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Make it HuGE: human genome epidemiology reviews, population health, and the IJE. Int J Epidemiol

University of Bristol, Bristol, England, United Kingdom
International Journal of Epidemiology (Impact Factor: 9.2). 07/2006; 35(3):507-10. DOI: 10.1093/ije/dyl071
Source: PubMed

ABSTRACT The International Journal of Epidemiology is concerned with scientific evidence that can ultimately form the basis of strategies for improving population health. Hence, the IJE would be expected to remain cautious about the technological advances heralded by the sequencing of the human genome. The classical epidemiological approaches of examining secular trends in disease risk, changes in risk consequent upon migration, and differences in disease rates between populations indicate that little of the global burden of common disease can be attributed to simple differences in genetically determined risk. It is not surprising that many social epidemiologists and public health practitioners (including, in the past, some of the authors of this editorial) have pointed this out. More surprising, perhaps, is that in the spirit of honest accounting, some geneticists and genetic epidemiologists have also punctured the inflated claims of genetic epidemiology by emphasizing that the population-attributable risk of most common genetic variants will be low and that in any case the influence of genetic factors is not reversible through changing genetic make-up. Thus Terwilliger and Weiss 1 point out that alleles identified as

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    • "The development of high throughput techniques has resulted in an explosion of available genetic and genomic information . This creates challenges in analyzing, synthesizing and finally translating this rapidly accumulating evidence in useful clinical and public health applications (Burke et al. 2006; Guttmacher and Collins 2003; Higgins et al. 2007; Smith et al. 2006). Human genome epidemiology addresses associations between genetic variation and risk for complex common diseases. "
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    ABSTRACT: Kidney transplantation (Tx) is the treatment of choice for end stage renal disease. Immunosuppressive medications are given to prevent an immunological rejection of the transplant. However, immunosuppressive drugs increase e.g. the risk of infection, cancer or nephrotoxicity. A major genetic contributors to immunological acceptance of the graft are human leukocyte antigen (HLA) genes. Also other non-HLA gene polymorphisms may predict the future risk of complications before Tx, possibly enabling individualised immunotherapy. Graft function after Tx is monitored using non-specific clinical symptoms and laboratory markers. The definitive diagnosis of graft rejection however relies on a biopsy of the graft. In the acute rejection (AR) diagnostics there is a need for an alternative to biopsy that would be an easily repeatable and simple method for regular use. Frequent surveillance of acute or subclinical rejection (SCR) may improve long-term function. In this thesis, associations between cytokine and thrombosis associated candidate genes and the outcome of kidney Tx were studied. Cytotoxic and co-stimulatory T lymphocyte molecule gene expression biomarkers for the diagnosis of the AR and the SCR were also investigated. We found that polymorphisms in the cytokine genes tumor necrosis factor and interleukin 10 (IL10) of the recipients were associated with AR. In addition, certain IL10 gene polymorphisms of the donors were associated with the incidence of cytomegalovirus infection and occurrence of later infection in a subpopulation of recipients. Further, polymorphisms in genes related to the risk of thrombosis and those of certain cytokines were not associated with the occurrence of thrombosis, infarction, AR or graft survival. In the study of biomarkers for AR, whole blood samples were prospectively collected from adult kidney Tx patients. With real-time quantitative PCR (RT-QPCR) gene expression quantities of CD154 and ICOS differentiated the patients with AR from those without, but not from the patients with other causes of graft dysfunction. Biomarkers for SCR were studied in paediatric kidney Tx patients. We used RT-QPCR to quantify the gene expression of immunological candidate genes in a low-density array format. In addition, we used RT-QPCR to validate the results of the microarray analysis. No gene marker differentiated patients with SCR from those without SCR. This research demonstrates the lack of robust markers among polymorphisms or biomarkers in investigated genes that could be included in routine analysis in a clinical laboratory. In genetic studies, kidney Tx can be regarded as a complex trait, i.e. several environmental and genetic factors may determine its outcome. A number of currently unknown genetic factors probably influence the results of Tx. