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An Extensive Study of the Functional Polymorphisms of Kinin-Kallikrein System in Rheumatoid Arthritis Susceptibility.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder in which hypertrophy, hyperplasia and angiogenesis of synovial tissue may contribute to inflammatory joint destruction. (1,2) Kinin-kallikrein system (KKS) may be involved in RA pathogenesis since various molecules in the cascade of molecular reactions are related to: (i) cell growth and proliferation, (ii) production of cytokines (interleukin-6 and interleukin-8), (iii) generation of reactive oxygen species and nitric oxide, (iv) vasodilation, and (v) increased vascular permeability. (3)

Bradykinin (BK) is a nine amino acid vasoactive peptide that is produced by the proteolytic action of kallikrein on the precursor kininogen (KNG). (4) BK promotes the inflammatory signs of hyperemia, pain, and leakage of plasma proteins and affects blood pressure, platelet activation and aggregation, and fibrinolysis. BK acts through two types of receptors: bradykinin receptor (BR) 2 that is present constitutively in most tissues and has higher affinity to BK than BR1 that is induced during inflammatory conditions. (4-7) In addition, BR2 is optimally stimulated by the full sequence of BK or Lys-BK, while BR1 is sensitive to fragments of kinins without the C-terminal arginine (des-Arg9-BK, Lys-des-Arg9-BK). (8,9) Angiotensin converting enzyme (ACE) is also of great importance in BK mediated effects since it metabolizes BK and produces the inactive metabolite BK 1-5. (3,10)

Previous studies reported increased levels of ACE and BK in RA synovial fluid and up-regulation of BR1 and BR2. (3,11-16) Furthermore, KNG gene showed differential expression in studies of its association with RA, (17-19) while genome wide screens revealed that BR1 may be related to RA. (20) Additionally, to our knowledge, only one study in the literature described the association of the insertion/deletion polymorphism in ACE gene with RA. (21) Therefore, genetic variants that may affect ACE, BK, and BR genes expression and function may predispose to RA manifestation. Even though the role of KKS in autoimmunity and RA is reviewed extensively in the recent literature, (22) no genotypic data and associations are reported. Consequently, the present study is the first that examineds extensively the relationship of certain functional polymorphisms of KNG, ACE, BK, BR1 and BR2 genes with RA susceptibility. (2)

Specifically, the below functional polymorphisms were studied in this study: (i) the cytosine to thymine transition at nucleotide 22 (nucleotide 587 of cDNA) in exon 5 of KNG gene (3q27) which results in the substitution of amino acid arginine by a stop codon (Arg196Stop) leading to the low molecular weight KNG and therefore deficiency of KNG, (23) (ii) the 287 bp Alu repeat presence (insertion) or absence (deletion) in intron 16 of ACE gene (17q23); the deletion was associated with higher tissue and plasma levels of ACE and increased ACE activity, (24) (iii) the 9 bp insertion or deletion in exon 1 of BR2 gene (14q32); the deletion was associated with higher expression of BR2, (25,26) (iv) the -58T>C variant in the promoter of BR2 gene; the T allele was associated with higher expression levels of BR2, (25) and (v) the -699G>C variant in the promoter of BR1 gene (14q32); the C allele was associated with higher expression levels of BR1. (27) Therefore, in this study, we aimed to examine the following functional polymorphisms in rheumatoid arthritis susceptibility: (i) the 587C>T of KNG gene, (ii) the 287 bp Alu repeat insertion of ACE gene, (iii) the 9 bp insertion of BR2 gene, (iv) the -58T>C of BR2 gene, and (v) the -699G>C of BR1 gene.

PATIENTS AND METHODS

The study, which was conducted at Ioannina University Hospital between February 2012 and August 2016, included 136 unrelated patients with RA (27 males; 109 females; mean age 60.8 years; range 39 to 75 years). RA patients were classified according to the American College of Rheumatology criteria. (28) The demographic characteristics of patients are shown in Table 1.

Additionally, 149 ethnic matching healthy volunteers (30 males, 119 females; mean age 56.2 years; range 35 to 78 years) with no personal or family history of chronic autoimmune, metabolic or infectious diseases were enrolled. The study protocol was approved by the Ioannina University Hospital Ethics Committee. A written informed consent was obtained from each patient. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Genomic DNA was extracted from peripheral blood lymphocytes according to the standard salt extraction procedure. Polymorphisms 587C>T of KNG, (29) 287 bp I/D of ACE, (30) 9 bp I/D of BR2, (31) -58T>C of BR2, (32) and -699G>C of BR1 (27,33) were studied as described previously.

