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NDT Advance Access originally published online on April 23, 2007
Nephrology Dialysis Transplantation 2007 22(9):2571-2577; doi:10.1093/ndt/gfm225
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association between oestrogen receptor {alpha} gene polymorphism and mortality in female end-stage renal disease patients

Sawako Kato1, Bengt Lindholm1, Jonas Axelsson1,2, Rashid A. Qureshi1, Peter Barany1, Olof Heimbürger1, Jan-Åke Gustafsson3, Peter Stenvinkel1,2 and Louise Nordfors2

1Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital Huddinge, 2The Nephrogenetics Unit, Department of Molecular Medicine and Surgery and 3Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

Correspondence and offprint requests to: Bengt Lindholm, MD, PhD, Divisions of Renal Medicine and Baxter Novum, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, K-56, 141 86, Stockholm, Sweden. Email: bengt.lindholm{at}ki.se



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. In the general population, genetic variations in the oestrogen receptor {alpha} (ER{alpha}) gene may influence lipid abnormalities, cardiovascular disease (CVD), and mortality, but this has not previously been studied in end-stage renal disease (ESRD) patients.

Methods. A total of 227 ESRD (141 men and 86 women) patients starting renal replacement therapy (RRT) were genotyped for three ER{alpha} gene polymorphisms (Ser10Ser, PvuII and XbaI) and the associations between these polymorphisms and clinical and laboratory parameters and survival were analysed. Patients were followed for a median period of 55 months (range 1–126 months).

Results. The PvuII and XbaI polymorphisms were not associated with any of the clinical parameters. The ER{alpha} Ser10Ser CC genotype was present in 24 (28%) of the female and in 37 (26%) of the male patients. When comparing the CC genotype with the CT and TT genotypes, there were significant differences in lipid levels and inflammatory marker levels, especially in female patients. In female patients, the CC genotype was associated with lower prevalence of protein energy wasting (PEW) (17.4% vs 43.1%; P = 0.03), lower median serum triglyceride (1.7 vs 2.1 mmol/l; P = 0.001), higher median serum albumin (34.0 vs 32.5 g/l; P = 0.03) and lower median high sensitivity-CRP (hsCRP) (2.2 vs 5.5 mg/l; P = 0.03) levels compared with the CT plus TT genotypes. In male patients only HDL-cholesterol and ApoA levels were associated with this polymorphism. Whereas this polymorphism did not influence survival in males, the mortality was lower in female patients with the CC genotype (Kaplan–Meier; Log-rank 2.2, P = 0.02). Moreover, female patients with the CT plus TT genotypes had a borderline significant increased relative risk (Cox hazard model; 6.6, 95% CI: 0.87–49.9 P = 0.06) of death as compared with those with the CC genotype, even after adjustment for age and prevalence of CVD.

Conclusions. Female, but not male ESRD patients with the ER{alpha} Ser10Ser CC genotype had lower prevalence of PEW, lower serum triglyceride, higher serum albumin and lower hsCRP levels. As this genotype was associated with a significantly decreased risk of all-cause death during the initial years of RRT, its protective properties need further study.

Keywords: end-stage renal disease; oestrogen receptor {alpha}; mortality; single nucleotide polymorphisms



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Although women in the general population live longer than men, there is no reported survival advantage of female gender in end-stage renal disease (ESRD) patients [1]. The longer life span in women compared with men in the general population has in part been attributed to the effects of sex hormones, especially oestrogen, on bone status, the vascular system and on inflammation. Thus, osteoporosis, a common disease in the elderly is very much related to oestrogen [2]. Indeed, the percentage of female patients with osteoporosis reaches 80% in the postmenopausal population, and oestrogen replacement therapy has been advocated to maintain a healthy bone status [3]. Moreover, the lower incidence of cardiovascular disease (CVD) in premenopausal women than in men of the same age, is thought to be due in part to the influence of sex hormones, including oestrogen [4].

In ESRD patients, CVD is a leading cause of morbidity and mortality due to the impact of uraemia as such, and alterations in mineral metabolism including calcium and phosphorous that may contribute to vascular calcification and accelerating arteriosclerosis [5]. Traditional risk factors such as hypertension, dyslipidemia and diabetes mellitus (DM) also contribute to CVD in these patients. In addition, oxidative stress, overhydration and protein energy wasting (PEW) play a role [5,6]. Also, inflammation is thought to be an important inducer of vascular injury in uraemia [6]. Elevated levels of circulating pro-inflammatory cytokines are a common phenomenon in ESRD patients [7], and an inflammatory response may be a major cause of endothelial dysfunction in these patients [8]. As the impact of inflammation on outcome is less severe in female as compared with male ESRD patients [1], it is possible that this is, at least in part, related to oestrogen.

