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Genetic background of urinary incontinence – state-of-the-art and perspectives

Genetic background of urinary incontinence – state-of-the-art and perspectives The paper presents an overview of the current studies attempting to determine the genetic background of urinary incontinence (UI) problems. The overview referred to the adaptations of biomedical literature from Medline, life science journals, and online books were searched from the earliest date possible to March 2015. Genetic variability studies (mostly with the use of single nucleotide polymorphism) in the context of UI are discussed. The authors indicate the variability of polymorphic forms of proteins, whose modified function may be related to the observed phenotypic symptoms: UI. The paper includes a discussion of the varied level of gene expression and the issue of defective process of the development of the urinary system in the context of UI disorders. The literature does not present any general, unequivocal description of the relationship between the genetic background and phenotype as UI. It is suggested that the methods of integration of data from various techniques (e.g. high throughputs) in reference to social, demographic, and other data may be the way of the approach used for the effective description of the relationship between genetic background and observed UI. Keywords: genetic association studies; genetic variation; urinary incontinence. loss of urine and is a common condition in middle-aged and elderly women and men. SUI is caused by the leakage of urine when coughing, sneezing, laughing, lifting, exercise, or even standing leads to increased intraabdominal pressure. The problem of UI is more often affecting women, aggravates with age, and is related to decrease in sexual hormones [2]. The escalation of symptoms is associated with natural delivery, a heavy birth weight, vaginal procedures, a high body mass index (BMI), and chronic diseases [3]. The problem of UI often arises in pregnant women. About 41% of pregnant women experience SUI [4]. The problem of UI is also present in the group of young women. It is stipulated that the source of the problem should be, in many cases, found in the genetic background [5]. The paper includes the overview of the literature related to UI on the effect of the genetic background on the recorded phenotypical symptoms in UI. Polymorphic versions of genes suspected of the relationship with UI, differences in the level of gene expression in the analyzed group (with UI) compared with the control group, and the possible underdevelopment of the urinary tract are discussed. The paper tackles also the issues of the effect of polymorphic genes encoding proteins metabolizing drugs on UI and the problem of UI as a complication in treating other disease entities. Materials and methods The up-to-date literature in the area of studies related to the problem of urinary incontinency has been reviewed (March 2015). The focus of the work is on the issues of the relationship of the genetic background with UI and SUI. To identify studies related to the genetic background of UI, the following terms were used for searching: "genetics background of urinary incontinence," "genetics association of urinary incontinence," and "polymorphism in urinary incontinence." Language of reviewed publications: English. The visualization of the protein association network was done with the STRING tool, which includes Introduction Urinary incontinence (UI) is a problem that affects almost 200 million people in the world [1]. UI is the involuntary *Corresponding author: Dr. Monika Piwowar, Bioinformatics and Telemedicine, Jagiellonian University Collegium Medicum, Kopernika 16, 31-501 Cracow, Poland, E-mail: mpiwowar@cm-uj.krakow.pl Klaudia Stangel-Wjcikiewicz: Department of Gynaecology and Oncology, Jagiellonian University Collegium Medicum, Cracow, Poland. http://orcid.org/0000-0001-9773-6767 198Stangel-Wjcikiewicz and Piwowar: Genetic background of UI the database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations; they are derived from four sources: genomic context, high-throughput experiments, (conserved) coexpression, and previous knowledge [6]. the single nucleotide polymorphism (SNP) type, present in the human population, research is very intensive on the assessment of the relationship of these variations [12] in reference to phenotypic (clinical) symptoms. Studying genetic variability has become one of the most important tools used to describe the relationship between the genetic background and the phenotypical symptoms [13]. It allows the differentiation and categorization of symptoms observed in patients even within one disease entity. A number of studies are focused on the analysis of polymorphisms present throughout the genome sequence [genome-wide association studies (GWAS)], which allows the detection of changes in all the genes that have an effect on the observed clinical symptoms [14, 15]. In the context of UI, no GWAS-type study has been conducted so far, whereas there are some papers on the assessment of the relationship of the selected polymorphic changes, mostly of the SNP type, present in specific genes and suspected of being the original cause of ailments related to UI in some women. The determination of the relationship between more frequent SUI after damages to connective tissue has become the basis for studies in the effect of polymorphic variations of collagen. The study conducted by the Lublin team assessed the relationship of the G/T polymorphism present in the place of the Sp1 link of the gene encoding the 1 chain of the type 1 collagen with SUI in females. The polymorphic change in the analyzed gene has been proven to be significantly related to the increased risk of SUI in females (odds ratio=4.98 for the GT genotype and 2.23 for the TT genotype) [16]. The team of the Athens University reached similar conclusions [17]. Another example of the study in association of polymorphisms in the context of SUI comes in the form of the research in T102C polymorphism in the 2A serotonin receptor gene (5-HT2A) in elderly persons. The result of this research indicates an important relationship of the analyzed polymorphism and UI. UI is suggested to have a genetic background related to the path of the serotonin neurotransmitter [18, 19]. There are also some reports in the medical literature that exclude the relationship between specific polymorphisms and UI. The polymorphic regions of the MMP-1 and MMP-2 gene encoding promoters were suspected to be related to SUI. However, it turned out that the type G/ GG polymorphism present in MMP-1 and 5A/6A present in MMP-3 are not related to the risk of the occurrence and development of SUI [20]. More sophisticated genetic testing includes association studies performed on unrelated affected individuals, and sib-pair linkage studies that are limited to related affected individual are carried out. It is the source of some Results UI in the sociodemographic context The research has been conducted for several years aimed at proving the relationship of the genetic background with the UI problem. Wennberg et al. described 25,364 pairs of twins among whom they showed SUI and nocturnal enuresis in females to be highly dependent on genetic factors. The authors describe also the environmental impact on the appearance of phenotypic symptoms related to UI. For SUI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Their research clearly showed that the number of persons with the UI problem varies with age and gender. The susceptibility to the symptoms is higher in the group of women and aggravates with age [5, 7]. Further studies stated a higher incidence of SUI in females with earlier episodes of incontinence compared with those who had not had such issues. Moreover, UI in the family history and symptoms appearing at a younger age in females with positive medical history suggest that heredity (apart from many other factors) may play a significant role in this problem [8]. The studies by Rohr et al. emphasize the significant role of genetic factors in the development of urgency and UI of the mixed type with lesser effect on the stress type [9]. Apart from studying hereditary predispositions to UI, attempts are undertaken, mostly based on questionnaires and interviews with patients, to explain the root cause of this problem. Further hypotheses are proposed. Some believe that UI may depend on disorders in the function of extracellular matrix (ECM). Disturbance in the ECM expression of proteins with change in their composition proved to be predisposing for the occurrence of UI. The studies in these relationships suggest an important effect of estrogens and progesterone on ECM proteins [10, 11]. UI in the genetic variability context At present, when many polymorphisms have become known (within the HapMap Project), particularly those of Stangel-Wjcikiewicz and Piwowar: Genetic background of UI199 of the most important genetic discoveries also in the UI context [21]. In another work, the authors suggest that the causes of UI should be found in the abnormal development of the lower urinary tract, which may result, among others, in UI [22]. The studies of the relationship of the illness with the genetic background with large groups of patients proved that, in families with the UI problem, coupling (linkage) of the inherited DNA fragments on the chromosome 9 is found [22]. It is also suggested that the genetic background, particularly the analysis of variability of single nucleotides, will allow to explain the effect of genetic factors on the observed phenotypical symptoms in the future. The explanation of the mechanism underlying the diseases related to UI was undertaken in a number of animal studies. One of the papers presented results of the tests on rats (with urine incontinence and continence). The analysis covered the level of expression of 22,000 genes (with the tissue material from urethra) in two groups of rats. The level of expression of 42 genes proved to be significantly different [23]. It was proven that the expression of genes involved in the transforming growth factor (TGF) cellular signaling pathway (Smad2), collagen breakdown [matrix metalloproteinase 13 (MMP13)], and smooth muscle inhibition [regulator of G protein signaling 2 (Rgs2)] was significantly increased in the incontinent group [23]. The authors of the paper [23] indicate the relation between the three main biochemical paths, whose level of gene expression was significantly different in the group of the rats with UI against the control group. One of them is the TGF signal path, which is responsible for, among others, the regeneration of tissues [24, 25], and the different level of activity of this protein may be a significant risk factor for the incidence of UI. Another indication is the ECM protein Mmp13. It is thought to play a critical role in cartilage destruction [26]. The dysfunction or modified activity of metalloproteinase is described in a number of papers on various disease entities [27], including in some neoplastic diseases [28]. Another was the Rgs2 Table 1:A list of genes that were tested for association