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P40U0`U�ORZBLZPaET8�4444�Title: Association between rs6226 and rs6224 polymorphisms of the furin gene and cardiovascular diseases
Running title: Polymorphisms of the furin gene and cardiovascular diseases

Ewa Podolecka, PhD1, Ewa {ukowska-Szczechowska, professor1

1 Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland

Corresponding author: Ewa Podolecka, PhD
Department of Internal Medicine, Diabetology and Nephrology, 
Medical University of Silesia, Zabrze, Poland 
Address: 3 Maja 13/15
              41-800 Zabrze, Poland
 HYPERLINK "mailto:epodolecka@interia.pl" epodolecka@interia.pl
tel.  +48 32 271 25 11
fax +48 32 271 46 17







ABSTRACT
Purpose: This study focused on the association between functional polymorphisms of the furin gene and cardiovascular disease. 
Methods: Genotyping was conducted on 504 subjects with a mean age of 56.7�9.5 years. Allelic discrimination assay was used to detect rs6226 and rs6224 polymorphisms. Along with echocardiography and BP, vascular compliance of large (C1) and small (C2) arteries was also measured.
Results: Women with the CC genotype of the rs6226 polymorphism had higher systolic blood pressure (SBP) compared to the CG genotype (p=0.0199). Men with CC and CG genotypes of the rs6226 polymorphism had lower small artery elasticity indices (C2) compared to GG genotype (p="0.0185). Ischemic heart disease was more common in women with  CC when compared to CG genotype of the rs6226 polymorphism (p=0.00080) and with TT compared to GG and GT genotypes of the rs6224 polymorphism (p=0.0059). Myocardial infarction was more common among men with CC compared to GG genotype of the rs6226 polymorphism (p=0.0250) and with GT and TT compared to GG genotype of rs6224 polymorphism (p=0.0053). A weak link was found between rs6226 and rs6224 polymorphisms (r2=0.4724).
Conclusions: The rs6226 and rs6224 furin polymorphisms are associated with cardiovascular diseases, but appear to exert independent functional effects on their pathogenesis.

Key words: furin, functional polymorphisms, metalloproteinases, extracellular matrix, cardiovascular risk factors



BACKGROUND
Furin is an enzyme of the serine proteinase family that catalyses the maturation of a group of pro-protein substrates. The protein is encoded by the furin gene located on the q arm of chromosome 15, locus 26.1.1-3 Furin is synthesized in a non-active form, as a pro-protein, which changes into the active form during autocatalysis. The furin gene transcript has been detected in all tested human cells and tissues4-7 and plays an important role in the pathogenesis of numerous bacterial, viral, and neoplastic diseases. It is also believed to modulate the development and progression of atherosclerosis via the activation of specific matrix metalloproteinases (MMPs).8
Furin activates pro-metalloproteinase 1 (MT-1-MMP) in the Golgi apparatus during proteolysis. Later, enzymatically active MMP-1 is released outside the cell and triggers pro-metalloproteinase-2 (pro-MMP-2) activation.9, 10  
MMP-1 and MMP-2 play a significant role in the migration and proliferation of smooth muscle cells; they participate in vascular wall remodelling and in the development and progression of atherosclerotic lesions.11As a result of vascular wall remodelling, vascular compliance decreases. Increased arterial wall stiffness is an established risk factor of cardiovascular diseases12, 13 and increases pulse wave velocity in the cardiovascular system. Measurement of vascular compliance is a non-invasive method to assess arterial wall stiffness.14 
The aim of our study was to determine the relationship between the rs6226 and rs6224 polymorphisms of the furin gene and risk factors for cardiovascular disease including blood pressure, vascular compliance, and parameters of left ventricular hypertrophy. We also sought to determine the relationship between individual polymorphisms and the incidence of ischemic heart disease and myocardial infarction, and further investigated a potential link between these 2 polymorphisms.