The atheroprotective effects of oestrogen include not only oestrogen-induced alterations in serum lipids [9,10], but more importantly, oestrogen modulates adhesion molecules, pro-inflammatory cytokines, and chemokines after endothelial injury, and may thereby protect blood vessels [11]. In addition, oestrogen has direct effects on blood vessels, both a rapid non-genomic effect and a genomic longer-term effect, which further contribute to the protective effects of oestrogen [12]. Moreover, oestrogen may influence several other risk factors for CVD, such as hypercoagulation and mental stress [13].

Although there are several reports on the association between ER{alpha} polymorphisms and risk factors [14] and incidence of CVD [15] in the general population, the impact of oestrogen receptor gene polymorphisms on clinical outcome has, to the best of our knowledge, not previously been investigated in ESRD patients. We hypothesized that polymorphisms in the ER{alpha} gene (Ser10Ser, PvuII and XbaI), could influence oestrogen signalling and thus affect various risk factors, such as inflammation and thereby mortality also in ESRD patients. PvuII and XbaI have previously been associated with CVD, ischaemic heart disease [15–17] and atherosclerosis [18] in the general population. In addition, because of a recent report of an association with adiposity [14], the Ser10Ser polymorphism was selected because of its reported high heterozygosity and its position in exon 1.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Two hundred and twenty-seven Caucasian ESRD patients were investigated close to the start of renal replacement therapy (RRT) in a prospective cohort study. The patients comprised 141 males (62%) and 86 females (38%) with an average age of 52.2 ± 12.3 years (range 22–70 years). Exclusion criteria were as follows: age older than 70 years, acute infectious complications and unwillingness to participate in this study. The present study is a post hoc analysis of an ongoing prospective study and part of the data have already been reported [19]. The cause of ESRD was chronic glomerulonephritis in 71 patients (31.3%), diabetic nephropathy in 66 (29.1%), polycystic kidney disease in 26 (11.5%), collagen disease in 8 (3.5%), interstitial nephritis in 4 (1.8%) and other or unknown causes in 52 patients (22.9%). Diabetes was present in 28.2% of the patients. CVD (defined as clinical history of cerebrovascular, cardiovascular and/or peripheral vascular disease) was present in 30.8% of the patients. Two hundred and seven volunteers without known chronic kidney disease served as controls. The Ethics Committee of the Karolinska Institutet at the Karolinska University Hospital Huddinge approved this study protocol, and informed consent was obtained from all patients and control subjects.

Blood sampling and laboratory analysis
Blood samples were drawn after an overnight fast and were kept frozen at –70°C, if not analysed immediately. GFR, was estimated as the mean of urea and creatinine clearances. Determinations of haemoglobin, serum albumin (s-albumin), total cholesterol (chol), triglyceride (TG), high density lipid (HDL) cholesterol, apolipoprotein A (Apo A), apolipoprotein B (Apo B) and lipoprotein-a [Lp (a)] were performed by routine procedures at the Department of Clinical Chemistry, Karolinska University Hospital Huddinge. In addition, hsCRP was measured by nephelometry and S-albumin by the bromcresol purple method. Inflammation was defined as an hsCRP ≥10 mg/l [1]. Plasma interleukin-6 (IL-6) was measured by a high sensitivity photometric enzyme-linked immunosorbent assay (ELISA) (Boerhinger Mannheim, Mannheim, Germany). The plates were read using ELISA VERSAmax readerTM (Molecular Devices Corp., Sunnyvale, CA, USA) and the data were analysed with the SoftmaxPRO® software (Molecular Devices Corp., Sunnyvale, CA, USA).

Subjective global assessment (SGA) was used to obtain an overall clinical estimate of PEW [19]. Each patient was given a score that reflects the nutritional status as follows: 1 = normal nutritional status, 2 = mild wasting, 3 = moderate wasting, and 4 = severe wasting. In this study, PEW was defined as an SGA >1. Body mass index (BMI) was defined as the body weight in kilograms divided by the square of the height in metres.

Genotyping methods
DNA was extracted from a 5 ml EDTA sample of peripheral blood, using QIAamp® DNA kit. Samples were stored at –20°C. Sequence amplification was performed by the polymerase chain reaction (PCR) on a PTC-225 Thermocycler (MJ Research Inc., Cambridge, MA, USA). The PCR reaction volume was 50 µl, containing 20–50 ng of DNA, 10 pmoles of each forward and reverse primer, 0.2 mM of each dNTP, 0.3 U of DyNAzymeTM II (DNA Polymerase, Finnzymes, CA, USA), 10 mM of Tris–HCl, 1.5 mM of MgCl2, 50 mM of KCl and 0.1% Triton X-100. The PvuII (rs2234693) and XbaI (rs9340799) variations were analysed by the RFLP technique, as previously described [20,21]. PCR primers for amplification of the Ser10Ser (rs2077647) polymorphism were designed using the software Primer Designer 4 for Windows, version 4.1©. The sequences of the forward and the reverse primers were 5'- CTGTGCTCTTTTTCCAGGTG-3' and 5'-biotin TTGCTGCTGTCCAGGTACAC-3', respectively. The sequencing primer was placed adjacent to the single nucleotide polymorphism and was 5'- ACCCTCCACACCAAAGCATC-3'. The oligonucleotides were synthesized by Thermo Electron Corporation (Waltham, MA, USA). The pyrosequencing reaction was performed on a PSQTM96 Instrument from Biotage AB (Uppsala, Sweden) as described previously [22].

Statistical analysis
Data are presented as mean ± SD and range as appropriate. A P-value of <0.05 was considered to be statistically significant. For comparisons between groups, Wilcoxon rank-sum test was used. Nominal variables were tested using chi-square test. Survival analyses were made with the Kaplan–Meier and the Cox proportional hazard model and the relative risk of death was calculated The hazard ratio for mortality was determined by univariate and multivariate Cox regression analysis and presented as HR [95% confidence intervals (CI)]. The Cox proportional-hazards model was used to examine the effects of baseline and follow-up variables on the outcome variables. Plots of log [–log (survival rate)] against log (survival time) were performed to establish the validity of the proportionality assumption. Chi-square analysis was used to test the genotype distributions for Hardy–Weinberg equilibrium (HWE). The statistical analysis was performed using statistical software SAS version 9.1 (SAS Campus Drive, Cary, NC, USA 27513).



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Baseline characteristics
The basal clinical characteristics and selected well-established risk factors for CVD in the 227 ESRD patients (141 men) close to the start of RRT are given in Tables 1, 2 and 3. While the genotype distribution for the ER{alpha} Ser10Ser, PvuII and XbaI polymorphisms was in HWE in the control group, the genotype distribution deviated from HWE in the patients, both as regards XbaI (data not shown) and Ser10Ser (Table 1). This could suggest that the ESRD patients may have been subjected to selection pressure regarding factors related to oestrogen-associated disease. In the following, only the data regarding the ER{alpha} Ser10Ser polymorphism are described as the other two polymorphisms were not associated with any clinical parameters (except serum calcium and triglyceride levels) or mortality. Based on preliminary statistical analyses, we grouped the patients according to Ser10Ser genotypes into non-T (CC) and T (CT and TT) allele carriers in accordance with a recessive genetic model.


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  		Table 1. Tests for Hardy–Weinberg equilibrium for ER{alpha} Ser10Ser polymorphism in patients and control subjects

 

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  		Table 2. Baseline clinical characteristics of male and female patients enrolled in this study

 

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  		Table 3. Laboratory characteristics in male and female patients at the initiation of renal replacement therapy

 
Table 2 shows the basic clinical characteristics for the different genotype groups. In female patients, the prevalence of PEW was markedly lower in the CC (17.4%) as compared with the CT plus TT (43.1%) genotype group. As shown in Table 3, there were also differences, especially in the women, in lipid levels and inflammatory marker levels between the genotypes. In the whole patient group, the patients with the CC genotype had higher levels of HDL-cholesterol [1.3 (0.6–2.6) vs 1.1 (0.4–4.1) mmol/l, P = 0.005] and Apo A [1.35 (0.91–2.46) vs 1.22 (0.45–3.16) g/l, P = 0.01], and a lower level of hsCRP [3.7 (0.2–218.0) vs 6.3 (0.2–163.0) mg/l, P = 0.03]. When analysed by gender, the female patients with the CC genotype had significantly lower levels of triglycerides [1.7 (0.6–3.5) vs 2.1 (0.8–8.6) mmol/l; P = 0.001], and hsCRP [2.2 (0.4–57.0) vs 5.5 (0.2–78.0) mg/l; P = 0.03] and higher serum albumin levels [34.0 (24.0–44.0) vs 32.5 (13.0–47.0) g/l; P = 0.03] and tended to have higher levels of HDL-cholesterol and Apo A, as compared with CT plus TT carriers. In male patients, significant differences between the genotype groups were only observed for HDL and Apo A levels, which were higher in the patients carrying the CC genotype.

Survival analysis
The survival of the patients was analysed after a median period of 30 months (range 1–60 months) following the start of RRT. There was no significant difference in Kaplan–Meier curves of all-cause-survival between females and males (data not shown, log-rank 1.23, P = 0.27), or between patients with the CC and CT plus TT genotypes (log-rank 0.81, P = 0.42, Figure 1). Considering the more significant impact of the ER{alpha} gene polymorphism on lipids and inflammation markers in females as compared with males, we analysed men and women separately. Figure 2 shows Kaplan–Meier curves for the CC genotype compared with the CT plus TT genotypes. Female patients carrying the CC genotype showed lower mortality than T-allele carriers (log-rank = 2.2, P = 0.02), whereas no such difference was observed in the men. During the observation period, 21 (24%) of 86 women died: 1 (4%) of 24 patients with the CC genotype and 20 (33%) of 62 patients in the CT plus TT genotype group. Fourteen women (16%) died from CV events. Using the Cox proportional hazard model, we analysed the risk of death in the women according to their genotype. The unadjusted relative risk was (7.16, 95% CI: 0.96–53.5 P = 0.05), and when adjusted for age and history of CVD, female patients carrying the T-allele (CT plus TT genotypes) had a borderline significant increased relative risk (6.6, 95% CI: 0.87–49.9 P = 0.06) of death as compared with females carrying the CC genotype.


Figure 1
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  		Fig. 1. Kaplan–Meier curves for the ER{alpha} Ser10Ser genotypes (CC vs CT plus TT). The all-cause mortality (without adjustments) for the whole group of 227 ESRD patients starting renal replacement therapy did not differ between the genotypes (Log-rank 0.81, P = 0.42).

 

Figure 2
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  		Fig. 2. Kaplan–Meier curves for the ER{alpha} Ser10Ser genotypes (CC vs CT plus TT). The all-cause mortality (without adjustments) in male ESRD patients (A) and female ESRD patients (B) starting renal replacement therapy. In female ESRD patients, there was a significant difference (Log-rank 2.2, P = 0.02) between the genotypes.

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
More than 50% of all deaths in dialysis patients are attributed to CVD, especially in young ESRD patients [5]. This is not only due to a high prevalence of traditional risk factors such as hypertension, hyperlipidemia, DM and physical inactivity, but also various factors associated with uraemia per se, such as volume overload, anaemia, increased oxidative stress, PEW and inflammation [23]. Interestingly, ESRD patients show a reverse association between various risk factors and clinical outcome in that lower mortality [24] is associated with higher BMI [25], blood pressure [26], cholesterol [27] and homocysteine levels [28]. It is not known whether genetic variations or gene-environment interactions may explain these paradoxical findings.

We have previously reported that inflamed female ESRD patients have a better outcome than inflamed male patients [1], and that inflammation predicts mortality in male, but not in female, patients [29]. These findings suggest that female gender may protect against the detrimental consequences of persistent systemic inflammation. Indeed, in the present study, there were significant differences in the inflammatory marker hs-CRP both between genders and between genotypes (Tables 2 and 3). Furthermore, despite reanalysis, the genotype distribution of ER{alpha} Ser10Ser deviated markedly from the expected (Table 1), suggesting that the ESRD patients carrying the TT genotype had been exposed to negative selection, i.e. died prematurely.

As the Ser10Ser polymorphism does not affect the amino acid sequence of the oestrogen receptor protein, we hypothesize that it is instead in linkage disequilibrium with another polymorphism of the ER{alpha} gene that affects its biological activity. The atheroprotective role of oestrogen may be attributed to several effects, such as its effect on serum lipids [30], enhanced release of matrix metalloproteinase 2 from human vascular smooth muscle cells [31] and suppressed genetic expression of monocyte chemotactic protein-1 [32]. In addition, oestrogen signalling through ER{alpha} directly mediates the rapid activation of endothelial nitric oxide synthase, which relaxes vascular smooth muscle cells and inhibits platelet activation [33].

There are several reports on the association between ER{alpha} polymorphisms and CVD mortality in the general population. In the Framingham Heart Study, Shearman et al. [17] reported that ER{alpha} PvuII was associated with ischaemic heart disease in men. Moreover, Fox et al. [14] reported that, whereas ER{alpha} PvuII, XbaI and C1335G were associated with measures of adiposity, no associations with ER{alpha} T30C (equivalent to Ser10Ser) were found. Schuit et al. [16] reported that an ER{alpha} PvuII and XbaI haplotype was associated with CVD in women. As oestrogen has a direct effect on vessels, it is of interest that an association between coronary artery wall atherosclerosis and ER{alpha} PvuII was reported [18]. In contrast, Koch et al. [34] reported that neither ER{alpha} PvuII, XbaI or haplotypes based on these polymorphisms were associated with myocardial infarction in a case-control study. To the best of our knowledge, this study is the first showing an association between the ER{alpha} Ser10Ser polymorphism and all-cause mortality in ESRD patients. Moreover, in contrast to males, female patients with the ER{alpha} Ser10Ser CC genotype had lower hsCRP, less abnormal lipid status and lower prevalence of PEW compared with patients carrying the T allele. Thus, it appears that even after menopause, oestrogen signalling is more important in females than in males.

Some caveats of the study need consideration. First, Ser10Ser polymorphism was not in HWE at the start of the observation period (shortly before initiation of RRT), which may suggest a selection bias. Thus, if we instead had studied a group of patients with mild–moderate CKD the impact of ER{alpha} on survival might have been even stronger. Second, this study is a post hoc analysis, and thus we did not analyse the possible impact of HRT treatment (only present in a few patients) and menopause (almost all female patients). Third, the possible synergistic effects with ACEi/ARB and statin medication should be considered in future studies on ER{alpha} polymorphisms. Finally, as the number of patients in this study is rather small, confirmatory studies in other larger ESRD cohorts are needed.

In summary, female, but not male, ESRD patients with the ER{alpha} Ser10Ser CC genotype had a significantly decreased risk of all-cause death during the first years of RRT, even after correction for age and CVD. This suggests a possible protective effect of this genotype on mortality in female ESRD patients, which we speculate is derived from the effects of oestrogen on the cardiovascular system. Supporting this assumption, the CC genotype was associated with lower prevalence of PEW, lower serum triglyceride levels, higher serum albumin and lower hsCRP levels in women.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
This study was supported by Baxter Healthcare Corporation, Deerfield, Illinois, USA, the Harald Jeansson Foundation, the Harald and Greta Jeansson Foundation (LN), Stockholm, Sweden, the Swedish Research Council (PS), the Karolinska Institutet Center for Gender Research (PS), Stockholm, Sweden and benefited from support from the GENECURE project, funded through the European Union 6th Framework Program (grant LSHM- CT-2006-037697).