with UI. Gene symbol SP1 HTR2A (5-HT2A) MMP9 Smad2 MMP13 Rgs2 Gene description Location protein. The regulators of G protein signaling fine-tune G protein-coupled receptor-induced signaling by regulating its magnitude and duration through a direct interaction with the subunits of heterotrimeric G proteins. The Rgs2 regulator is described in a number of papers as a factor responsible for the appearance of many disease entities [29, 30]. The studies of selected genes or even groups of genes (Table 1) do not give the full description of the relationship of the genetic background with the observed phenotypic symptoms. It is the indication and suggestion in which direction answers may be looked for to the question about the source of the problem of UI not dependent on the aging process. An assessment of the effect of proteins encoded by genes identified as differentiating or those that are specific polymorphic variants (Table 1) allow some approximation or indication of the direction to be followed in the explanation of the causes of the UI phenotype in persons when the source of the problem is not related to environmental impact (Figure 1). UI in the context of genetic variability of enzymes that metabolize drugs Various drugs are nowadays used in treating UI [31, 32]. However, the issue of genetic variability of the genes coding proteins participating in their metabolism is not taken into account. An important factor in the assessment of the effectiveness of treatment is the assessment of polymorphic variants of proteins that interact with medicinal substances administered to the patients. Here, first of all, the forms of the enzymes participating in the metabolism of drugs are important, as well as transporting proteins and drug receptors. At present, a number of drugs used clinically in reference to UI (e.g. trospium chloride, tolterodine tartrate, solifenacin succinate, or Ditropan, Mictonorm) may be related to a weaker or ineffective impact (Table 2). Genetic methods SNP analysis Publication references [16, 17] [18, 19] [20] [22] [23] Association with UI + + ­ + + + + Transcription factor 5-Hydroxytryptamine (serotonin) receptor 2A Matrix metallopeptidase 9 SMAD family member 2 Matrix metalloproteinase 13 Regulator of G protein signaling 2 Chromosome 12, NC_000012.12 Chromosome 13, NC_000013.11 Chromosome 20, NC_000020.11 Chromosome 9 Chromosome 18, NC_000018.10 Chromosome 11, NC_000011.10 Chromosome 1, NC_000001.11 SNP analysis Linkage analysis Gene expression analysis 200Stangel-Wjcikiewicz and Piwowar: Genetic background of UI A B Figure 1:Interaction networks: A) MMP13, B) SP1, C) SMAD2, D) Rgs2. Scheme prepared based on the STRING database [6]. Table 2:List of chemical substances uses as a drug in UI KEGG: http://www.genome.jp/kegg/drug/. Substance name KEGG drug ID References D01269 D01103 D01148 D05996 D01007 D00722 D04057 [33] [34] [35] ­ [36] [37] ­ Solifenacin succinate Trospium chloride Tolterodine tartrate Talnetant hydrochloride Propiverine hydrochloride Oxybutynin chloride Esoxybutynin chloride Drugs are metabolized by enzymes that may occur in a broad range of polymorphic versions in the human population. Some alleles feature a lack of physiological activity, others have reduced effectiveness of activity. In each such case, the degree of metabolization of the drug taken by the patient is of importance [38]. In some cases, it may be related to a number of unwanted side effects; in others, it is the reason to change the dose of the drug [39]. In the case of the drugs used clinically in the UI problem, mostly those that require the proper functioning of the enzymes in the first and second stages of Stangel-Wjcikiewicz and Piwowar: Genetic background of UI201 metabolism are used. The enzyme of the first stage of metabolism, cytochrome P450, features a high degree of polymorphism [40, 41]. The drugs metabolized with cytochrome P450 include tolterodine tartrate (alternative names: Detrol, Detrusitol), metabolized by the CYP2D6 protein (cytochrome P450, family 2, subfamily D, polypeptide 6; EC:1.14.14.1) and CYP3A4 (EC:1.14.13.67, 1.14.13.97, 1.14.13.32, 1.14.13.157). The CYP2D6 gene occurs in 365 allelic variations, of which 176 SNPs are present in the coding region (the data of March 2015). From among 176 polymorphisms, the changes of amino acids in the protein are caused by the changes in amino acids in 112 positions. This means that each of the 112 polymorphic versions of the protein affects, to a larger or slammer degree, the structure of the CYP2D6 protein and thus its biochemical function in the cell. In the case of the CYP3A4 gene sequence, 1153 polymorphisms have been identified in the human population. There are 124 variabilities in the coding regions, thus directly affecting the structure and function of protein. Ninety-eight polymorphisms of this cause the changes of amino acids in the protein. The rest are synonymic variabilities, that is, mutations that cause the changes of nucleotides in the gene sequence but do not cause the changes in amino acids on the protein level. If the fact is taken into account that CYP2D6 and CYP3A4 interact with other proteins (Figure 2), then the presence of the proper genotype is the condition to achieve the objective of the correct treatment of patients with UI. Complications after therapies not related to UI but causing UI There are at least several disease entities in which UI is a complication after the treatment. It is directly related to using pharmacological substances. For example, clozapine, the drug used in psychiatry as an antipsychotic drug, interacts with many