Polymorphism related to cardiovascular risk in hemodialysis subjects: a systematic review

Balbino, Karla Pereira; Hermsdorff, Helen Hermana Miranda; Bressan, Josefina

doi:10.1590/2175-8239-JBN-3857

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Brazilian Journal of Nephrology

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Review Article • J. Bras. Nefrol. 40 (2) • Apr-Jun 2018 • https://doi.org/10.1590/2175-8239-JBN-3857 copy

Polymorphism related to cardiovascular risk in hemodialysis subjects: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Cardiovascular disease (CVD) is one of the leading causes of mortality in hemodialysis (HD) subjects. In addition to the traditional risk factors that are common in these individuals, genetic factors are also involved, with emphasis on single nucleotide polymorphs (SNPs). In this context, the present study aims to systematically review the studies that investigated the polymorphisms associated with cardiovascular risk in this population. In general, the SNPs present in HD individuals are those of genes related to inflammation, oxidative stress and vascular calcification, also able of interfering in the cardiovascular risk of this population. In addition, polymorphisms in genes related to recognized risk factors for CVD, such as dyslipidemia, arterial hypertension and left ventricular hypertrophy, also influence cardiovascular morbidity and mortality.

Keywords:
Chronic Renal Failure; Inflammation; Oxidative Stress; Vascular Calcification; Hypertrophy, Left Ventricular; Polymorphism Single Nucleotide

Gene	Molecule	SNP	Methodology	Result	Reference
SELE	E Selectin, adhesion molecule	rs5355C > T	Cross-sectional study. 40 subjects (median age: 45 years; 50% women) and 30 controls (median age: 36.5 years; 63.3% women). SNP determination by PCR-RFLP	There was no difference in comparing the right and left media-intima thickness and the right and left cross-sectional areas between the CC, CT and TT from the do SELE SNP rs5355C > T	Isaac et al., 2014⁴⁰40 Issac MSM, Afif A, Gohar NA, Fayek NA, Zayed B, Sedrak H, et al. Association of E-selectin gene polymorphism and serum PAPP-A with carotid atherosclerosis in end-stage renal disease. Mol Diagn Ther 2014;18:243-52.
HMOX1	Heme oxigenase 1	The allele frequencies of the dinucleotide-guanosinatimidine repetitions length (the S allele represents shorter repetitions (< 27) and the L allele represents longer repetitions (≥ 27).	Cohort study. 1080 subjects (51.1% men; age: 59 years) and 365 controls (52.1% men; age: 57 years). SNP determination by PCR	The L/L genotype had higher mortality by CVD and by all causes.	Chen et al., 2013⁴⁵45 Chen YH, Hung SC, Tarng DC. Length polymorphism in heme oxygenase-1 and cardiovascular events and mortality in hemodialysis patients. Clin J Am Soc Nephrol 2013;8:1756-63.
ICAM-1	Intercellular –I adhesion molecule	K469E; TT, TC and CC genotypes	Cross-sectional study. 1016 Caucasian subjects (656 with CVD: age 62.8 ± 15 59.9% men and 360 without CVD: age: 56.8 ± 14.3, 51.9% men); 824 controls (age: 52.1 ± 14; 55.2% men). SNP determination by PCR + allele-specific.	Upon stratifying the patients according to CVD clinical characteristics, there was a trend for higher frequencies of the T allele and TT genotype in patients with AMI; Bearing the T allele was an independent risk factor for CVD susceptibility.	Buraczynska et al., 2012²⁰20 Buraczynska M, Zaluska W, Baranowicz-Gaszczyk I, Buraczynska K, Niemczyk E, Ksiazek A. The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease. Hum Immunol 2012;73:824-8.
IL-6	Interleukin-6	-634C/G, -174G/C and -572C/G.	Cross-sectional study 216 subjects with CAD (age: 58.6±10.6 years; 61.1% men). SNP determination by PCR RFLP.	Positive association of the -634GG and -174CC genotypes and risk of cardiovascular events; There was no association between the 572C/G SNP and the risk of cardiovascular events.	Song et al., 2015⁸8 Song Y, Gu HD, He Y, Wang JW. Role of IL-6 polymorphism on the development of cardiovascular events and coronary artery disease in patients receiving hemodialysis. Genet Mol Res 2015;14:2631-7.
IL-6, IL-10 and the tumor necrosis factor	Interleucina-6 and 10 and the tumor necrosis factor	TNF:-308 G/A (rs 1800629); IL-6: -174 G/A (rs 1800795); IL-10: -1082 G/A (rs1800896)	Cross-sectional study. 169 Caucasian subjects (age: 62 ± 11 years; 62.1% men). SNP determination by PCR.	Heterozygotes for the IL-10 gene had less cardiovascular events; Patients with the A allele (TNF gene) had higher risk of developing cardiovascular events Having the G allele (IL-6 gene) had a protective effect over cardiovascular events.	Tosic Dragovic et al., 2016¹⁷17 Tosic Dragovic J, Popovic J, Djuric P, Jankovic A, Bulatovic A, Barovic M, et al. Relative risk for cardiovascular morbidity in hemodialysis patients regarding gene polymorphism for Il-10, Il-6 and TNF. Can J Physiol Pharmacol. 2016;94:1106-9.
NOX	NADP oxidase	C242T	Cross-sectional study. 289 Chinese subjects: 192 without CVD (Group N; Age: 53.3 ± 12.6; 51.6% men) and 97 with CVD (Group D; age 54.4 ± 11.5 years; 51.4% men). SNP determination by PCR RFLP.	T+TT genotype frequency was significantly lower in the D Group when compared to the N Group.	Tang et al., 2010²⁹29 Tang FY, Zhu Y, Wang GH, Xie XW. Relation between development of cardiovascular disease and the C242T CYBA polymorphism of the NADPH oxidase in ESRD patients. Dis Markers 2010;29:89-93.
RAGE	Advanced glycation final products receptor	-374 T/A	Case control study 1866 Caucasian subjects (age: 61.6 ± 17.2; 57.0% men) and 1143 healthy subjects (age: 54 ± 19.1; 55.2% men); 63 subjects with ischemic stroke (age: 66.3 ± 14.5 years; 52.1% women). SNP determination by PCR.	Stroke subjects had lower frequencies of the A allele when compared to those patients without CVD.	Buraczynska et al., 2015²⁵25 Buraczynska M, Zaluska W, Buraczynska K, Markowska-Gosik D, Ksiazek A. Receptor for advanced glycation end products (RAGE) gene polymorphism and cardiovascular disease in end-stage renal disease patients. Hum Immunol 2015;76:843-8.
UGT1A1	Uridine diphosphato-glucuronosiltransferase	UGT1A1*28	Cohort study. 661 subjects (50.7% men; age: 58 years) and 152 controls (53.9% men; age: 59 years). SNP determination by PCR.	Subjects with the 7/7 genotype had significantly higher bilirubin levels when compared to those with the 6/6 and 7/6 genotypes; Subjects with the 7/7 genotype had approximately 1/10 of the risk for cardiovascular events and 1/4 of the risk for all-cause mortality when compared to those bearing the allele 6.	Chen et al., 2011³⁷37 Chen YW, Hung SC, Tarng DC. Serum bilirubin links UGT1A1*28 polymorphism and predicts long-term cardiovascular events and mortality in chronic hemodialysis patients. Clin J Am Soc Nephrol 2011;6:567-74.

Gene	Molecule	SNP	Study/Sample	Result	Reference
ANRIL	Non-codifying antisense RNA	rs10757278, rs4977574, rs10757274 and rs6475606	Cohort study. 284 subjects (age: 56.0 ± 2.0; 59.9% women). SNP determination by PCR.	Homozygote subjects for the risk allele (GG) from SNP rs10757278 had twice the risk of developing adverse cardiovascular event than those with the protective allele (AA or AG), even after adjusting for other risk factors such as diabetes mellitus.	Arbiol-Roca et al., 2017⁸¹81 Holdt LM, Teupser D. From genotype to phenotype in human atherosclerosis-recent findings. Curr Opin Lipidol 2013;24:410-8.
MTHFR	Methylenotetrahydropholato redutase	C677T	Cross-sectional study. 152 subjects (age: 56.8 ± 13.8; 54.6% men). SNP determination by PCR.	Higher VC score in subjects with the TT genotype than those with CC and CT; Higher prevalence of peripheral vascular disease with the polymorphism for all the individuals; Higher incidence of stroke with the polymorphism in young subjects (≤ 60 years); Positive association of CT and TT genotypes and VC.	Lee et al., 2011⁷³73 Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Giacone G, Cataliotti A, et al.; CREED Investigators. Prognostic impact of the indexation of left ventricular mass in patients undergoing dialysis. J Am Soc Nephrol 2001;12:2768-74.
Matrix Gla protein	Matrix Gla protein	T-138C (rs1800802) G-7A (rs1800801)	Cohort study. 134 subjects. SNP determination by PCR.	VC progression velocity in subjects with the CC genotype. In the CC genotype subjects it was slow than in the CT or TT subjects; CT/TT genotype association with advanced age upon HD onset, male gender, high concentrations of calcium X phosphorus and LDL-c, low concentrations of HDL-c and ferritin and no use of angiotensin II receptor blockers with VC progression.	Yoshikawa et al., 2013⁶⁸68 Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr 2012;3:166-73.
VKORC1	Epoxid-redutase Vitamin K	C1173T and G-1639A	Cross-sectional study. 54 subjects (age: 40.1 ± 12.5 years; 54% women). SNP determination by PCR.	Association between C1173T polymorphism and VC; The T allele was associated with higher likelihoods of VC and CVD clinically evident; The G-1639A polymorphism was not associated with VC and did show lower prevalence of clinically evident CVD.	Osman et al., 2016⁷7 Osman NA, El-Abd N, Nasrallah M. VKORC1 gene (vitamin k epoxide reductase) polymorphisms are associated with cardiovascular disease in chronic kidney disease patients on hemodialysis. Saudi J Kidney Dis Transpl 2016;27:908-15.

