic and cultural factors also affect SUA levels, particularly alcohol consumption and
IP
T
cigarette smoking are factors that are associated with a high mortality rate. Finally, due to menopausal status and use of hormone replacement therapy were unavailable, these factors could
SC R
have modified the relationship between SUA levels and risk of mortality in women.
In conclusion, this meta-analysis suggests that there is no statistically significant gender
NU
difference in the relationship between SUA level and the subsequent risk of mortality. More welldesigned prospective studies are needed to evaluate gender-specific relation between SUA level
TE
D
MA
and cardiovascular and all-cause mortality risk.
References
CE P
[1] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. Jama. 2000;283:2404-10.
AC
[2] Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995;141:637-44.
[3] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7-13. [4] Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum. 2009;61:225-32. [5] Juraschek SP, Tunstall-Pedoe H, Woodward M. Serum uric acid and the risk of mortality during 23 years follow-up in the Scottish Heart Health Extended Cohort Study. Atherosclerosis. 2014;233:623-9. [6] Sakata K, Hashimoto T, Ueshima H, Okayama A. Absence of an association between serum 4
ACCEPTED MANUSCRIPT uric acid and mortality from cardiovascular disease: NIPPON DATA 80, 1980-1994. National Integrated Projects for Prospective Observation of Non-communicable Diseases and its Trend in the Aged. Eur J Epidemiol. 2001;17:461-8.
IP
T
[7] Hu P, Seeman TE, Harris TB, Reuben DB. Is serum uric acid level associated with all-cause mortality in high-functioning older persons: MacArthur studies of successful aging? J Am Geriatr
SC R
Soc. 2001;49:1679-84.
[8] Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the
NU
MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Epidemiology. 1999;10:391-7.
MA
[9] Jee SH, Lee SY, Kim MT. Serum uric acid and risk of death from cancer, cardiovascular disease or all causes in men. Eur J Cardiovasc Prev Rehabil. 2004;11:185-91.
D
[10] Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, et al. Uric
TE
acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004;164:1546-51.
CE P
[11] Meisinger C, Koenig W, Baumert J, Doring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol.
AC
2008;28:1186-92.
[12] Wang Y, Xu Y, Hu D, Guo X, Zhao D, Li J. Joint association of ankle-brachial index and serum uric acid on the outcomes of six-year all-cause mortality and cardiovascular mortality in Chinese patients. Int J Cardiol. 2012;158:144-5. [13] Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis. 2013;231:61-8. [14] Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed May 6, 2014). [15] Rodrigues SL, Baldo MP, Capingana P, Magalhaes P, Dantas EM, Molina Mdel C, et al. Gender distribution of serum uric acid and cardiovascular risk factors: population based study. Arq 5
ACCEPTED MANUSCRIPT Bras Cardiol. 2012;98:13-21. [16] Adamopoulos D, Vlassopoulos C, Seitanides B, Contoyiannis P, Vassilopoulos P. The relationship of sex steroids to uric acid levels in plasma and urine. Acta Endocrinol (Copenh).
AC
CE P
TE
D
MA
NU
SC R
IP
T
1977;85:198-208.
6
ACCEPTED MANUSCRIPT Legend to figures Figure 1 RR and 95% CI from the eligible studies of elevated SUA level with all-cause mortality by gender comparing the highest SUA to the lowest category group in a random effect model.
IP
T
Figure 2 RR and 95% CI from the eligible studies of elevated SUA level and cardiovascular mortality by gender comparing the highest SUA to the lowest category group in a random effect
SC R
model.
Figure 3 Female-to-male relative RR and 95% CI comparing the highest SUA to the lowest
AC
CE P
TE
D
MA
NU
category group in a random effect model.
7
AC
Figure 1
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
8
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
Figure 2
9
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
Figure 3
10
ACCEPTED MANUSCRIPT
Table 1 - Summary of clinical studies included in meta-analysis.
Culleton et al [10] 1999
USA
Prospective study
6763 (54.5)
45±15 M 48±16 F
Hu et al [14] 2001
USA
Prospective cohort study
870(53.2)
70-79
Sakata et al [13] 2001
Japan
Prospective study
8172 (56.0)
≥30
Chen et al [11] 2009
Taiwan
Prospective cohort study
90393(53.7)
51.5±11.5
Juraschek et al [12] 2014
Scotland
Prospective cohort study
15,083(49.9)
48.7± 9.3
Highest vs. lowest ≥7 mg/dl vs. < 4 mg/dl
Death certificate or proxy respondent.
Highest quintile vs. lowest quintile ≥400 µmol/l vs. < 280µmol/l in men and ≥311 vs. 6.8 mg/dl vs. 5.9 mg/dl vs.
S0167-5273(15)00360-5 doi: 10.1016/j.ijcard.2015.03.121 IJCA 19885
To appear in:
International Journal of Cardiology
Received date: Accepted date:
12 December 2014 7 March 2015
Please cite this article as: Yang Yu, Fan Yichuan, Li Jun, Liu Bing, Shao Yang, Cao Hui, Wang Junpeng, Zou Rui, Zhang Qiang, Hu Xinhua, Serum uric acid as a predictor for cardiovascular and all-cause mortality in women versus men, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.03.121
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Serum uric acid as a predictor for cardiovascular and all-cause
T
mortality in women versus men
IP
Yu Yang* , Yichuan Fan, Jun Li, Bing Liu, Yang Shao, Hui Cao, Junpeng Wang, Rui Zou, Qiang
SC R
Zhang, Xinhua Hu*
Department of Vascular and Thyroid Surgery, The First Affiliated Hospital, China Medical
MA
NU
University, Shenyang, 110001, China
*Correspondence to: Mrs. Yu Yang and Prof. Xinhua Hu, Department of Vascular and Thyroid Surgery, the First Affiliated Hospital, China Medical University, Shenyang 110001, China. E-mail:
TE
D
[email protected] and [email protected]. Tel: +86 2483283288; fax: +86243283288.
Keywords: Serum uric acid; mortality; gender difference; meta-analysis
CE P
Acknowledgements: This work was supported by National Nature Science Foundation of China (81070254, 30872527, and 30672048).
AC
Conflict of interest: None
1
ACCEPTED MANUSCRIPT Uric acid is the end product of purine metabolism in humans. Higher levels of serum uric acid (SUA) are confirmed in men than in women at all ages [1]. Many studies [2-5] indicated excess mortality in women than men, but others [6, 7] did not confirm these findings. Most studies on
IP
T
SUA levels and mortality risk were conducted in a single sex populations [8-11] or not conducted gender specific analyses [12]. Therefore, whether SUA confering the same risk of mortality
SC R
between women and men is conflicting. A meta-analysis [13] suggested that elevated SUA increased all-cause mortality risk among men but not in women, and the risk of cardiovascular mortality was more pronounced in women. However,these conclusions were based on the indirect
NU
comparisons. Direct comparisons of the relation between SUA levels and mortality risk in men and women through within-study comparisons could reduce the impact of extraneous
MA
between-study factors. Therefore, we conducted this meta-analysis to investigate SUA levels and risk of cardiovascular or all-cause mortality comparing women with men using the female-to-male
TE
D
ratio of relative risks (RRR).