neurotransmitter receptors on the molecular level. One of the side effects of this chemical is UI, which is suspected to originate from the variability of the 1a adrenoceptor [42]. The authors report in another paper a complication in treating Alzheimer's disease (cholinesterase inhibitors) in the form of UI [43]. Figure 2:CYP2D6 and CYP3A4 ­ Human network of protein interactions. Scheme prepared based on the STRING database [6]. Discussion and conclusions UI may originate from various causes. Apart from typical environmental impact, genetic factors are also significant [5, 9]. The authors of the studies discussed in the publication indicate that the causes of UI, apart from environmental effects, should be found in abnormalities occurring at the development stage of the urinary tract but also in the specific genotype that predisposes for UI incidence. The changed level of expression of some genes in persons with UI compared with control groups is also reported. The literature offers some information proving that the treatment of disease entities other than UI may cause complications resulting in, among others, UI. Considering the fact that pharmacological treatment may be related to varied responses, due to the polymorphism of the proteins participating in metabolism, the genetic component is becoming important in this illness. 202Stangel-Wjcikiewicz and Piwowar: Genetic background of UI The current research in the relationship of the genetic background with the observed phenotypic symptoms presents a fragmentary description of the genotype-phenotype relation despite some broad studies on the association of genes with UI symptoms. To describe in more detail the association of genotype with phenotype, the integration of social, demographical, biochemical, and genetic data may be a good source of information [44, 45]. Taking into consideration a large-scale representation of the determined features may disclose the relationship between the genetic make-up and the observed symptoms. With this, biomarkers that signal the pathological type of the patient may be determined in the future. It may be the case that factors that classify patients in terms of the degree of progress of the UI problem are then determined. The accurate diagnosis of the causes of UI in patients, especially at a younger age, is highly important in the context of the implemented modern therapies of UI in the form, for example, of implantation of parent cells in the urethral sphincter [46­48]. The knowledge of the "condition" of the muscle tissue may be the key to achieve the required therapeutic effect in this approach. It may also be important in the assessment of chances for success in the rehabilitation of patients with UI after various UI therapies [49]. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. 5. Wennberg A-L, Altman D, Lundholm C, Klint A, Iliadou A, Peeker R, et al. Genetic influences are important for most but not all lower urinary tract symptoms: a population-based survey in a cohort of adult Swedish twins. Eur Urol 2011;59:1032­8. 6. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013;41:D808­15. 7. Altman D, Forsman M, Falconer C, Lichtenstein P. Genetic influence on stress urinary incontinence and pelvic organ prolapse. Eur Urol 2008;54:918­23. 8. Ertunc D, Tok EC, Pata O, Dilek U, Ozdemir G, Dilek S. Is stress urinary incontinence a familial condition? Acta Obstet Gynecol Scand 2004;83:912­6. 9. Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand 2004;83:978­82. 10. McKenzie P, Rohozinski J, Badlani G. Genetic influences on stress urinary incontinence. Curr Opin Urol 2010;20:291­5. 11. Stothers L, Friedman B. Risk factors for the development of stress urinary incontinence in women. Curr Urol Rep 2011;12:363­9. 12. Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, et al. Integrating common and rare genetic variation in diverse human populations. Nature 2010;467:52­8. 13. Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, et al. Clinical experience and follow-up with large scale singlenucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1­17. 14. Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, et al. Genome-wide detection and characterization of positive selection in human populations. Nature 2007;449:913­8. 15. Piwowar M. Elementy Informatyki Medycznej, Genomika. I. Jagiellonian University Press, 2012. 16. Skorupski P, Król J, Starega J, Adamiak A, Jankiewicz K, Rechberger T. An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence. Am J Obstet Gynecol 2006;194:346­50. 17. Sioutis D, Economou E, Lambrinoudaki I, Tsamadias V, Creatsa M, Liapis A. Sp1 collagen I A1 polymorphism in women with stress urinary incontinence. Int Urogynecol J 2011;22:835­9. 18. Noronha JA, Schwanke CH, Machado DC, Braga R, Lubianca JM, Sesti FL, et al. Association between T102C polymorphism of serotonin 2A receptor gene and urinary incontinence in older women. J Invest Med 2010;58:32­7. 19. Schwanke CH, Bittencourt L, Noronha JA, Augustin SA, Jung IE, Cruz IB. Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence? Braz J Med Biol Res 2007;40:1315­22. 20. Skorupski P, Miotla P, Jankiewicz K, Rechberger T. MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence. Ginekol Pol 2010;81:594­9. 21. Allen-Brady K, Norton PA, Farnham JM, Teerlink C, CannonAlbright LA. Significant linkage evidence for a predisposition gene for pelvic floor disorders on chromosome 9q21. Am J Hum Genet 2009;84:678­82. 22. Norton P, Milsom I. Genetics and the lower urinary tract. Neurourol Urodyn 2010;29:609­11. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bio-Algorithms and Med-Systems de Gruyter

Genetic background of urinary incontinence – state-of-the-art and perspectives

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Abstract

The paper presents an overview of the current studies attempting to determine the genetic background of urinary incontinence (UI) problems. The overview referred to the adaptations of biomedical literature from Medline, life science journals, and online books were searched from the earliest date possible to March 2015. Genetic variability studies (mostly with the use of single nucleotide polymorphism) in the context of UI are discussed. The authors indicate the variability of polymorphic forms of proteins, whose modified function may be related to the observed phenotypic symptoms: UI. The paper includes a discussion of the varied level of gene expression and the issue of defective process of the development of the urinary system in the context of UI disorders. The literature does not present any general, unequivocal description of the relationship between the genetic background and phenotype as UI. It is suggested that the methods of integration of data from various techniques (e.g. high throughputs) in reference to social, demographic, and other data may be the way of the approach used for the effective description of the relationship between genetic background and observed UI. Keywords: genetic association studies; genetic variation; urinary incontinence. loss of urine and is a common condition in middle-aged and elderly women and men. SUI is caused by the leakage of urine when coughing, sneezing, laughing, lifting, exercise, or even standing leads to increased intraabdominal pressure. The problem of UI is more often affecting women, aggravates with age, and is related to decrease in sexual hormones [2]. The escalation of symptoms is associated with natural delivery, a heavy birth weight, vaginal procedures, a high body mass index (BMI), and chronic diseases [3]. The problem of UI often arises in pregnant women. About 41% of pregnant women experience SUI [4]. The problem of UI is also present in the group of young women. It is stipulated that the source of the problem should be, in many cases, found in the genetic background [5]. The paper includes the overview of the literature related to UI on the effect of the genetic background on the recorded phenotypical symptoms in UI. Polymorphic versions of genes suspected of the relationship with UI, differences in the level of gene expression in the analyzed group (with UI) compared with the control group, and the possible underdevelopment of the urinary tract are discussed. The paper tackles also the issues of the effect of polymorphic genes encoding proteins metabolizing drugs on UI and the problem of UI as a complication in treating other disease entities. Materials and methods The up-to-date literature in the area of studies related to the problem of urinary incontinency has been reviewed (March 2015). The focus of the work is on the issues of the relationship of the genetic background with UI and SUI. To identify studies related to the genetic background of UI, the following terms were used for searching: "genetics background of urinary incontinence," "genetics association of urinary incontinence," and "polymorphism in urinary incontinence." Language of reviewed publications: English. The visualization of the protein association network was done with the STRING tool, which includes Introduction Urinary incontinence (UI) is a problem that affects almost 200 million people in the world [1]. UI is the involuntary *Corresponding author: Dr. Monika Piwowar, Bioinformatics and Telemedicine, Jagiellonian University Collegium Medicum, Kopernika 16, 31-501 Cracow, Poland, E-mail: mpiwowar@cm-uj.krakow.pl Klaudia Stangel-Wjcikiewicz: Department of Gynaecology and Oncology, Jagiellonian University Collegium Medicum, Cracow, Poland. http://orcid.org/0000-0001-9773-6767 198Stangel-Wjcikiewicz and Piwowar: Genetic background of UI the database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations; they are derived from four sources: genomic context, high-throughput experiments, (conserved) coexpression, and previous knowledge [6]. the single nucleotide polymorphism (SNP) type, present in the human population, research is very intensive on the assessment of the relationship of these variations [12] in reference to phenotypic (clinical) symptoms. Studying genetic variability has become one of the most important tools used to describe the relationship between the genetic background and the phenotypical symptoms [13]. It allows the differentiation and categorization of symptoms observed in patients even within one disease entity. A number of studies are focused on the analysis of polymorphisms present throughout the genome sequence [genome-wide association studies (GWAS)], which allows the detection of changes in all the genes that have an effect on the observed clinical symptoms [14, 15]. In the context of UI, no GWAS-type study has been conducted so far, whereas there are some papers on the assessment of the relationship of the selected polymorphic changes, mostly of the SNP type, present in specific genes and suspected of being the original cause of ailments related to UI in some women. The determination of the relationship between more frequent SUI after damages to connective tissue has become the basis for studies in the effect of polymorphic variations of collagen. The study conducted by the Lublin team assessed the relationship of the G/T polymorphism present in the place of the Sp1 link of the gene encoding