METHODS
The study group consisted of 504 unrelated men and women (mean age 56.7�9.5 years). There were 320 men (mean age 57.3�9.2 years) and 184 women (mean age 55.8�10.0 years) in the study group (Tables 1 and 2). Subjects were recruited in 3 reference centers for cardiovascular diseases in the south of Poland. Recruitment was conducted through probands-index patients with high cardiovascular risk: co-existence of cardiovascular disease, hypertension, or cardiovascular risk factors. A total of 1139 subjects - male and female - were examined. Among them there were 273 families and 497 subjects, who presented for the examination without their relatives. From the entire group, 504 parents who were unrelated male and female subjects were selected and enrolled in the study and in whom the furin gene polymorphisms were analyzed.
The written informed consent for participation in the study was obtained from participants.
The research project entitled �The study of pathogenesis of cardiovascular diseases, from the vascular and cardiac intermediate phenotypes to the candidate genes�� was conducted with the consent of the Ethical Board at the Silesian Medical University (Consent No. NN-013-145/03).
Fasting serum glucose, TC-cholesterol, HDL-cholesterol, triglycerides and LDL-cholesterol were determined in all subjects. LDL cholesterol levels were determined using Friewald formula: LDL [mmol/l] = [TC-HDL-(TG/2, 2)]. 
Genotyping was conducted using the iPLEXTM assay on Sequenom MassARRAY� system (Sequenom Inc., San Diego, US) according to the manufacturer�s protocol. Allelic discrimination assay was performed to detect the rs6226 and rs6224 polymorphisms of the furin gene. 
The cardiac echo involved the measurement of parameters characterizing the left ventricle, such as posterior wall diastolic diameter (PWDd), inter-ventricular septum diastolic diameter (IVSDd), left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF%). The left ventricular mass (LVM) was calculated using Devereux formula: 
LVM [g] =1.04 [(IVSDd+PWDd+LVEDV)B-(LVEDV)B]   13.6. 
The vascular compliance of large (C1) and small (C2) arteries was performed using the HDI/Pulse Wave"! CR-2000 Research Cardiovascular Profiling Instrument. This instrument differentiates between 2 systems - the high-pressure system, i.e. the aorta with its main branches and the low-pressure system, consisting of peripheral arteries. The results of these measurements were the large artery elasticity index (C1) expressed in ml/mmHg�10 and the small artery elasticity index (C2) expressed in ml/mmHg�100, as well as the oscillometric measurement of SBP and DBP.15, 16

Statistical analysis
The values of quantitative variables were compared between subjects with the respective analyzed genotypes of furin gene polymorphism using non-parametric Kruskal Wallis one-way analysis of variance. The distribution of qualitative variables in the analysed patient groups was compared using the �2 test. 
Multiple linear regression analysis was used in order to determine which parameters were independently related to such variables as C1 and C2; SBP and DBP; as well as LVM and LVMI. This analysis involves all possible combinations of the variables, apart from individual genotypes of both studied furin gene polymorphisms. A p value of <0.05 was assumed as the statistical significance criterion.
The Hardy-Weinberg law was used in order to determine the distribution of genotypes of rs6226 and rs6224 polymorphisms of the furin gene. In order to investigate a potential association between these 2 polymorphisms, the CubeX software was used.17 The measurement of the association between the polymorphisms is referred to as r2 coefficient, which can have a value between 0 (zero association) and 1 (100% association).
 
RESULTS
Mean basal and clinical characteristics of the study group (mean age 56.7�9.5 years) are shown in Tables 1 and 2, including SBP and DBP, serum glucose and lipid levels, parameters characterizing the left ventricle, and the large (C1) and small artery (C2) elasticity indices. In the study population, the large artery elasticity index (C1) was inversely proportional to the subject's age, SBP and coronary artery disease, while the negative determinants of C2 were age, SBP, WHR, smoking and coronary artery disease (Table 3). Factors independently related to higher SBP included age, BMI, female gender and diabetes. Multifactorial analysis further revealed a linear relationship between LVM and SBP, body surface area (BSA), WHR, male gender and ischemic heart disease (Table 3).  
Women with the CC genotype of the rs6226 polymorphism had higher SBP compared to the CG genotype (p=0.0199) (Table S1). Men with the CC and CG genotypes of the rs6226 polymorphism showed lower values of small artery elasticity index (C2) compared to men with the GG genotype (p= 0.0185). Women with the CC genotype variant of the rs6226 polymorphism developed ischemic heart disease more often, compared to those with the CG and GG genotypes (Table S1). In the same group of women, higher SBP was also found. Women with the TT genotype variant of the rs6224 polymorphism also developed ischemic heart disease more often, compared to those with the GG and GT genotypes (Table S2). These female subjects did not differ significantly in terms of pre-existing risk factors for cardiovascular disease (Table S2). 
In our study, men with the CC variant of the rs6226 polymorphism developed myocardial infarction more often compared to those with the CG and GG genotypes (Table S1). In the same group of male subjects, lower values of small artery elasticity index (C2) were found, which confirms previous results that demonstrated a relationship between reduced small artery compliance and an increased incidence of cardiovascular disease. On the other hand, men with the GT and TT variants of the rs6224 polymorphism developed myocardial infarction more often compared to those with the GG genotype (Table S2). Male subjects with the GG, GT and TT genotypes did not differ significantly in terms of pre-existing risk factors of cardiovascular disease. 
Women with the TT variant of the rs6224 polymorphism developed ischemic heart disease more often compared to those with the GG and GT genotypes, whereas men with GT and TT variants of the rd6224 polymorphism developed myocardial infarction more often (Table S2).  Therefore it can be assumed that the GT and TT genotype variants of the rs6224 polymorphism are also related to higher activity of the enzyme. 
The r2coefficient calculated for the rs6226 and rs6224 polymorphisms was 0.4724.

DISCUSSION
Atherosclerosis is a multifactorial process involving cellular, extracellular and inflammatory components. Matrix metalloproteinases (MMPs), including matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), are involved in vascular wall remodelling and in the development and proliferation of atherosclerotic plaques. Both MMPs are activated by furin. Furin also activates - by means of intracellular proteolysis - pro-metalloproteinase-1 (MT-1-MMP), transforming it into matrix metalloproteinase-1 (MMP-1). At a later stage, enzymatically active MMP-1 is released outside the cell and acts as a trigger for pro-metalloproteinase 2 (pro-MMP-2) activation and its transformation to MMP-2. These proteases play a substantial role in migration and proliferation of smooth muscle cells, thus participating in vascular wall remodelling. 8, 9 Vascular wall remodelling requires degradation and re-synthesis of extracellular matrix (ECM), which is composed of structural proteins (collagen and elastin), glycosaminoglycans, proteoglycans and adhesion ligands. MMPs are the main enzymes responsible for collagen degradation, and furin participates in vascular wall remodelling by means of MMP activation.18, 19 The inflammatory process shows a correlation with increased vascular wall stiffness. A relationship was also shown to exist between the increased levels of C-reactive protein and fibrinogen and reduced vascular compliance. As atherosclerosis progresses, vascular compliance decreases.20-23
Hypertension predisposes patients to develop atherosclerosis, while reducing vascular compliance at the same time.24,25  Raffetto et al. showed an increased MMP-2 expression in the aortic walls of patients with primary hypertension.26 In our study, the large artery elasticity index (C1) was inversely proportional to the subject's age, SBP and coronary artery disease (Table 3). 
Syeda et al. demonstrated the relationship between reduced small artery compliance and the incidence of ischemic heart disease.27 Takeuchi et al. found lower values of small artery elasticity index in patients with ischemic heart disease compared to the control group. Increased small artery stiffness was related to ischemic heart disease, regardless of patient's age, gender and blood pressure.28 Increased vascular wall stiffness leads to left ventricular hypertrophy because of increased vascular resistance. Our results are in agreement with data published before.29-31 For example, in the MESA study Heckbert et al. demonstrated a relationship between LVM and SBP, BMI, diabetes and smoking.29
In atherosclerosis, which plays a crucial role in the pathogenesis of ischemic heart disease, macrophages and smooth muscle cells migrate from the tunica media to the tunica adventia and proliferate.32-34 Inflammatory cytokines increase MT-1-MMP activity in vascular endothelial cells, smooth muscle cells and macrophages. Furin participates in the activation of this enzyme by proteolysis. MMP-2 activated by MMP-1 is the most frequently found among all the metalloproteinases in smooth muscle cells. Its activation gives a rise to smooth muscle cell migration to the tunica adventia. Zempo et al. demonstrated a relationship between MMP-2 activity and smooth muscle cell migration to the tunica adventia after vascular wall injury.35 In patients with acute coronary syndromes, elevated MMP-2 levels are observed.36-38 This protease was identified in 83% of specimens of atherosclerotic plaque, collected from patients after acute coronary syndrome.39 MMP-2 changes the nature of the atherosclerotic plaque and increases the risk of its rupturing. A correlation was demonstrated between MMP expression and blood platelet aggregation.36, 40
Our results show that in subjects with the CC genotype of rs6226 polymorphism, furin shows increased proteolytic activity compared to those with CG and GG genotypes. This increased enzymatic activity is reflected in the increased activity of matrix metalloproteases. As a result, vascular wall remodelling takes place, involving small arteries in particular, as shown by their decreased compliance and the higher incidence of ischemic heart disease and myocardial infarction in these subjects.
The r2coefficient calculated for the rs6226 and rs6224 polymorphisms was 0.4724, which indicates that there exists a weak association between the rs6226 and rs6224 polymorphisms of the furin gene. This suggests that these 2 polymorphisms exert independent functional effects on the pathogenesis of cardiovascular disease.

CONCLUSIONS 
The rs6226 and rs6224 furin polymorphisms are associated with cardiovascular diseases, but appear to exert independent functional effects on their pathogenesis.


List of abbreviations
BMI-body mass index, C1-large artery elasticity index, C2-small artery elasticity index,
DBP-diastolic blood pressure, IVSDd-intraventricular septum diastolic diameter,
LVEDV-left ventricle end-diastoloc volume, LVEF-left ventricle ejection fraction,
LVM-left ventricle mass, LVMI- left ventricle mass index, MMPs- metalloproteinases,
MMP-1�matrix metalloproteinase-1, MMP-2�matrix metalloproteinase-2,
MMP-9 �matrix metalloproteinase-9, MT-1-MMP-pro-metalloproteinase 1, pro-MMP-2- pro-metalloproteinase 2, PWDd-posterior wall diastolic diameter, SBP-systolic blood pressure,
WHR-waist/hip ratio.
Trial Registration
The research project entitled �The study of pathogenesis of cardiovascular diseases, from the vascular and cardiac intermediate phenotypes to the candidate genes�� was conducted with the consent of the Ethical Board at the Silesian Medical University (Consent No. NN-013-145/03).
Competing interests
None financial or non-financial competing interests to declare.











REFERENCES
Steiner DF. The proprotein convertases. Curr Opin Chem Biol 1998;2:31-39.
Denault JB, Leduc R: Furin/PACE/SPC1: a convertase involved in exocytic and endocytic processing of precursor proteins. FEBS Lett 1996;379:113-116.
Roebroek AJ, Pauli IG, Zhang Y, van de Ven WJM. cDNA sequence of a Drosophila melanogaster gene, Dfur1, encoding a protein structurally related to the subtilisin-like proprotein processing enzyme furin. FEBS Lett 1991;289:133-137.
Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J 1997;327:625-635.
Schapiro FB, Soe TT, Mallet WG, Maxfield FR. Role of cytoplasmic domain serines in intracellular trafficking of furin. Mol Biol Cell 2004;15:2884-2894.
Feliciangeli SF, Thomas L, Scott GK, et al. Identification of a pH sensor in the furin propeptide that regulates enzyme activation. J Biol Chem 2006;281:16108-16116.
Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Cell Biol 1999;9:28-35.
Stawowy P, Meyborg H, Stibenz D, et al. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Circulation 2005;111:2820-2827.
Stawowy P, Margeta C, Kallisch H, et al. Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-�1 involves furin-convertase. Cardiovasc Res 2004;63:87-97. 
 Golubkov VS, Chekanov AV, Shiryaev SA, et al. Proteolysis of the membrane type-1 matrix metalloproteinase prodomain. J Biol Chem 2007;282:36283-36291.
 Rajavashisth TB, Xu XP, Jovinge S, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation 1999;99:3103-3109.
 Weber T, Auer J, O�Rourke MF, et al. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 2004;109:184-189.
 Herrington DM, Brown WV, Mosca L, et al. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation 2004;110:432-437.
 Hansen TW, Staessen JA, Torp-Pedersen C, et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 2006; 113:664-670.
Cohn JN, Finkelstein S, McVeigh G, et al. Noninvasive pulse wave analysis for the early detection of vascular disease. Hypertension 1995;26:503-508.
 O�Rourke MF, Pauca A, Jiang XJ. Pulse wave analysis. Br J Clin Pharmacol 2001;51:507-522.
 Gaunt TR, Rodriguez S, Day INM. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'. BMC Bioinformatics 2007;8:428.
