Genetic Polymorphisms

This book provides a glimpse into the dynamic process of genetic polymorphism by presenting studies carried out on different kinds of organisms at the DNA level or gene expression level. Chapters address such topics as genetic polymorphism in animals, gametocyte biomarkers, thrombotic disorders, prostate cancer, and more

Genetics and the general physician: insights, applications and future challenges

Scientific and technological advances in our understanding of the nature and consequences of human genetic variation are now allowing genetic determinants of susceptibility to common multifactorial diseases to be defined, as well as our individual response to therapy. I review how genome-wide association studies are robustly identifying new disease susceptibility loci, providing insights into disease pathogenesis and potential targets for drug therapy. Some of the remarkable advances being made using current genetic approaches in Crohn's disease, coronary artery disease and atrial fibrillation are described, together with examples from malaria, HIV/AIDS, asthma, prostate cancer and venous thrombosis which illustrate important principles underpinning this field of research. The limitations of current approaches are also noted, highlighting how much of the genetic risk remains unexplained and resolving specific functional variants difficult. There is a need to more clearly understand the significance of rare variants and structural genomic variation in common disease, as well as epigenetic mechanisms. Specific examples from pharmacogenomics are described including warfarin dosage and prediction of abacavir hypersensitivity that illustrate how in some cases such knowledge is already impacting on clinical practice, while in others prospective evaluation of clinical utility and cost-effectiveness is required to define opportunities for personalized medicine. There is also a need for a broader debate about the ethical implications of current advances in genetics for medicine and society

Familial thrombophilia : Resistance to activated protein C and protein S deficiency

Inherited resistance to activated protein C (APC-resistance) and protein S deficiency are associated with functional impairment of the protein C anticoagulant system, resulting in lifelong hypercoagulability andincreased risk of thrombosis. APC-resistance is the most common genetic cause of thrombosis being present in 20% to 60% of thrombosis patients.A linkage study was performed in a large thrombophilic family with independent inheritance of APCresistance and protein S deficiency. APC-resistance was found to co-segregate with two neutral polymorphisms in the factor V gene. A point mutation changing Arg506 to a Gln in the factor V gene was the cause of APC-resistance in the family. The mutation (FV:Q506) is localised in one of the APC-cleavage sites of factor V, rendering mutated factor Va resistant to cleavage by activated protein C (APC). The factor V mutation was analysed in 308 members from 50 thrombosis-prone families with inherited APC-resistance.In 94% (47/50) of APC-resistant families the same factor V gene mutation was identified. The magnitude of thrombotic risk was dependent on the factor V genotype. We investigated 327 individuals in 18 thrombosis-prone families with inherited deficiency of free protein S. Deficiency of free protein S was caused by equimolar relationship between total protein S and B-chain containing isoforms of C4BP. Moreover, type I deficiency (low free and total protein S) and type IIIdeficiency (low free but normal total protein S) coexisted in 14 out of 18 families, demonstrating the twotypes to be phenotypic variants of the same genetic disease. Deficiency of free protein S was a strong riskfactor for thrombosis in these families. However, thrombophilia penetrance was highly variable. TheFV:Q506 mutation causing APC-resistance was identified as an additional genetic risk factor in 39% (7/18)of the families. Thus, familial thrombophilia isa multiple genetic disorder.Biochemically affected family members had higher levels of prothrombin fragment Fl +2 than their normalrelatives. The results demonstrate that individuals with APC-resistance or protein S deficiency have animbalance between pro- and anti-coagulant forces, resulting in increased thrombin generation andhypercoagulability

