Human Genome Project Using A Polymerase Chain Reaction - Essay Example

Human Genome Project Using PCR Inserts Insert Grade Insert 20th March, The Sex hormone-binding globulin gene (SHBG) is the gene responsible for the transport of male sex hormones that include estradiol and testosterone. The gene plays an important role in the steroid response control as it helps in the movement of sex steroids into the target tissues. The gene is found in the plasma of most species with its expression being in the liver and testis. The level of the SHGB, whether low or high, determines the quantity of the bioavailable testosterone. This makes the assessment of the gene levels among patients undergoing tests for Polycystic Ovarian Syndrome (PCOS) very important. The aims of this project entail; the selection of the gene, the access of all possible information and knowledge about the gene, its structure, location and functions. The projects looks at the relationship between the SHGB and PCOS and focuses on the molecular basis of disease and how the changes in the SHBG gene relate to the disease as well as to other health conditions such as cancer. Contents Abstract 2 Contents 2 Human Genome Project 4 INTRODUCTION 4 The official name of the SHBG gene 4 Normal Functions of the SHBG Gene 5 Location of the SHBG gene 5 Other names people use for the SHBG gene 6 Polycystic Ovary Syndrome (PCOS) 6 Health conditions related to the gene 7 The symptoms which show PCOS 8 Molecular Basis of Polycystic Ovary Syndrome (PCOS) 9 Processes used in genetic studies of PCOS 11 Risk factors of PCOS 12 Conclusion 13 References 13 Trang, L., Nestler, J., Strauss,J. & Wickham, E., 2011. Sex hormone-binding globulin and type 2 diabetes mellitus. Trends in Endocrinology & Metabolism, 23 (1), 32-41. 14 Zawadzki, J., Dunaif, A., 1992. Diagnostic Criteria for Polycystic Ovary Syndrome. Boston, USA: Blackwell Scientific. 14 Human Genome Project INTRODUCTION SHBG is the principal plasma transport protein for sex steroid hormones and it controls the bioavailability of these hormones to the target tissues. The gene encoding SHBG is compound and any of numerous polymorphisms in SHBG have been linked with changes in circulating SHBG levels. Studies of Epidemiological have shown that low plasma SHBG levels are an insulin resistance early indicator and they can predict the development of type diabetes mellitus 2 (T2DM) in both women and men (Chittenden & Maheshwari, 2009). The official name of the SHBG gene The sex hormone-binding globulin gene is also known as (ABP) androgen binding protein. Even though, associations linking low SHBG levels and the risk of diabetes might be explained by the theory that elevations in insulin levels suppress the production of hepatic SHBG (Cangemi et al, 2011), modern studies are documenting that the SHBG-altering polymorphisms transmission are connected with risk of T2DM imply that SHBG can have an additional direct physiologic task in glucose homeostasis. Nevertheless, the precise mechanisms underlying this connection are unknown. A non-diabetic woman with the (PCOS) polycystic ovary syndrome, a widespread endocrine disorder that is linked with insulin resistance, similarly demonstrates lower SHBG levels. In this report, we evaluate studies investigating the connection between SHBG polymorphisms and PCOS. Numerous studies in women with PCOS prove that certain genetic polymorphisms are connected with circulating SHBG levels, but they are not constantly connected with PCOS. (Chen et al. 2010) Normal Functions of the SHBG Gene The SHBG has a number of functions that include steroid binding, physiological functions and role in the male reproductive system. In the case of steroid binding, the greatest binding affinity for plasma SHBG is with the Dihydro testosterone (DHT). The second in affinity is testosterone, followed by estradiol. For the best possible binding to occur, there is need for an electro-negative group at C-3 found within a planar C-19 steroid as well as a 17β-OH group to be available. , and are required for optimal binding (Hammond and Bocchinfuso, 1995). The existing bond between SHGB and testosterone and between SHGB and Dihydro testosterone resembles that of the AR (androgen receptor). The gene, however, has no affinity for various antiestrogens like cyproterone and antiandrogens like tamoxifen. The presence of SHBG in the plasma of human beings has been described as that with a high androgen affinity and a low estradiol capacity. For this reason, the gene is said to play a great role in the control and metabolic clearance/ transportation of the two steroids. According to Burke and Anderson (2002), the higher affinity of SHBG to testosterone as compared to that of estradiol, makes it possible for the gene to increase the level of estrogen in women. SHGB has been found to play a role in the movement of sex steroids into the target tissues. This is evident with the affinity between estardiaol and SHBG and estardiol