 de Kleijn DP, Sluijter JP, Smit J, et al. Furin and membrane type-1 metalloproteinase mRNA levels and activation of metalloproteinase-2 are associated with arterial remodeling. FEBS Lett 2001;501:37-41.
 Jacob MP. Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother 2003;57:195-202.
 Schnabel R, Larson MG, Dupuis J, et al. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension 2008; 51:1651-1657.
 Duprez DA, Somasundaram PE, Sigurdsson G, Hoke L, Florea N, Cohn JN. Relationship between C-reactive protein and arterial stiffness in an asymptomatic population. J Hum Hypertens 2005;19:515-519.
 Nakhai-Pour HR, Grobbee DE, Bots ML, Muller M, van der Schouw YT. C-reactive  protein and aortic stiffness and wave reflection in middle-aged and elderly men from the community. J Hum Hypertens 2007;21:949-955.
 Vlachopoulos C, Pietri P, Aznaouridis K, et al. Relationship of fibrinogen with arterial stiffness and wave reflections. J Hypertens 2007;25:2110-2116.
 Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007;50:228-233.
 Safar ME, Boudier HS. Vascular development, pulse pressure, and the mechanisms of hypertension. Hypertension 2005;46:205-209.
 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2008;75:346-359.
 Syeda B, Gottsaunder-Wolf M, Denk S, Pichler P, Khorsand A, Glogar D. Arterial compliance: a diagnostic marker for atherosclerotic plaque burden? Am J Hypertens 2003;16:356-62.
 Takeuchi K, Zhang B, Ideishi M, et al. Influence of age and hypertension on the association between small artery compliance and coronary artery disease. Am J Hypertens 2004;17:1188-1191. 
 Heckbert SR, Post W, Pearson GD, et al. Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis. J Am Coll Cardiol 2006;11:2285-2292. 
 Meijs MF, Bots ML, Cramer MJ, et al; SMART Study group. Differences in determinants of left ventricular mass assessed by cardiac magnetic resonance imaging across subjects with and without previous symptomatic atherosclerotic disease. Int J Cardiol 2010;s138:145-150. 
 Turakhia MP, Schiller NB, Whooley MA. Prognostic significance of increased left ventricular mass index to mortality and sudden death in patients with stable coronary heart disease (from the Heart and Soul Study). Am J Cardiol 2008;9:1131-1135. 
 Tao J, Liu DH, Wang LC, et al. Arterial elasticity identified by pulse wave analysis and its relation to endothelial function in patients with coronary artery disease. J Hum Hypertens 2007;21:149-153. 
 Pasterkamp G, de Kleijn DP, Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovasc Res 2000;45:843-852. 
 McNulty M, Mahmud A, Spiers P, Feely J. Collagen type-I degradation is related to arterial stiffness in hypertensive and normotensive subjects. J Hum Hypertens 2006;20:867-873. 
 Zempo N, Koyama N, Kenagy RD, Lea HJ, Clowes AW. Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor. Arterioscler Thromb Vasc Biol 1996;16:28-33. 
 Shah PK, Galis ZS. Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain. Circulation 2001;104:1878-1880. 
 Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes: part IV: matrix metalloproteinases and biomarkers of platelet activation. Circulation 2006;113:e382-e385. 
 Jones CB, Sane DC, Herrington DM. Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome. Cardiovasc Res 2003;59:812-823. 
 Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation 1995;91:2125-2131. 
 Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94:2493-2503.