Estudio funcional de polimorfismos de la vía de activación de la proteína C

La trombosis venosa es una enfermedad multifactorial, originada por una suma de factores endógenos que predisponen al evento trombótico bajo la influencia de una exposición a factores exógenos. Dicha predisposición engloba factores de riesgo adquiridos que provocan en el individuo una disminución de su capacidad para enfrentarse a las alteraciones normales de la hemostasia, producto de la edad, dislipemias, diabetes, embarazo o puerperio, inmovilizaciones, intervenciones quirúrgicas, uso de píldoras anticonceptivas, tratamientos hormonales, etc. Además, se han identificado diferentes factores de riesgo genéticos, tales como las mutaciones factor V Leiden y protrombina G20210A, y el déficit de diversas proteínas con función anticoagulante, como es el déficit de antitrombina (AT), proteína C (PC), proteína S (PS), hiperhomocisteinemia, disfibrinogenemias e hipo- o displasminogenemias, que aumentan en mayor o menor medida el riesgo de trombosis. Sin embargo, todas estas deficiencias, por sí solas, no consiguen explicar más que alrededor de un 50% de los casos de trombosis, de forma que es posible la existencia de mutaciones o alteraciones en alguno de los componentes del sistema hemostático todavía desconocidos, que por sí solas o sumadas a otras alteraciones, nos permitan explicar mejor el evento trombótico. El sistema de la proteína C (PC) es esencial para la regulación de la coagulación y para la prevención de trombosis venosas y arteriales. De hecho, casi la mitad de todas las causas conocidas de trombofilia están asociadas a una alteración hereditaria o adquirida de la vía de la proteína C tales como deficiencias de PC, proteína S (PS) o resistencia a la proteína C activada (APC). La vía de la PC se inicia cuando la trombina se une a su receptor localizado en la superficie de la célula endotelial, denominado trombomodulina. El complejo trombina-trombomodulina (T-TM) activa a la PC. La PC activada (APC), junto con su cofactor la proteína S, limita la amplificación y progresión de la cascada de la coagulación al inhibir proteolíticamente a los cofactores de la coagulación Va y VIIIa. Además, otro receptor, el receptor endotelial de la PC (EPCR), acelera la activación de la PC por el complejo T-TM. Dado que estos dos receptores endoteliales son esenciales para la activación de la proteína C y consiguiente generación de APC, cualquier alteración disfuncional de los mismos puede reducir la generación de APC circulante. Puesto que una reducción de APC en la circulación es un riesgo independiente de trombosis venosa y arterial, el estudio funcional de los polimorfismos de estos dos receptores resulta esencial

Review: Determinants and modifiers of bleeding phenotypes in haemophilia-A: General and tropical perspectives

Haemophilia-A is an X-linked recessive bleeding disorder characterized by deficiency of FVIII. Although severity of haemophilia is largely determined by the extent to which different mutations abolish FVIII production, the overall phenotypic variations among haemophiliacs is determined by a combination of several other factors, which range from general to tropical factors on the one hand, and from genetic to immunologic and infective factors on the other hand. Determinants and modifiers of haemophilic bleeding phenotypes are important predictors of prognosis. However,  tropical determinants of haemophilic bleeding phenotypes are virtually ignored because majority of haemophilia research originated from developed non-tropical countries. The aim of this paper is to present a balanced review of the haemophilic bleeding phenotypes from general and tropical perspectives. Hence, we present a concisely updated comprehensive review of the  pathophysiologic and clinical significance of general vis-à-vis tropical determinants and modifiers of haemophilic bleeding phenotypes from genetic, immunologic and infective perspectives. Understanding of general phenotypic determinants such as FVIII gene mutations, immunological (inhibitors) and infective (e.g. hepatitis and HIV)  complications, classical thrombophilias (e.g. FV-Leiden) and non-classical thrombophilias (e.g. non-O blood groups) will throw more light into the mechanisms by which some tropical prothrombotic gene mutations (such as sickle b-globin gene) and certain chronic tropical pro-haemorrhagic parasitic infections (such as urinary and gastrointestinal helminthiasis) may modify frequency, intensity and pattern of bleeding among haemophiliacs in the tropics. The clinical significance of iron deficiency within the context of helminthiasis and haemophilia is also reviewed. More research is needed to determine the precise effect of non-classical thrombophilias such as sickling disorders and ABO blood groups on haemophilic bleeding phenotypes. Meanwhile, tropical healthcare workers should incorporate regular screening and treatment for common prohaemorrhagic parasitic diseases and iron deficiency into standard of care for management of haemophilia.Keywords: Haemophilia Bleeding Phenotype Thrombophilia ABO blood  group Sickle cell Helminthiasis Iron deficienc