Gene	Molecule	SNP	Study/Sample	Results	Reference
CTGF2	Connective tissue growth factor	G-945C	Cross-sectional study. 99 Caucasian subjects (age: 64 ± 13 years, 64% men). SNP determination by PCR.	Positive association between the GG genotype in cardiovascular events (CVA and MI) and CVD mortality.	Cozzolino et al., 2010⁷⁸78 Oemar BS, Lüscher TF. Connective tissue growth factor. Friend or foe? Arterioscler Thromb Vasc Biol 1997;17:1483-9.
ACE	Angiotensin converter enzyme	I/D	Cross-sectional study. 196 subjects (56,6% men; age: 62,3 ± 11.4 years). SNP determination by PCR RFLP.	Higher incidence of left ventricular hypertrophy and peripheral vascular disease in subjects with the D allele; Association between polymorphism and CVA incidence and hyperlipoproteinemia.	Tošić et al., 2014⁵⁸58 Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res 2006;98:1123-33.
PPAR γ	Receptors activated by peroxisome proliferator	Pro12Ala and C161T	Cross-sectional study. 99 Chinese subjects (age: 60.2 ± 11.9 years; 53.5% men) and 149 controls (age: 51.7 ± 15.9 years; 56.4% men). SNP determination by PCR RFLP.	PC and CIMT in subjects with the CT + TT or Pro12Ala were lower than in the subjects with CC or Pro12Pro; CIMT of the Pro12Ala-CT161 subgroup was lower than in the Pro12Pro-CC161 and Pro12Pro-CT161 subgroups; CP of subgroup Pro12Ala-CT161 was lower than in the Pro12Pro-CC161 subgroup.	Liu et al., 2014⁹9 Liu F, Mei X, Zhang Y, Qi H, Wang J, Wang Y, et al. Association of peroxisome proliferator-activated receptorγ gene Pro12Ala and C161T polymorphisms with cardiovascular risk factors in maintenance hemodialysis patients. Mol Biol Rep 2014;41:7555-65.
VDR	Vitamin D receptor	BsmI	Cross-sectional study. 182 Caucasian subjects (57.1% men); 175 healthy subjects. SNP determination by PCR.	Direct association between the number of B alleles and LVMI, independently of treatment with anti-hypertensive and calcitriol; The number of B alleles was positively associated with LVMI changes.	Testa et al., 2010⁷⁵75 El-Shehaby AM, El-Khatib MM, Marzouk S, Battah AA. Relationship of BsmI polymorphism of vitamin D receptor gene with left ventricular hypertrophy and atherosclerosis in hemodialysis patients. Scand J Clin Lab Invest 2013;73:75-81.
VDR		BsmI	Cross-sectional study. 80 subjects (66.3% men; age: 57.3 ± 10.6 years); 40 healthy controls (65% men; age: 56.5 ± 11.2 years). SNP determination by PCR RFLP.	Subjects with the BB genotype had lower serum concentrations of 25-hidroxi vitamin D in comparison with the Bb and bb genotypes; The number of B alleles was positively correlated with the LVMI, but not with the intima-media thickness.	El-Shehaby et al., 2013⁷⁶76 Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-13.
SIRT 1	Sirtuin 1	rs7895833, rs7069102 e rs2273773	Cross-sectional study. 219 Japanese subjects (54.3% men; age: 60.4 ± 13.3 years); 803 control subjects (65.1% women; age: 61.3 ± 10.3 years). SNP determination by PCR.	TC and LDL-c serum concentrations were higher among bearers of the G allele (rs7069102) in comparison with the CC genotype in males; Coronary artery calcification scores were higher among bearers of the C allele (rs2273773) among all the individuals and in males.	Shimoyama et al., 2012⁵¹51 Kliewer SA, Willson TM. The nuclear receptor PPARgamma - bigger than fat. Curr Opin Genet Dev 1998;8:576-81.

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[1] Correspondence to: Josefina Bressan. E-mail: jbrm@ufv.br