The authors investigated associations of polymorphism of interleukins genes with nephritic survivance of the ill with chronic glomerulonephritis among 238 patients with CGN and 241 control group individual

Churnosov, M. I.

Kalmykova, E. V.

Nekipelova, E. V.

Proshchaev, K. I.

Sirotina, S. S.

DSpace at Belgorod State University

          ISSN: 0975-8585 September - October 2014  RJPBCS   5(5)  Page No. 1036 Research Journal of Pharmaceutical, Biological and Chemical Sciences   Association of Interleukins Genes Polymorphic Markers with Speed of CGN’s Advance.     Elena Vasil'evna Nekipelova*, Svetlana Sergeevna Sirotina, Kirill Ivanovich Proshchaev, Elena Vasil'evna Kalmykova, and Mikhail Ivanovich Churnosov.  Belgorod State National Research University, 85, Pobedy St., Belgorod, 308015, Russia.    ABSTRACT   The authors investigated associations of polymorphism of interleukins genes (-511C/T IL-1B, -889C/T IL-1А, VNTR IL-1Ra, C-703T IL-5, T113M IL-9, -592C/A IL-10, -4257G/A IL-13) with nephritic survivance of the ill with chronic glomerulonephritis among 238 patients with CGN and 241 control group individuals. It is found that genetic variants 2R/5R, 4R/5R VNTR IL-1Ra are associated with accelerated hypotrophy of kidneys. The authors revealed factors reducing nephritic survivance. They are alleles -889C IL-1А and -592A IL-10, and arterial hypertension during CGN. Keywords: chronic glomerulonephritis, accelerated hypotrophy of kidneys, nephritic survivance, genetic polymorphism, interleukins.                             *Corresponding author           ISSN: 0975-8585 September - October 2014  RJPBCS   5(5)  Page No. 1037 INTRODUCTION   Nowadays chronic glomerulonephritis (CGN) is a serious problem for modern medical science because of disease’s severity and high prevalence rate in different regions of the world [1]. It should be noted that the disease involves mainly active working aged persons, and that causes a significant social and economical damage [2].          Chronic glomerulonephritis is an allelically determined immune inflammatory disease [3], for progress of which, as shown in the literature, interleukins play an important role [4]. Interleukins genes are very diverse from the point of view of population. Some mutations in genes, which code corresponding interleukins, substantially change level of their expression, and that can have an impact on the progress of  chronical inflammatory process [5].        Results of works dedicated to investigation of relations between interleukins candidate genes and advance of chronic glomerulonephritis are not identical for different populations. As aforesaid, in this work you can find estimation of the role of interleukins genetic polymorphisms (-511C/T IL-1B, -889C/T IL-1А, VNTR IL-1Ra, C-703T IL-5, T113M IL-9, -592C/A IL-10, -4257G/A IL-13) in accelerated hypotrophy of kidneys of patients with chronic glomerulonephritis.    MATERIALS AND METHODS   Interleukins genes polymorphisms analysis was carried out on the basis of the material of two sample groups: 238 patients with chronic glomerulonephritis and 241 control group persons aged 15-79 years old. The control group included individuals of Russian ethnicity, born in Central region of Russia and having no blood relationship among themselves. Patients were included to the illness group only after disease diagnosis ascertainment with the help of clinical and laboratory-instrumental examination technics. Clinical examination and diagnostics were performed by workers of  nephrology department of Belgorod regional clinical hospital.          Exclusionary criteria for the CGN group were diabetes mellitus (in anamnesis or found during the examination), hypertensive disease.     Nephritic survivance of persons with CGN was estimated in the group of 138 patients without end-stage renal disease. Among them 104 patients had unharmed functioning of kidneys (creatinine level was less than 140 mcM/l), 34 patients had chronic renal disease (creatinine level was more than 140 mcM/l during 6 months of observation). For analysis of nephritic survivance and influence of different factors on it we used the method of multiplicative estimators of Kaplan-Meier with Cox regression model [6].            We researched 7 polymorphic variants of interleukins genes (-511C/T IL-1B, -889C/T IL-1А, VNTR IL-1Ra, C-703T IL-5, T113M IL-9, -592C/A IL-10, -4257G/A IL-13), being of great importance for the progress of immune inflammatory diseases [7].    DNA was disengaged from peripheral blood via method of phenolic chloroform spirit extraction [8]. Analysis of all loci was performed via method of polymerase chain reaction (PCR) of DNA synthesis. Procedures and sequences of oligonucleotide primers and probes used are represented in works [9-12].  DNA markers genotyping was performed via methods of analysis of amplificated fragments lengths polymorphism (AFLP) (VNTR IL-1Ra), analysis of restriction fragments lengths polymorphism (-511C/T IL-1B, -889C/T IL-1А, C-703T IL-5, T113M IL-9, -4257G/A IL-13).  Associations of alleles and genotypes of investigated DNA-markers with speed of chronic glomerulonephritis advance were estimated wth the help of analysis of contingency tables 2x2 with calculation of criterion 2 with Yates' correction for continuity and odds ratio (OR) with 95% confidence interval (CI). Analysis of associations of nephritic survivance with polymorphic genetic markers was performed via method of multiplicative estimators of Kaplan-Meier (“STATISTICA 6.0”) [6].               ISSN: 0975-8585 September - October 2014  RJPBCS   5(5)  Page No. 1038 RESULTS  We examined 238 patients with chronic glomerulonephritis and 241 control group persons. Main characteristics of examined group of patients with chronic glomerulonephritis and control group are shown in table 1. It should be noted that the CGN group level of arterial pressure and creatinine exceeded that of the control group (p<0.001). During comparative analysis of frequencies of alleles and genotypes of investigated loci of interleukins among patients with CGN and the control group we revealed no statistically-valid differences (table 2).       Table 1: Characteristics of the subjects from the case and control groups  Characteristics Cases Controls Total Males Females Age, yrs Weight, kg Height, cm SBP, mm Hg DBP, mm Hg Creatinine, μmol/L GFR, ml/min 238 127 (53.4%)* 111 (46.6%)* 39.58 ± 14.58* 63.4 ± 2.1* 165.4 ± 3.4* 148.4 ± 26.5** 92.7 ± 14.0** 337.2 ± 44.1** 28,2±1,8 304 125 (51.86%) 116 (46.64%) 42.20 ± 6.28 67.4 ± 1.7 168.6 ± 2.7 128.1 ± 4.4 82.2 ± 2.0 130.4 ± 7.8 81,6±3,4 Note: *p>0.05; **p<0.001.  Table 2: Summary information about the studied polymorphisms.)  Polymorphism Studied groups Minor allele MAF (%) HWE χ2 p (-511) C/T IL-1B (-511) C/T IL-1B (-889) C/T IL-1A (-889) C/T IL-1A VNTR IL-1Ra VNTR IL-1Ra C-703T IL-5 C-703T IL-5 T113M IL-9 T113M IL-9 (-592) C/A IL-10 (-592) C/A IL-10 (-4257)G/A IL-13 (-4257)G/A IL-13 Case Control Case Control Case Control Case Control Case Control Case Control Case Control (-511)T IL-1B (-511)T IL-1B (-889)T IL-1A (-889)T IL-1A IL-1Ra*2 IL-1Ra*2 -703T IL-5 -703T IL-5 113M IL-9 113M IL-9 (-592)A IL-10 (-592)A IL-10 (-4257)A IL-13 (-4257)A IL-13 33.84 35.21 28.03 32.06 25.13 21.84 25.29 28.48 17.66 18.67 27.73 22.67 27.93 23.90 0.01 0.87 0.21 0.89 0.75 0.11 0.10 0.98 0.19 0.36 0.24 0.41 1.53 0.93 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 Notes: MAF, minor allele frequency; HWE, Hardy–Weinberg equilibrium. P values were calculated using the χ2 test.  During estimation of nephritic survivance of patients with CGN, depending on genetic polymorphisms of interleukins, performed with the help of the method of multiplicative estimators of Kaplan-Meier, we found statistically-valid relations with progress speed for a locus IL-1Ra: individuals, which are carriers of genotypes 2R/5R, 4R/5R, tend to accelerated hypotrophy of kindeys (χ2=8.29; p=0.05) (fig. 1).  For identification of factors having unfavourable prognostic value for CGN, we carried out a monofactor analysis of nephritic survivance with the help of Cox regression model. It was found that presence of allele -889C of gene IL-1А (р=0.05),  allele -592A of gene IL-10 (р=0.05) and arterial hypertension during CGN (р=0.01) declines nephritic survivance.             ISSN: 0975-8585 September - October 2014  RJPBCS   5(5)  Page No. 1039  Figure 1:  Renal survival of CGN patients with different genotypes of the VNTR polymorphism of the IL-1Ra gene.  SPECULATION   It was found that carriers of genotypes 2R/5R, 4R/5R VNTR IL-1Ra tend to accelerated hypotrophy of kidneys. The question of a functional significance of this polymorphism remains open. It is estimated that increase in repeats number promotes transcriptional activity of IL-1Rа. However, most of researches showed that decrease in production of IL-1Ra, having anti-inflammatory effect, leads to increase in production of  IL-1B with anti-inflammatory effect [11,12]. Thus, this fact explains associations we found: accelerated hypotrophy of kidneys with genotypes 2R/5R, 4R/5R VNTR IL-1Ra.  We found factors declining nephritic survivance. Independent factors of risk are carrying of allele -889C of gene IL-1А, having anti-inflammatory effect, allele -592A of gene IL-10, having atopic effect, and arterial hypertension during CGN. These allelic variants (-889C   IL-1А, -592A IL-10) are являются high-productive [10, 12, 13] and can cause more express pathogenetic effects of interleukin 10 (atopic effect) and interleukin 1A (anti-inflammatory effect) in an organism in the process of CGN advance.    RESUME  Thus, the work’s results allow to judge molecular genetic markers   2R/5R, 4R/5R VNTR IL-1Ra to be factors of risk of accelerated hypotrophy of kidney during CGN. Factors declining nephritic survivance are carrying of allele  -889C IL-1А,  allele -592A IL-10, arterial hypertension during CGN.   REFERENCES  [1] Pirkle JL, Freedman BI. Minerva Urol Nefrol 2013;65(1):37-50.  [2] Ekart R, Ferjuc A, Furman B, Gerjevič Š, Bevc S, Hojs R. Ther Apher Dial 2013;17(4):363-7.  [3] Litovkina O, Nekipelova E, Dvornyk V, Polonikov A, Efremova O, Zhernakova N, Reshetnikov E, Churnosov M. Gene 2014;546(1):112-6.  [4] Deltas C, Pierides A, Voskarides K. Nephrol Dial Transplant 2013;28(12):2946-60.  [5] Syrjänen J, Hurme M, Lehtimäki T, Mustonen J, Pasternack A. Kidney Int 2002;61(3):1079-85. [6] Jager KJ, van Dijk PC, Zoccali C, Dekker FW. Kidney Int 2008;74(5):560-5.  [7] Mathew CC. Human Press 1984;2:31-34. [8] Zhu W, Liu N, Zhao Y, Jia H, Cui B, Ning G. J Endocrinol Invest 2010;33(10):751-5.            ISSN: 0975-8585 September - October 2014  RJPBCS   5(5)  Page No. 1040 [9] Sehouli J., Mustea A., Koensgen D. et. al. Ann Oncol 2003;14:1501-1504. [10] Kim J, Kim Y, Lee KA. World J Gastroenterol 2014;20(16):4558-65.  [11] Hao L, Li JL, Yue Y, Tian Y, Wang M, Loo WT, Cheung MN, Chow LW, Liu Q, Yip AY, Ng EL. Int J Biol Markers 2013;28(1):92-9.  [12] JS Song, HJ Jeong, SJ Kim. Am J Chin Med 2008;36(1):71-80. [13] L Williams, G Jarai, A Smith et al. Leukocyte Biol 2002;72(4):800-809. 

Association of Interleukins Genes Polymorphic Markers with Speed of CGN’s Advance

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Association of Interleukins Genes Polymorphic Markers with Speed of CGN’s Advance

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