Molecular genetic markers as a basis for personalized medicine

Genetika i genomika su danas potpuno integrisane u medicinsku praksu. Personalizovana medicina, poznata i kao medicina zasnovana na genomu, koristi znanja o genetičkoj osnovi bolesti da bi se individualizovalo lečenje svakog pacijenta. Veliki broj genetičkih varijanti, molekularno-genetičkih markera, već se koristi u kliničkoj praksi za dijagnozu, prognozu i praćenje bolesti (monogenska nasledna oboljenja, fuzioni geni i rearanžmani u pedijatrijskim i adultnim leukemijama) i presimptomatsku procenu rizika od obolevanja (BRCA1/2 za kancer dojke). Osim toga, primena farmakogenomike u kliničkoj praksi značajno je doprinela individualizaciji terapije u skladu sa genotipom i profilom ekspresije gena pacijenta. Genetičko testiranje za nekoliko farmakogenomičkih markera (TPMT, UGT1A1, CYP2C9, VKORC1) obavezno je ili se preporučuje pre započinjanja terapije. Najvažniji doprinos medicine zasnovane na genomu je ciljana molekularna terapija, prilagođena genetskom profilu bolesti. Testiranje genetičkih varijanti u malignim oboljenjima (BCR-ABL, PML/RARa, RAS, BCL-2, KIT, PDGFR, EGF) doprinosi tačnijoj stratifikaciji različitih kancera i adekvatnom izboru terapije. Krajnji cilj medicinske nauke je da primeni gensku terapiju koja bi eliminisala uzrok bolesti ili prevenirala bolest, ciljajući genetički defekt koji leži u osnovi bolesti. Tehnologija koja prati gensku terapiju veoma se brzo razvija i već se uspešno primenjuje. Iako je medicina oduvek suštinski bila "personalizovana", prilagođena svakom pacijentu, personalizovana medicina danas koristi modernu tehnologiju i znanja iz oblasti molekularne genetike i genomike, omogućujući stepen personalizacije koji vodi ka značajnom napretku medicinske prakse.Nowadays, genetics and genomics are fully integrated into medical practice. Personalized medicine, also called genome-based medicine, uses the knowledge of the genetic basis of disease to individualize treatment for each patient. A number of genetic variants, molecular genetic markers, are already in use in medical practice for the diagnosis, prognosis and follow-up of diseases (monogenic hereditary disorders, fusion genes and rearrangements in pediatric and adult leukemia) and presymptomatic risk assessment (BRCA 1/2 for breast cancer). Additionally, the application of pharmacogenomics in clinical practice has significantly contributed to the individualization of therapy in accordance with the patient's genotype and gene expression profile. Genetic testing for several pharmacogenomic markers (TPMT, UGT1A1, CYP2C9, VKORC1) is mandatory or recommended prior to the initiation of therapy. The most important achievement of genome-based medicine is molecular-targeted therapy, tailored to the genetic profile of a disease. Testing for gene variants in cancer (BCR-ABL, PML/RARa, RAS, BCL-2) is part of the recommended evaluation for different cancers, in order to achieve better management of the disease. The ultimate goal of medical science is to develop gene therapy which will fight or prevent a disease by targeting the disease-causing genetic defect. Gene therapy technology is rapidly developing, and has already been used with success. Although medicine has always been essentially "personal" to each patient, personalized medicine today uses modern technology and knowledge in the field of molecular genetics and genomics, enabling a level of personalization which leads to significant improvement in health care