the 1 chain of the type 1 collagen with SUI in females. The polymorphic change in the analyzed gene has been proven to be significantly related to the increased risk of SUI in females (odds ratio=4.98 for the GT genotype and 2.23 for the TT genotype) [16]. The team of the Athens University reached similar conclusions [17]. Another example of the study in association of polymorphisms in the context of SUI comes in the form of the research in T102C polymorphism in the 2A serotonin receptor gene (5-HT2A) in elderly persons. The result of this research indicates an important relationship of the analyzed polymorphism and UI. UI is suggested to have a genetic background related to the path of the serotonin neurotransmitter [18, 19]. There are also some reports in the medical literature that exclude the relationship between specific polymorphisms and UI. The polymorphic regions of the MMP-1 and MMP-2 gene encoding promoters were suspected to be related to SUI. However, it turned out that the type G/ GG polymorphism present in MMP-1 and 5A/6A present in MMP-3 are not related to the risk of the occurrence and development of SUI [20]. More sophisticated genetic testing includes association studies performed on unrelated affected individuals, and sib-pair linkage studies that are limited to related affected individual are carried out. It is the source of some Results UI in the sociodemographic context The research has been conducted for several years aimed at proving the relationship of the genetic background with the UI problem. Wennberg et al. described 25,364 pairs of twins among whom they showed SUI and nocturnal enuresis in females to be highly dependent on genetic factors. The authors describe also the environmental impact on the appearance of phenotypic symptoms related to UI. For SUI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Their research clearly showed that the number of persons with the UI problem varies with age and gender. The susceptibility to the symptoms is higher in the group of women and aggravates with age [5, 7]. Further studies stated a higher incidence of SUI in females with earlier episodes of incontinence compared with those who had not had such issues. Moreover, UI in the family history and symptoms appearing at a younger age in females with positive medical history suggest that heredity (apart from many other factors) may play a significant role in this problem [8]. The studies by Rohr et al. emphasize the significant role of genetic factors in the development of urgency and UI of the mixed type with lesser effect on the stress type [9]. Apart from studying hereditary predispositions to UI, attempts are undertaken, mostly based on questionnaires and interviews with patients, to explain the root cause of this problem. Further hypotheses are proposed. Some believe that UI may depend on disorders in the function of extracellular matrix (ECM). Disturbance in the ECM expression of proteins with change in their composition proved to be predisposing for the occurrence of UI. The studies in these relationships suggest an important effect of estrogens and progesterone on ECM proteins [10, 11]. UI in the genetic variability context At present, when many polymorphisms have become known (within the HapMap Project), particularly those of Stangel-Wjcikiewicz and Piwowar: Genetic background of UI199 of the most important genetic discoveries also in the UI context [21]. In another work, the authors suggest that the causes of UI should be found in the abnormal development of the lower urinary tract, which may result, among others, in UI [22]. The studies of the relationship of the illness with the genetic background with large groups of patients proved that, in families with the UI problem, coupling (linkage) of the inherited DNA fragments on the chromosome 9 is found [22]. It is also suggested that the genetic background, particularly the analysis of variability of single nucleotides, will allow to explain the effect of genetic factors on the observed phenotypical symptoms in the future. The explanation of the mechanism underlying the diseases related to UI was undertaken in a number of animal studies. One of the papers presented results of the tests on rats (with urine incontinence and continence). The analysis covered the level of expression of 22,000 genes (with the tissue material from urethra) in two groups of rats. The level of expression of 42 genes proved to be significantly different [23]. It was proven that the expression of genes involved in the transforming growth factor (TGF) cellular signaling pathway (Smad2), collagen breakdown [matrix metalloproteinase 13 (MMP13)], and smooth muscle inhibition [regulator of G protein signaling 2 (Rgs2)] was significantly increased in the incontinent group [23]. The authors of the paper [23] indicate the relation between the three main biochemical paths, whose level of gene expression was significantly different in the group of the rats with UI against the control group. One of them is the TGF signal path, which is responsible for, among others, the regeneration of tissues [24, 25], and the different level of activity of this protein may be a significant risk factor for the incidence of UI. Another indication is the ECM protein Mmp13. It is thought to play a critical role in cartilage destruction [26]. The dysfunction or modified activity of metalloproteinase is described in a number of papers on various disease entities [27], including in some neoplastic diseases [28]. Another was the Rgs2 Table 1:A list of genes that were tested for association with UI. Gene symbol SP1 HTR2A (5-HT2A) MMP9 Smad2 MMP13 Rgs2 Gene description Location protein. The regulators of G protein signaling fine-tune G protein-coupled receptor-induced signaling by regulating its magnitude and duration through a direct interaction with the subunits of heterotrimeric G proteins. The Rgs2 regulator is described in a number of papers as a factor responsible for the appearance of many disease entities [29, 30]. The studies of selected genes or even groups of genes (Table 1) do not give the full description of the relationship of the genetic background with the observed phenotypic symptoms. It is the indication and suggestion in which direction answers may be looked for to the question about the source of the problem of UI not dependent on the aging process. An assessment of the effect of proteins encoded by genes identified as differentiating or those that are specific polymorphic variants (Table 1) allow some approximation or indication of the direction to be followed in the explanation of the causes of the UI phenotype in persons when the source of the problem is not related to environmental impact (Figure 1). UI in the context of genetic variability of enzymes that metabolize drugs Various drugs are nowadays used in treating UI [31, 32]. However, the issue of genetic variability of the genes coding proteins participating in their metabolism is not taken into account. An important factor in the assessment of the effectiveness of treatment is the assessment of polymorphic variants of proteins that interact with medicinal substances administered to the patients. Here, first of all, the forms of the enzymes participating in the metabolism of drugs are important, as well as transporting proteins and drug receptors. At present, a number of drugs used clinically in reference to UI (e.g. trospium chloride, tolterodine tartrate, solifenacin succinate, or Ditropan, Mictonorm) may be related to a weaker or ineffective impact (Table 2). Genetic methods SNP analysis Publication references [16, 17] [18, 19] [20] [22] [23] Association with UI + + ­ + + + + Transcription factor 5-Hydroxytryptamine (serotonin) receptor 2A Matrix metallopeptidase 9 SMAD family member 2 Matrix metalloproteinase 13 Regulator of G protein signaling 2 Chromosome 12, NC_000012.12 Chromosome 13, NC_000013.11 Chromosome 20, NC_000020.11 Chromosome 9 Chromosome 18, NC_000018.10 Chromosome 11, NC_000011.10 Chromosome 1, NC_000001.11 SNP analysis Linkage analysis Gene expression analysis 200Stangel-Wjcikiewicz and Piwowar: Genetic background of UI A B Figure 1:Interaction networks: A) MMP13, B) SP1, C) SMAD2, D) Rgs2. Scheme prepared based on the STRING database [6]. Table 2:List of chemical substances uses as a drug in UI KEGG: http://www.genome.jp/kegg/drug/. Substance name KEGG drug ID References D01269 D01103 D01148 D05996 D01007 D00722 D04057 [33] [34] [35] ­ [36] [37] ­ Solifenacin succinate Trospium chloride Tolterodine tartrate Talnetant hydrochloride Propiverine hydrochloride Oxybutynin chloride Esoxybutynin chloride Drugs are metabolized by enzymes that may occur in a broad range of polymorphic versions in the human population. Some alleles feature a lack of physiological activity, others have reduced effectiveness of activity. In each such case, the degree of metabolization of the drug taken by the patient is of importance [38]. In some cases, it may be related to a number of unwanted side effects; in others, it is the reason to change the dose of the drug [39]. In the case of the drugs used clinically in the UI problem, mostly those that require the proper functioning of the enzymes in the first and second stages of Stangel-Wjcikiewicz and Piwowar: Genetic background of UI201 metabolism are used. The enzyme of the first stage of metabolism, cytochrome P450, features a high degree of polymorphism [40, 41]. The drugs metabolized with cytochrome P450 include tolterodine tartrate (alternative names: Detrol, Detrusitol), metabolized by the CYP2D6 protein (cytochrome P450, family 2, subfamily D, polypeptide 6; EC:1.14.14.1) and CYP3A4 (EC:1.14.13.67, 1.14.13.97, 1.14.13.32, 1.14.13.157). The CYP2D6 gene occurs in 365 allelic variations, of which 176 SNPs are present in the coding region (the data of March 2015). From among 176 polymorphisms, the changes of amino acids in the protein are caused by the changes in amino acids in 112 positions. This means that each of the 112 polymorphic versions of the protein affects, to a larger or slammer degree, the structure of the CYP2D6 protein and thus its biochemical function in the cell. In the case of the CYP3A4 gene sequence, 1153 polymorphisms have been identified in the human population. There are 124 variabilities in the coding regions, thus directly affecting the structure and function of protein. Ninety-eight polymorphisms of this cause the changes of amino acids in the protein. The rest are synonymic variabilities, that is, mutations that cause the changes of nucleotides in the gene sequence but do not cause the changes in amino acids on the protein level. If the fact is taken into account that CYP2D6 and CYP3A4 interact with other proteins (Figure 2), then the presence of the proper genotype is the condition to achieve the objective of the correct treatment of patients with UI. Complications after therapies not related to UI but causing UI There are at least several disease entities in which UI is a complication after the treatment. It is directly related to using pharmacological substances. For example, clozapine, the drug used in psychiatry as an antipsychotic drug, interacts with many neurotransmitter receptors on the molecular level. One of the side effects of this chemical is UI, which is suspected to originate from the variability of the 1a adrenoceptor [42]. The authors report in another paper a complication in treating Alzheimer's disease (cholinesterase inhibitors) in the form of UI [43]. Figure 2:CYP2D6 and CYP3A4 ­ Human network of protein interactions. Scheme prepared based on the STRING database [6]. Discussion and conclusions UI may originate from various causes. Apart from typical environmental impact, genetic factors are also significant [5, 9]. The authors of the studies discussed in the publication indicate that the causes of UI, apart from environmental effects, should be found in abnormalities occurring at the development stage of the urinary tract but also in the specific genotype that predisposes for UI incidence. The changed level of expression of some genes in persons with UI compared with control groups is also reported. The literature offers some information proving that the treatment of disease entities other than UI may cause complications resulting in, among others, UI. Considering the fact that pharmacological treatment may be related to varied responses, due to the polymorphism of the proteins participating in metabolism, the genetic component is becoming important in this illness. 202Stangel-Wjcikiewicz and Piwowar: Genetic background of UI The current research in the relationship of the genetic background with the observed phenotypic symptoms presents a fragmentary description of the genotype-phenotype relation despite some broad studies on the association of genes with UI symptoms. To describe in more detail the association of genotype with phenotype, the integration of social, demographical, biochemical, and genetic data may be a good source of information [44, 45]. Taking into consideration a large-scale representation of the determined features may disclose the relationship between the genetic make-up and the observed symptoms. With this, biomarkers that signal the pathological type of the patient may be determined in the future. It may be the case that factors that classify patients in terms of the degree of progress of the UI problem are then determined. The accurate diagnosis of the causes of UI in patients, especially at a younger age, is highly important in the context of the implemented modern therapies of UI in the form, for example, of implantation of parent cells in the urethral sphincter [46­48]. The knowledge of the "condition" of the muscle tissue may be the key to achieve the required therapeutic effect in this approach. It may also be important in the assessment of chances for success in the rehabilitation of patients with UI after various UI therapies [49]. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. 5. Wennberg A-L, Altman D, Lundholm C, Klint A, Iliadou A, Peeker R, et al. Genetic influences are important for most but not all lower urinary tract symptoms: a population-based survey in a cohort of adult Swedish twins. Eur Urol 2011;59:1032­8. 6. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013;41:D808­15. 7. Altman D, Forsman M, Falconer C, Lichtenstein P. Genetic influence on stress urinary incontinence and pelvic organ prolapse. Eur Urol 2008;54:918­23. 8. Ertunc D, Tok EC, Pata O, Dilek U, Ozdemir G, Dilek S. Is stress urinary incontinence a familial condition? Acta Obstet Gynecol Scand 2004;83:912­6. 9. Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand 2004;83:978­82. 10. McKenzie P, Rohozinski J, Badlani G. Genetic influences on stress urinary incontinence. Curr Opin Urol 2010;20:291­5. 11. Stothers L, Friedman B. Risk factors for the development of stress urinary incontinence in women. Curr Urol Rep 2011;12:363­9. 12. Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, et al. Integrating common and rare genetic variation in diverse human populations. Nature 2010;467:52­8. 13. Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, et al. Clinical experience and follow-up with large scale singlenucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1­17. 14. Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, et al. Genome-wide detection and characterization of positive selection in human populations. Nature 2007;449:913­8. 15. Piwowar M. Elementy Informatyki Medycznej, Genomika. I. Jagiellonian University Press, 2012. 16. Skorupski P, Król J, Starega J, Adamiak A, Jankiewicz K, Rechberger T. An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence. Am J Obstet Gynecol 2006;194:346­50. 17. Sioutis D, Economou E, Lambrinoudaki I, Tsamadias V, Creatsa M, Liapis A. Sp1 collagen I A1 polymorphism in women with stress urinary incontinence. Int Urogynecol J 2011;22:835­9. 18. Noronha JA, Schwanke CH, Machado DC, Braga R, Lubianca JM, Sesti FL, et al. Association between T102C polymorphism of serotonin 2A receptor gene and urinary incontinence in older women. J Invest Med 2010;58:32­7. 19. Schwanke CH, Bittencourt L, Noronha JA, Augustin SA, Jung IE, Cruz IB. Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence? Braz J Med Biol Res 2007;40:1315­22. 20. Skorupski P, Miotla P, Jankiewicz K, Rechberger T. MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence. Ginekol Pol 2010;81:594­9. 21. Allen-Brady K, Norton PA, Farnham JM, Teerlink C, CannonAlbright LA. Significant linkage evidence for a predisposition gene for pelvic floor disorders on chromosome 9q21. Am J Hum Genet 2009;84:678­82. 22. Norton P, Milsom I. Genetics and the lower urinary tract. Neurourol Urodyn 2010;29:609­11.

Journal

Bio-Algorithms and Med-Systemsde Gruyter

Published: Dec 1, 2015

References