Statistical analysis

Arlequin software was used in the statistical analysis of the studied polymorphisms in order to establish Hardy-Weinberg equilibrium in RA and control groups. Chi-square test provided by the IBM SPSS statistical package version 21.0 (IBM Corp., Armonk, NY, USA) was used to test differences in polymorphisms' distribution between RA and control groups. Statistical significance was set at p [less than or equal to] 0.05.

RESULTS

The distribution of genotypes of each polymorphism in RA and control groups was shown in Table 2. High-molecular KNG was present in all patients and controls. All the studied polymorphisms were found in Hardy-Weinberg equilibrium in both RA and control groups, with the exception of -699G>C of BR1, which show little variance (Table 2). No significant difference was found in genotype or allele distribution of the studied polymorphisms between RA and control groups (Table 2).

DISCUSSION

Several pro-inflammatory molecules are present in the progress of inflammatory processes, which act via complicated molecular pathways. Kinins such as BK are considered pro-inflammatory mediators and were found to induce bone resorption in RA (34,35) Bone loss due to the increased activity of osteoclasts is the result of the concerted actions of stimulatory and inhibitory cytokines. (34-37) Cytokines were reported to induce the expression of both BR1 and BR2 through which BK exerts its pro-inflammatory action and induces molecular mechanisms involved in bone resorption. (36-38-39) The above data are further supported by the fact that cytokines are mostly derived from monocyte or macrophage cells, which have been reported to play a role in RA manifestation. (40) In addition, the increased ACE activity in monocytes and synovial cells of RA patients that inactivates BK might support the role of KKS in RA susceptibility. (41,42) Finally, the increased amounts and activity of kallikrein, BK, and BR found in synovial fluid of RA patients and the reduction of the high molecular weight KNG in synovial fluid raise the question of a potential association of the functional polymorphisms of KKS related genes with RA susceptibility. (16,43-46)

However, in the present study, no significant difference was observed in genotypes distribution of the functional polymorphisms 587C>T of KNG, 287 bp I/D of ACE, 9 bp I/D of BR2, -58T>C of BR2, and -699G>C of BR1 between RA patients and controls. To our knowledge, this is the first study that explored extensively the role of the functional polymorphisms of genes related to KKS with RA susceptibility. Therefore, we hope that the present study adds knowledge to the contradictory results of previous studies based on a single genetic variant of a KKS gene.

Specifically, only in one previous study, the deletion of ACE allele was associated with RA pathogenesis. (20) However, this study involved half of the number of patients compared to our study and the revealed association seems to be questionable. It is known that the deletion of ACE polymorphism is associated with increased levels and activity of ACE and therefore one could expect higher levels of BK to be transformed to the inactive form of BK1-5 reducing the inflammatory processes that are induced by BK.

On the other hand, the reported high levels and activity of ACE in monocytes and synovial cells of RA patients seem to be concordant with the high frequency of the homozygous ACE deletion in RA patients. (41,42) However, the latter may be attributed to the fact that ACE is also implicated in renin-angiotensin system (RAS); transforming the inactive angiotensin I to the active angiotensin II, which mediates with cell growth and proliferation by the stimulation of cytokines and growth factors. (10,47) Therefore, ACE increased activity in monocytes and synovial cells of RA patients may explain disease manifestation through RAS induced inflammatory processes, while the extent of the induced inflammation may be the equilibrium between the RAS and KKS function.

The above may provide an excuse for other studies of inflammatory diseases where the homozygous insertion ACE genotype -decreased ACE activity- was associated with juvenile RA and chronic plaque psoriasis. (38,48) In addition, the results for the role of ACE genotypes in systemic lupus erythematosus and asthma are contradictory; (49-53) while the data on the role of BR2 and BR1 polymorphisms in asthma and inflammatory bowel disease are limited and need further confirmation. (54,55)

In conclusion, this study, which concerns a large number of KKS functional polymorphisms, revealed that genetic variants in genes of KKS cannot be considered as susceptibility factors to RA. However, additional studies on both KKS and RAS gene polymorphisms and in larger groups of patients may reveal that specific genotypic combinations of KKS and RAS are related to inflammatory disease susceptibility and/or severity.

doi: 10.5606/ArchRheumatol.2018.6389

Declaration of conflicting interests

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding

The authors received no financial support for the research and/or authorship of this article.