Conflict of interest statement. B.L. is employed by Baxter Healthcare Corporation.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Stenvinkel P, Wanner C, Metzger T, et al. Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage? Kidney Int (2002) 62:1791–1798.[CrossRef][Web of Science][Medline]
  2. Altkorn D, Vokes T. Treatment of postmenopausal osteoporosis. JAMA (2001) 285:1415–1418.[Free Full Text]
  3. Armitage M, Nooney J, Evans S. Recent concerns surrounding HRT. Clin Endocrinol (2003) 59:145–155.[CrossRef][Medline]
  4. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med (2004) 351:2599–2610.[Abstract/Free Full Text]
  5. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol (1999) 10:1606–1615.[Free Full Text]
  6. Stenvinkel P, Pecoits-Filho R, Lindholm B. Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem. J Am Soc Nephrol (2003) 14:1927–1939.[Free Full Text]
  7. Kimmel PL, Phillips TM, Simmens SJ, et al. Immunologic function and survival in hemodialysis patients. Kidney Int (1998) 54:236–244.[CrossRef][Web of Science][Medline]
  8. Stenvinkel P. Endothelial dysfunction and inflammation—is there a link? Nephrol Dial Transplant (2001) 16:1968–1971.[Free Full Text]
  9. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and non-contraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation (1987) 75:1102–1109.[Abstract/Free Full Text]
  10. Mendelsohn ME, Karas RH. Estrogen and the blood vessel wall. Curr Opin Cardiol (1994) 9:619–626.[Web of Science][Medline]
  11. Miller AP, Feng W, Xing D, et al. Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured arteries. Circulation (2004) 110:1664–1669.[Abstract/Free Full Text]
  12. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med (1999) 340:1801–1811.[Free Full Text]
  13. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med (2002) 346:340–352.[Free Full Text]
  14. Fox CS, Yang Q, Cupples LA, et al. Sex-specific association between estrogen receptor-alpha gene variation and measures of adiposity: the Framingham Heart Study. J Clin Endocrinol Metab (2005) 90:6257–6262.[Abstract/Free Full Text]
  15. Shearman AM, Cooper JA, Kotwinski PJ, et al. Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ Res (2006) 98:590–592.[Abstract/Free Full Text]
  16. Schuit SC, Oei HH, Witteman JC, et al. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. JAMA (2004) 291:2969–2977.[Abstract/Free Full Text]
  17. Shearman AM, Cupples LA, Demissie S, et al. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA (2003) 290:2263–2270.[Abstract/Free Full Text]
  18. Lehtimaki T, Kunnas TA, Mattila KM, et al. Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med (2002) 80:176–180.[CrossRef][Web of Science][Medline]
  19. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation and atherosclerosis in chronic renal failure. Kidney Int (1999) 55:1899–1911.[CrossRef][Web of Science][Medline]
  20. Castagnoli A, Maestri I, Bernardi F, Del Senno L. PvuII RFLP inside the human estrogen receptor gene. Nucleic Acids Res (1987) 15:866.[Free Full Text]
  21. Andersen TI, Heimdal KR, Skrede M, et al. Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet (1994) 94:665–670.[Web of Science][Medline]
  22. Nordfors L, Jansson M, Sandberg G, et al. Large-scale genotyping of single nucleotide polymorphisms by Pyrosequencingtrade mark and validation against the 5'nuclease (Taqman((R))) assay. Hum Mutat (2002) 19:395–401.[CrossRef][Web of Science][Medline]
  23. Sarnak MJ. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis (2003) 41:11–17.[CrossRef][Medline]
  24. Foley RN. Cardiac disease in chronic uremia: can it explain the reverse epidemiology of hypertension and survival in dialysis patients? Semin Dial (2004) 17:275–278.[CrossRef][Web of Science][Medline]
  25. Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD. Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int (2003) 63:793–808.[CrossRef][Web of Science][Medline]
  26. Klassen PS, Lowrie EG, Reddan DN, et al. Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA (2002) 287:1548–1555.[Abstract/Free Full Text]
  27. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int (2002) 61:1887–1893.[CrossRef][Web of Science][Medline]
  28. Suliman ME, Qureshi AR, Barany P, et al. Hyperhomocysteinemia, nutritional status, and cardiovascular disease in hemodialysis patients. Kidney Int (2000) 57:1727–1735.[CrossRef][Web of Science][Medline]
  29. Stenvinkel P, Barany P, Chung SH, Lindholm B, Heimburger O. A comparative analysis of nutritional parameters as predictors of outcome in male and female ESRD patients. Nephrol Dial Transplant (2002) 17:1266–1274.[Abstract/Free Full Text]
  30. Herrington DM, Howard TD, Hawkins GA, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med (2002) 346:967–974.[Abstract/Free Full Text]
  31. Wingrove CS, Garr E, Godsland IF, Stevenson JC. 17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta (1998) 1406:169–174.[Medline]
  32. Pervin S, Singh R, Rosenfeld ME, et al. Estradiol suppresses MCP-1 expression In vivo: implications for atherosclerosis. Arterioscler Thromb Vasc Biol (1998) 18:1575–1582.[Abstract/Free Full Text]
  33. Chen Z, Yuhanna IS, Galcheva-Gargova Z, et al. Estrogen receptor alpha mediates the non-genomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest (1999) 103:401–406.[Web of Science][Medline]
  34. Koch W, Hoppmann P, Pfeufer A, et al. No replication of association between estrogen receptor alpha gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent. Circulation (2005) 112:2138–2142.[Abstract/Free Full Text]
Received for publication: 21.12.06
Accepted in revised form: 22. 3.07


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