We searched from PubMed, Embase, and Cochrane Library databases for studies published
CE P
prior to May 2014. Potentially articles were identified by the following words: hyperuricemia, uric acid, mortality, death, prospective, follow-up. Studies were included if: 1) prospective design; 2) participants in the general population;3) providing multiple adjusted risk ratio (RR) with 95%
AC
confidence interval (CI) of cardiovascular or all-cause mortality for the highest versus lowest SUA levels in males and females,respectively. Studies were excluded if they were conducted in a single gender populations. Quality assessment was done using the Newcastle–Ottawa Scale (NOS)[14]. We pooled the sex-specific RR for the highest versus lowest SUA category from each study,and then used the sex-specific multivariate-adjusted RR and 95% CI in the individual study to estimate the female-to-male ratio of RRR. All analyses were carried out with STATA statistical software (version 12.0; Stata Corporation). Our initial search identified 629 articles, six studies [2-7] finally included in this meta-analysis. Characteristics of the individual studies are shown in Table 1. Overall quality of the included studies was good (range from 6 to 8) based on a 9-star NOS scales. Six studies [2-7] reported data on all-cause mortality according to the gender. Compared the highest to lowest SUA category, pooled RR of all-cause mortality was 1.15 (95% CI 0.89–1.49) for women and 1.13 2
ACCEPTED MANUSCRIPT (95% CI 1.05–1.20) for men (Fig.1). Three studies [3, 4, 6] reported data on cardiovascular mortality according to gender. Pooled RR of cardiovascular mortality compared the highest SUA with lowest SUA category was 1.27 (95% CI 0.78–2.07) for women and 1.20 (95% CI 1.00–1.43)
IP
T
for men (Fig.2).
Six studies [2-7] reported data on gender-stratified RR of all-cause mortality. Pooled
SC R
female-to-male RRR of all-cause mortality was 1·06 (95% CI 0.81–1.38) compared the highest with the lowest SUA category (Fig.3). Publication bias was not observed according to Begg’s rank correlation test (P=0.707) or Egger’s linear regression test (P=0.429). Three studies[3, 4, 6]
NU
reported data on gender-stratified RR of cardiovascular mortality. Pooled female-to-male RRR of cardiovascular mortality was 1.08 (95% CI 0.6–1.96) compared the highest with the lowest SUA
MA
category (Fig. 3).Sensitivity analyses indicated that there was little influence in the pooled
D
estimate of RRR and 95% CI when any one study was omitted from the analysis.
TE
To our knowledge, this is the first meta-analysis focusing on sex-specific differences on SUA levels and excess mortality risk. Our study suggests that there is no significant gender
CE P
difference in the relationship between SUA levels and mortality risk. However, elevated SUA levels show some trend to confer excessive risk of cardiovascular or all-cause mortality in women than those in men. The possible mechanisms for gender differences of mortality risk might be
AC
explained by different SUA levels between men and women. Many factors contribute to higher SUA levels with excess risk of mortality in women. SUA levels are influenced by sex, age, alcohol consumption, obesity, use of diuretics, glucose intolerance, hypertension, and dyslipidemia [15]. Higher SUA levels in men than in women might attribute to the gender-related steroids involved in uric acid regulation [16]. Moreover, inflammatory process appeared to have a strongly impact on the relationship between SUA and all-cause mortality and impact might be absent in men [7]. Lack of clear evidence of a sex difference in SUA-related risk of mortality is an intriguing finding. Despite our finding did not confirm the gender differences of higher SUA levels conferring greater risk of mortality, different participants’ characters and wide range of age across the included studies might partly account for the negative findings. Given the evidence of obvious differences in SUA levels between men and women, more studies focusing on gender and age-specific analysis are warranted. 3
ACCEPTED MANUSCRIPT Several limitations should be acknowledged. First, few studies reported gender-specific stratification of SUA levels and mortality risk which prevent us to conduct subgroup analysis. Second, genetic and cultural factors also affect SUA levels, particularly alcohol consumption and
IP
T
cigarette smoking are factors that are associated with a high mortality rate. Finally, due to menopausal status and use of hormone replacement therapy were unavailable, these factors could
SC R
have modified the relationship between SUA levels and risk of mortality in women.
In conclusion, this meta-analysis suggests that there is no statistically significant gender
NU
difference in the relationship between SUA level and the subsequent risk of mortality. More welldesigned prospective studies are needed to evaluate gender-specific relation between SUA level
TE
D
MA
and cardiovascular and all-cause mortality risk.
References
CE P
[1] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. Jama. 2000;283:2404-10.
AC
[2] Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995;141:637-44.