REFERENCES

(1.) Iguchi T, Ziff M. Electron microscopic study of rheumatoid synovial vasculature. Intimate relationship between tall endothelium and lymphoid aggregation. J Clin Invest 1986;77:355-61.

(2.) FitzGerald O, Soden M, Yanni G, Robinson R, Bresnihan B. Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected knee joints of patients with rheumatoid arthritis. Ann Rheum Dis 1991;50:792-6.

(3.) Couture R, Harrisson M, Vianna RM, Cloutier F. Kinin receptors in pain and inflammation. Eur J Pharmacol 2001;429:161-76.

(4.) Dray A, Perkins M. Bradykinin and inflammatory pain. Trends Neurosci 1993;16:99-104.

(5.) Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1-80.

(6.) Burch RM, Kyle DJ. Recent developments in the understanding of bradykinin receptors. Life Sci 1992;50:829-38.

(7.) Marceau F, Hess JF, Bachvarov DR. The B1 receptors for kinins. Pharmacol Rev 1998;50:357-86.

(8.) Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005;57:27-77.

(9.) Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 2004;3:845-52.

(10.) Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res 2006;98:1123-33.

(11.) Veale D, Yanni G, Bresnihan B, FitzGerald O. Production of angiotensin converting enzyme by rheumatoid synovial membrane. Ann Rheum Dis 1992;51:476-80.

(12.) Worthy K, Figueroa CD, Dieppe PA, Bhoola KD. Kallikreins and kinins: mediators in inflammatory joint disease? Int J Exp Pathol 1990;71:587-601.

(13.) Kellermeyer RW, Graham RC Jr. Kinins--possible physiologic and pathologic roles in man. N Engl J Med 1968;279:859-66.

(14.) Selwyn BM, Figueroa CD, Fink E, Swan A, Dieppe PA, Bhoola KD. A tissue kallikrein in the synovial fluid of patients with rheumatoid arthritis. Ann Rheum Dis 1989;48:128-33.

(15.) Uhl J, Singh S, Brophy L, Faunce D, Sawutz DG. Role of bradykinin in inflammatory arthritis: identification and functional analysis of bradykinin receptors on human synovial fibroblasts. Immunopharmacology 1992;23:131-8.

(16.) Cassim B, Naidoo S, Ramsaroop R, Bhoola KD. Immunolocalization of bradykinin receptors on human synovial tissue. Immunopharmacology 1997;36:121-5.

(17.) Maas K, Chen H, Shyr Y, Olsen NJ, Aune T. Shared gene expression profiles in individuals with autoimmune disease and unaffected first-degree relatives of individuals with autoimmune disease. Hum Mol Genet 2005;14:1305-14.

(18.) Liu Z, Maas K, Aune TM. Identification of gene expression signatures in autoimmune disease without the influence of familial resemblance. Hum Mol Genet 2006;15:501-9.

(19.) Lequerre T, Gauthier-Jauneau AC, Bansard C, Derambure C, Hiron M, Vittecoq O, et al. Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis. Arthritis Res Ther 2006;8:105.

(20.) Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. N Engl J Med 2007;357:1199-209.

(21.) Uppal SS, Haider MZ, Hayat SJ, Abraham M, Sukumaran J, Dhaunsi GS. Significant association of insertion/deletion polymorphism of the angiotensinconverting enzyme gene with rheumatoid arthritis. J Rheumatol 2007;34:2395-9.

(22.) Dutra RC. Kinin receptors: Key regulators of autoimmunity. Autoimmun Rev 2017;16:192-207.

(23.) Ishimaru F, Dansako H, Nakase K, Fujii N, Sezaki N, Nakayama H, et al. Molecular characterization of total kininogen deficiency in Japanese patients. Int J Hematol 1999;69:126-8.

(24.) Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.

(25.) Braun A, Kammerer S, Maier E, Bohme E, Roscher AA. Polymorphisms in the gene for the human B2-bradykinin receptor. New tools in assessing a genetic risk for bradykinin-associated diseases. Immunopharmacology 1996;33:32-5.

(26.) Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 1997;99:134-46.

(27.) Bachvarov DR, Landry M, Pelletier I, Chevrette M, Betard C, Houde I, et al. Characterization of two polymorphic sites in the human kinin B1 receptor gene: altered frequency of an allele in patients with a history of end-stage renal failure. J Am Soc Nephrol 1998;9:598-604.

(28.) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

(29.) Cheung PP, Kunapuli SP, Scott CF, Wachtfogel YT, Colman RW. Genetic basis of total kininogen deficiency in Williams' trait. J Biol Chem 1993;268:23361-5.

(30.) Lee YC, Cheon KT, Lee HB, Kim W, Rhee YK, Kim DS. Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with asthma. Allergy 2000;55:959-63.

(31.) Mukae S, Itoh S, Aoki S, Iwata T, Nishio K, Sato R, et al. Association of polymorphisms of the reninangiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough. J Hum Hypertens 2002;16:857-63.

(32.) Mulatero P, Williams TA, Milan A, Paglieri C, Rabbia F, Fallo F, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab 2002;87:3337-43.

(33.) Knigge H, Bluthner M, Bruntgens A, Sator H, Ritz E. G(-699)/C polymorphism in the bradykinin-1 receptor gene in patients with renal failure. Nephrol Dial Transplant 2000;15:586-8.

(34.) Lerner UH. The role of the kallikrein-kinin system in inflammation-induced bone metabolism. In: Farmer SG, editor. The kinin system. New York: Academic Press; 1997. p. 219-34.

(35.) Lerner UH, Lundberg P. Kinins and neuro-osteogenic factors, In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. 2nd ed. San Diego: Academic Pres; 2002. p. 773-99.

(36.) Brechter AB, Persson E, Lundgren I, Lerner UH. Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases. Bone 2008;43:72-83.

(37.) Brechter AB, Lerner UH. Bradykinin potentiates cytokine-induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression. Arthritis Rheum 2007;56:910-23.

(38.) Weger W, Hofer A, Wolf P, El-Shabrawi Y, Renner W, Kerl H, et al. The angiotensin-converting enzyme insertion/deletion and the endothelin -134 3A/4A gene polymorphisms in patients with chronic plaque psoriasis. Exp Dermatol 2007;16:993-8.

(39.) Lerner UH, Jones IL, Gustafson GT. Bradykinin, a new potential mediator of inflammation-induced bone resorption. Studies of the effects on mouse calvarial bones and articular cartilage in vitro. Arthritis Rheum 1987;30:530-40.

(40.) Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 1990;33:768-73.

(41.) Silverstein E, Pertschuk LP, Friedland J. Immunofluorescent localization of angiotensin converting enzyme in epithelioid and giant cells of sarcoidosis granulomas. Proc Natl Acad Sci U S A 1979;76:6646-8.

(42.) Okabe T, Yamagata K, Fujisawa M, Watanabe J, Takaku F, Lanzillo JJ, et al. Increased angiotensin-converting enzyme in peripheral blood monocytes from patients with sarcoidosis. J Clin Invest 1985;75:911-4.

(43.) Sharma JN. Involvement of the kinin-forming system in the physiopathology of rheumatoid inflammation. Agents Actions Suppl 1992;38:343-61.

(44.) Isordia-Salas I, Pixley RA, Sainz IM, Martinez-Murillo C, Colman RW. The role of plasma high molecular weight kininogen in experimental intestinal and systemic inflammation. Arch Med Res 2004;35:369-77.

(45.) Hernandez CC, Donadi EA, Reis ML. Kallikreins and kininogens in saliva and plasma of patients presenting with rheumatoid arthritis. Scand J Rheumatol 2002;31:38-40.

(46.) Sawai K, Niwa S, Katori M. The significant reduction of high molecular weight-kininogen in synovial fluid of patients with active rheumatoid arthritis. Adv Exp Med Biol 1979;120:195-202.

(47.) Carluccio M, Soccio M, De Caterina R. Aspects of gene polymorphisms in cardiovascular disease: the renin-angiotensin system. Eur J Clin Invest 2001;31:476-88.

(48.) Alsaeid K, Haider MZ, Ayoub EM. Angiotensin converting enzyme gene insertion-deletion polymorphism is associated with juvenile rheumatoid arthritis. J Rheumatol 003;30:2705-9.

(49.) Uhm WS, Lee HS, Chung YH, Kim TH, Bae SC, Joo KB, et al. Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE. Lupus 2002;11:227-33.

(50.) Kaufman KM, Kelly J, Gray-McGuire C, Asundi N, Yu H, Reid J, et al. Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus. Mol Cell Endocrinol 2001;177:81-5.

(51.) Pullmann R Jr, Lukac J, Skerenova M, Rovensky J, Hybenova J, Melus V, et al. Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. Clin Exp Rheumatol 1999;17:593-6.