Table 1. Demographic and clinical characteristics of the study group.
Phenotypic traits (n=504)Mean value � SDAge (years)     56.7�9.5Body mass index (BMI) (kg/m2)     27.7�4.1Waist to hip ratio (WHR)     0.9�0.1Systolic blood pressure (SBP) (mmHg)     148.3�22.3Diastolic blood pressure (DBP) (mmHg)     85.6�12.5Large artery elasticity index (C1)
 (ml/mmHgx10)     10.3�3.9Small artery elasticity index (C2) (ml/mmHgx100)     2.9�2.1Posterior wall diastolic diameter (PWDd) (mm)     10.6�1.8Interventricular septum diastolic diameter (IVSDd) (mm)     10.9�1.7Left ventricular end-diastolic volume (LVEDV) (cm3)     137.5�44.2Left ventricular mass (LVM) (Devereux) (g)     251.5�75.0Left ventricular mass index (LVMI) (g/m2)     133.2�36.1Left ventricular ejection fraction (LVEF) (%)     55.7�7.9Fasting serum glucose (mg %)     97.2�32.4Total cholesterol (mmol/l)     5.3�1.4HDL - cholesterol (mmol/l)     0.9�0.3Triglycerides (mmol/l)     1.8�1.0LDL - cholesterol (mmol/l)     3.5�1.3





















Table 2. Clinical characteristics of the study group.
Phenotypic trait (n=504) No. of subjectsPercentageStatin use  191   37.9%Hypotensive medication use   379   75.2%Smoking status   305   60.5%Blood hypertension   392   77.8%DM 2     72   14.3%Coronary artery disease   332   65.9%Myocardial infarction (MI)   207   41.1%


 Table 3. Multiple linear regression model for the variables independently related to systolic blood pressure (SBP), diastolic blood pressure (DBP), large artery elasticity index (C1), small artery elasticity index (C2), left ventricular mass (LVM) and left ventricular mass index (LVMI).
Dependent variableIndependent variablesStandardized regression 
coefficientStatistical significanceSBP
Corrected R2=0.12
p<0.001Age
BMI
Female sex
Diabetes mellitus�=0.23
�=0.20 
�=0.14
�=0.13 p<0.001
 p<0.001
 p=0.001
 p=0.003DBP 
Corrected 
R2=0.06; p<0.001BMI
Age�=0.18
�=0.13p<0.001
p=0.003C1 
Corrected 
R2=0.59
p<0.001SBP 
BSA
Age
Coronary 
artery disease�="0.67 
�=0.28 
�="0.14

�="0.11p<0.001
p<0.001
p<0.001

p<0.001C2 
Corrected
 R2=0.51
p<0.001
SBP
Body area
Coronary 
artery disease
Smoking 
GG polymorphism 
of rs6226
Waist to hip 
ratio (WHR)
Age�="0.57
�=0.34

�="0.18
�="0.12

�=0.12

�="0.11
�="0.09p<0.001
p<0.001

p<0.001
p<0.001

p<0.001

p=0.008
p=0.01LVM
Corrected 
R2=0.33
p<0.001
Waist to hip 
ratio (WHR)
Coronary 
artery disease
Body area 
SBP
Male sex
Height
�=0.14

�=0.22
�=0.32
�=0.10
�=0.21
�="0.17
p<0.001

p=0.02
p<0.001
p=0.02
p<0.001
p=0.03LVMI
Corrected
 R2=0.20
p<0.001
Coronary 
artery disease
Waist to hip 
ratio (WHR)
Age
Male sex
Height
SBP
�=0.20

� = 0.16
�=0.10
�=0.23
�="0.16
�=0.09
p<0.001

p=0.002
p=0.03
p=0.04
p=0.008
p=0.04

Table S1.  Analysis of qualitative variables in subjects with CC, CG, and GG variants of the rs6226 polymorphism. 
Table S2. Analysis of qualitative variables of subjects with GG, GT and TT variants of the rs6224 polymorphism.


































PAGE  


PAGE  10









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