[3] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7-13. [4] Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum. 2009;61:225-32. [5] Juraschek SP, Tunstall-Pedoe H, Woodward M. Serum uric acid and the risk of mortality during 23 years follow-up in the Scottish Heart Health Extended Cohort Study. Atherosclerosis. 2014;233:623-9. [6] Sakata K, Hashimoto T, Ueshima H, Okayama A. Absence of an association between serum 4
ACCEPTED MANUSCRIPT uric acid and mortality from cardiovascular disease: NIPPON DATA 80, 1980-1994. National Integrated Projects for Prospective Observation of Non-communicable Diseases and its Trend in the Aged. Eur J Epidemiol. 2001;17:461-8.
IP
T
[7] Hu P, Seeman TE, Harris TB, Reuben DB. Is serum uric acid level associated with all-cause mortality in high-functioning older persons: MacArthur studies of successful aging? J Am Geriatr
SC R
Soc. 2001;49:1679-84.
[8] Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the
NU
MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Epidemiology. 1999;10:391-7.
MA
[9] Jee SH, Lee SY, Kim MT. Serum uric acid and risk of death from cancer, cardiovascular disease or all causes in men. Eur J Cardiovasc Prev Rehabil. 2004;11:185-91.
D
[10] Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, et al. Uric
TE
acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004;164:1546-51.
CE P
[11] Meisinger C, Koenig W, Baumert J, Doring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol.
AC
2008;28:1186-92.
[12] Wang Y, Xu Y, Hu D, Guo X, Zhao D, Li J. Joint association of ankle-brachial index and serum uric acid on the outcomes of six-year all-cause mortality and cardiovascular mortality in Chinese patients. Int J Cardiol. 2012;158:144-5. [13] Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis. 2013;231:61-8. [14] Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed May 6, 2014). [15] Rodrigues SL, Baldo MP, Capingana P, Magalhaes P, Dantas EM, Molina Mdel C, et al. Gender distribution of serum uric acid and cardiovascular risk factors: population based study. Arq 5
ACCEPTED MANUSCRIPT Bras Cardiol. 2012;98:13-21. [16] Adamopoulos D, Vlassopoulos C, Seitanides B, Contoyiannis P, Vassilopoulos P. The relationship of sex steroids to uric acid levels in plasma and urine. Acta Endocrinol (Copenh).
AC
CE P
TE
D
MA
NU
SC R
IP
T
1977;85:198-208.
6
ACCEPTED MANUSCRIPT Legend to figures Figure 1 RR and 95% CI from the eligible studies of elevated SUA level with all-cause mortality by gender comparing the highest SUA to the lowest category group in a random effect model.
IP
T
Figure 2 RR and 95% CI from the eligible studies of elevated SUA level and cardiovascular mortality by gender comparing the highest SUA to the lowest category group in a random effect
SC R
model.
Figure 3 Female-to-male relative RR and 95% CI comparing the highest SUA to the lowest
AC
CE P
TE
D
MA
NU
category group in a random effect model.
7
AC
Figure 1
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
8
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
Figure 2
9
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
Figure 3
10
ACCEPTED MANUSCRIPT
Table 1 - Summary of clinical studies included in meta-analysis.
Culleton et al [10] 1999
USA
Prospective study
6763 (54.5)
45±15 M 48±16 F
Hu et al [14] 2001
USA
Prospective cohort study
870(53.2)
70-79
Sakata et al [13] 2001
Japan
Prospective study
8172 (56.0)
≥30
Chen et al [11] 2009
Taiwan
Prospective cohort study
90393(53.7)
51.5±11.5
Juraschek et al [12] 2014
Scotland
Prospective cohort study
15,083(49.9)
48.7± 9.3
Highest vs. lowest ≥7 mg/dl vs. < 4 mg/dl
Death certificate or proxy respondent.
Highest quintile vs. lowest quintile ≥400 µmol/l vs. < 280µmol/l in men and ≥311 vs. 6.8 mg/dl vs. 5.9 mg/dl vs.