taking place on the cell membranes in the endometrium. SHGB’s specific receptors are also evident on a number of other tissues that rely on sex steroids. Such tissues include the prostate and the testis. Location of the SHBG gene SHGB has been found to be located in the plasma of many different species .The expression of the SHBG is mainly in the testis and the liver. The gene is also evident in other tissues beneficial to the reproductive system. When the gene is expressed in the liver, plasma sex hormone- binding globulin is produced. The plasma hormone helps in the in the control of the biological presence of the sex steroids found in the blood. In human beings the SHGB expression takes place in the testis. However, the characterization of the gene functions is less evident in this case. Other names people use for the SHBG gene The other names people use for the gene are androgen binding protein, testosterone-binding beta-globulin, sex steroid-binding protein, testosterone-estrogen-binding globulin, testis-specific androgen-binding protein and testosterone-estradiol-binding globulin. Polycystic Ovary Syndrome (PCOS) SHBG has still been viewed as an indicator for PCOS by some writers with a sensitivity of 88%a threshold of 36 nmol / l and a specificity of 87%, superior to the total or free test in epidemiological studies.An additional factor that influences SHBG is genetics. The four genetic variants of SHBG have just been recently discovered and they are single nucleotide polymorphism (SNP) (Legro, 2003). Even though SHBG SNPs variables associated with diabetes type 2 mellitus does not seem to be linked with the PCOS status, rs727428 and rs1799941 genotypes are connected with the SHBG levels free of the effect of obesity and insulin resistance (Chen et al. 2010). SHBG ties testosterone with high similarity and is concerned with the regulating the free testosterone’s, active fraction. This is owed to two major factors that slow down the hepatic production of the protein: One is Hyperinsulinemia with SHBG as a sign of insulin resistance The second one is Hyperandrogenism itself. These variants are linked with the changes in circulation levels of SHBG and can predict the possibility of developing diabetes type 2 for both women and men. A study on a family in the United States on two of these variants did not show any direct association with PCOS but showed a correlation with SHBG levels, free of androgens, BMI or insulin resistance. The PCOS diagnosis has been attentive to the combination of a biological criterion and clinical criteria. As estimated, PCOS have biological and clinical hyperandrogenism with androgen circulating levels considerably high than non-OPK. The levels of SHBG are in turn essentially lower in the group OPK but considerably only in the clinical population (Treng et al. 2011). SHBG is a great candidate gene for PCOS. This reproductive and metabolic disease now recognized as complex mutagenic disposition with environmental features. However, this shows that there is a weak connection and the polymorphism of SHBG most likely plays a small role in the pathogenesis of PCOS (Legro, 2003). Health conditions related to the gene Oligomenorrhoea (infrequent) or absent - these problems occur in around 7 in 10 women with polycystic ovary syndrome. These women may possibly have light or irregular periods, or basically no periods at all. Miscarriages which are at times recurrent: This is one of the hormonal abnormalities in PCOS. It is caused by an increased level of the LH- luteinizing hormone which is a hormone that is produced by the brain and it affects ovary function this hormone is associated with miscarriage. 65 per cent of Women with increased levels of LH have a high miscarriage rate compared to 12 per cent of those with normal LH values. Anovulation is referred to as a menstrual cycle where ovaries do not release an oocyte. Due to this reason, ovulation doesn’t take place. Chronic anovulation is a very common cause of infertility. Infertility - Some women with polycystic ovary syndrome do not ovulate at all. PCOS is one of the main common causes of infertility. Excess hair growth-More than half of the women with PCOS have this problem. It is mostly on the chest, lower abdomen and face. In some cases this is the only symptom. Acne may also persist beyond the usual teenage years. Scalp hair may start thinning this is the same as male pattern baldness and it occurs in a number of cases. Obesity and Overweight - around 4 among 10 women with PCOS turn out to be obese or overweight this is a common discovery in women with PCOS since their body cells resist the sugar-control hormone insulin. This resistance of insulin stops cells from using the sugar in the blood in a normal way and the sugar is stored as fat instead Poor self-esteem and depression may possibly develop due to the other symptoms. PCOS Symptoms normally begin in their late teens or in their early 20s. However, not all the symptoms occur in all women for instance, some of the women with PCOS exhibit excess hair growth, but have regular periods and fertility. Symptoms may differ from mild to severe. For instance, unwanted mild hair is normal, and it may be tricky to identify when it becomes abnormal in the women suffering from mild PCOS. On the other hand, women with severe PCOS can have distinct hair growth, infertility, and obesity. These Symptoms can also change over the years (Chittenden & Maheshwari, 2009) The symptoms which show PCOS There are various ways in which PCOS is shown. These symptoms are connected to a number of internal changes, several of which can be reasonably easier to understand in the light of the hormone abnormalities that are regularly found. They include: Increased LH hormone in the menstrual cycles early part Increased male hormones (androgens) normally found in small amounts in women lower amounts of the blood protein that carries all sex hormones (sex-hormone-binding globulin) A tiny raise in the amount of cellular and insulin resistance to its actions Increased levels of anti-Mullerian hormone, when compared to women with regular and normal cycles. The majority of women with PCOS will have ultrasound findings, while 66 per cent of women are found with menstrual cycle abnormalities and 40 per cent with obesity. 70 per cent of women with PCOS are found to have an increase in acne and hair, while 50 per cent of women with PCOS are found with the hormone abnormalities. Molecular Basis of Polycystic Ovary Syndrome (PCOS) PCOS is an endocrine disorder that is most common in women in their reproductive ages. The clustering of PCOS along familial lines has provided consistent reports that suggest that genetic factors play a role in the syndrome development despite the fact that the cases of PCOS do not display a clear patter of Mendelian inheritance (Handwerger & Aronow, 2008). Patients suffering from PCOS have various characteristics that are interrelated including chronic anovulation, insulin resistance, gonadotropin dynamics, and polycystic ovaries. Development of PCOS might require the interaction of both environmental factors and multiple inherited factors (Azziz et al, 2006). Patients with hyperandrogenism that is associated with PCOS would normally display low levels of serum SHBG; this contributes to increased availability of tissue and androgen. The human SHBG as mentioned earlier is composed of a homodimeric glycoprotein that is produced by hepatocytes, encoded by a 4-kb gene at the 17p12-p13. At the promoter of this gene is (TAAAA)n pentanucleotide repeat polymorphism which has been shown to have an influence on the transcription of the SHBG gene. There is a proposal that the polymorphism in functionality of this gene has probable contribution to individual diversities in the levels of plasma SHBG, therefore, influencing androgen access to the target tissues (Escobar-Morreale et al, 2005).There is reportedly, a significant association between the repeat polymorphism of the SHBG gene and PCOS (Handwerger & Aronow, 2008). The principal source of hyperandrogenism in PCOS is the ovary. Excessive androgens interfere with the process of selection of the primary ovarian follicle. The biosynthesis of androgen in the human ovary occurs in thecal interstitial cells, TIC; their activity in PCOS is excessive. The increased activity in the steroid production pathway of thecal cells results in ovarian hyperandrogenism. The increased activity is inherent to the thecal cell since it carries on after manifold passages of thecal cell cultures in vitro (Escobar-Morreale et al, 2005). Findings have indicated a positive correlation between the antimullerian factor, testosterone, and androstenedione in PCOS. These findings could have a linking with a paracrine action of antimullerian factor on the over-activity of theca cells demonstrated by antimullerian type II receptor in theca interstitial cells in maturing follicles (Azziz et al, 2006). Another common feature of PCOS is a general increase in the concentrations of plasma luteinising hormone; this consist both the increased pulse amplitude and pulse frequency. The elevated concentrations of serum LH that results supposedly leads to a promotion of ovarian theca interstitial cell steroidogenesis (Handwerger & Aronow, 2008). The proof of the genetic basis of PCOS is very wide but by no way adequate to understand the pathogenesis of the syndrome. Molecular flaws in gonadotrophins and the receptors, in enzymes caught up in steroid genesis, as well as those basic secretion pathways and insulin action, have been under constant and extreme investigation with inconsistent results. Even though this scientific race is rather stimulatory, it hasn’t been possible to this far decisively establish the role of any specific gene on PCOS pathogenesis (Legro, 2003). Moreover, because the list of candidate genes is gradually increasing, major tribulations arise, while the results are not consistent among the different studies. As a matter of fact, there is complicatedness even in replicating results by the same investigator. Adding up to the constantly growing spectrum of fresh candidate genes makes the focal point less clear. Recent data favors the observation that PCOS is likely to stand for a compound disorder caused by various genetic defects (Zawadzki & Dunaif 1992). Processes used in genetic studies of PCOS There are two mainstream methods that are used to identify PCOS’s genetic locus they are; association studies this is where a disposing allele is likely to be encountered more regularly in the effected population than the ordinary individuals and the second is linkage studies this is where the pro-bands and their families are studied to determine if certain genomic landmarks are distributed separately or together with the phenotype. While the means of inheritance is not necessary for the association studies, a reasonably large number of individuals are required for a clear conclusion. The linkage studies require the method of inheritance to be known for the investigation procedure. These studies are rather robust to recognize single genes causing Medellin disorders but are inadequately suited to the genetic architecture of intricate traits such as PCOS. The changeable expressivity and penetrance are two main features that are set hurdles for both association and linkage methods (Legro, 2003). The regularity of the genomic landmarks that is used in linkage studies describes the mapping and the resolution power of the study. The complete genome scan approach developing the single nucleotide polymorphism micro-array gene-chip technology conveys the highest declaration in genetic mapping. However, there is no PCOS study available with this technique. Moreover the Hap-Map project carries additional power to association studies by genotyping over a million SNPs and differentiating genetic disparity patterns in linkage disequilibrium. Discovery and understanding of the individual’s genes function holds the guarantee for the establishment of the precise molecular basis for PCOS. The acquirement of genetic information concerning PCOS will be most valuable for providing new insight to the patho-physiology of the syndrome and will ultimately have a great effect on the clinical supervision of the PCOS patients (Zawadzki & Dunaif 1992). Risk factors of PCOS The increase in PCOS predominance in populations where the gene pool has been moderately constant proves that environmental factors assume an even more significant role. The increase of obesity is associated with the development of PCOS in vulnerable individuals. The current living situation in developed countries is made up of low daily energy expenses and an abundance and economical food supply this makes encouraging energy balance common. Though, this view is way too one-dimensional it is possible that other aspects in the environment, maybe poorly understood for example exposure to toxins may also play a role. (Zawadzki & Dunaif 1992). Additionally, most of the affirmative findings acquired with PCOS phenotypes have not been simulated in more than one population. This outcome is not surprising taking into consideration those genes with such a huge impact on the phenotype is not anticipated to be accountable for PCOS. Nonetheless, it is essential to emphasize that moderately small model size of study populations is a key limitation for nearly all of the studies. Conclusion The SHBG circulating levels are independently linked with slight allele incidence for two of the SHBG SNPs variables, rs727428 and rs1799941, after calculating the possible impact of BMI, hyperandrogenemia, and also the resistance of insulin on SHBG. Such results highlight the influence of genetic variation on SHBG circulating levels among women with PCOS. However, additional studies are important to establish whether additional novel polymorphisms in SHBG contribute to the path physiology of PCOS (Zawadzki & Dunaif 1992). The Polycystic ovary syndrome (PCOS) is very common. It may cause reduced fertility, period problems, acne and excess hair growth. Lots of women with PCOS are also obese. Treatment can include weight loss, and changing one’s lifestyle in addition to treating all the individual symptoms. References Azziz, R., Nestler, J. & Dewailly, D., 2006 Androgen excess disorders in women: Polycystic ovary syndrome and other disorders. Totowa, N.J: Humana Press. Cangemi, R., Friedmann, A., Holloszy ,J. & Fontana, L., 2010. Long-term effects of calorie restriction on serum sex-hormone concentrations in men. Aging Cell , 9 (2), pp. 236–42. Chen, C. , Smothers ,J., Lange, A., Nestler , J., Strauss , J., Wickham, E., 2010. Sex hormone-binding globulin genetic variation: associations with type 2 diabetes mellitus and polycystic ovary syndrome.Minerva Endocrinol. , 35(4), pp. 271-80. Chittenden BG & Maheshwari A. 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