(52.) Benessiano J, Crestani B, Mestari F, Klouche W, Neukirch F, Hacein-Bey S, et al. High frequency of a deletion polymorphism of the angiotensin-converting enzyme gene in asthma. J Allergy Clin Immunol 1997;99:53-7.

(53.) Tomita H, Sato S, Matsuda R, Ogisu N, Mori T, Niimi T, et al. Genetic polymorphism of the angiotensin-converting enzyme (ACE) in asthmatic patients. Respir Med 1998;92:1305-10.

(54.) Kusser B, Braun A, Praun M, Illi S, von Mutius E, Roscher AA. Polymorphisms in the bradykinin B2 receptor gene and childhood asthma. Biol Chem 2001;382:885-9.

(55.) Bachvarov DR, Landry M, Houle S, Pare P, Marceau F. Altered frequency of a promoter polymorphic allele of the kinin B1 receptor gene in inflammatory bowel disease. Gastroenterology 1998;115:1045-8.

Anthoula CHATZIKYRIAKIDOU, [1] Paraskevi V. VOULGARI, [2] Alexandros A. DROSOS [2]

[1] Laboratory of Medical Biology--Genetics, Medical School, Aristotle University, Thessaloniki, Greece

[2] Department of Internal Medicine, Rheumatology Clinic, Medical School, University of Ioannina, Ioannina, Greece

Received: February 13, 2017 Accepted: June 07, 2017 Published online: September 13, 2017

Correspondence: Anthoula Chatzikyriakidou, MD. Laboratory of Medical Biology--Genetics, Medical School, Aristotle University, 54124 Thessaloniki, Greece. Tel: +302310999013 e-mail: chatzikyra@auth.gr
Table 1. Characteristics of patients with rheumatoid
arthritis (n=136)

                                  n    %     Mean [+ or -] SD

Age (year)                                  60.8 [+ or -] 12.7
Sex
  Female                         109   80
Mean disease duration (year)                11.9 [+ or -] 7.7
Rheumatoid factor positivity     98    72
C-reactive protein
  Low levels (0-6 mg/L)          36    26
  Moderate to high levels        100   74
  (>6 mg/L)
Disease activity score in 28
  joints
  Low disease activity (<3.2)    33    24
  Moderate to high disease       103   76
  activity ([greater than or
  equal to] 3.2)

SD: Standard deviation.

Table 2. Distribution of 287 bp I/D of angiotensin converting
enzyme, 9 bp I/D of bradykinin receptor 2, -58T>C of bradykinin
receptor 2, and -699G>C of bradykinin receptor 1 genotypes in
rheumatoid arthritis patients and controls

                                   287 bp I/D of ACE
                      II             DD          ID
                    n     %       n      %     n     %       p

RA (n=136)         31    22.8    37     27.2   68   50.0   0.312
Controls (n=149)   29    19.5    53     35.6   67   45.0

                    I     D
                    n     n       p

RA                 130   142    0.161
Controls           125   173

                                    9 bp I/D of BR2
                      II             DD          ID
                    n     %       n      %     n     %       p

RA (n=136)         45    33.1    23     16.9   68   50.0   0.234
Controls (n=149)   36    24.2    31     20.8   82   55.0

                                        Alleles

                    I     D
                    n     n       p

RA                 158   114    0.125
Controls           154   144

                                        -58T>C of BR2
                      TT             CC          TC
                    n     %       n      %     n     %       p

RA (n=136)         24    17.6    49     36.0   63   46.3   0.980
Controls (n=149)   27    18.1    52     34.9   70   47.0

                                        Alleles

                    T     C
                    n     n       P

RA                 111   161    0.846
Controls           124   174

                                   -699G>C of BR1
                      GG             CC          GC
                    n     %       n      %     n     %       p

RA (n=136)         123   90.4     0     0.0    13   9.6    0.494
Controls (n=149)   130   87.2     1     0.7    18   12.1

                                        Alleles

                    G     C
                    n     n       p

RA                 272    0      --
Controls           278    20

ACE: Angiotensin converting enzyme; BR: Bradykinin receptor;
RA: Rheumatoid arthritis; p value: Level of significant
difference between rheumatoid arthritis patients and controls.
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Title Annotation:ORIGINAL ARTICLE
Author:Chatzikyriakidou, Anthoula; Voulgari, Paraskevi V.; Drosos, Alexandros A.
Publication:Turkish Journal of Rheumatology
Article Type:Report
Date:Mar 1, 2018
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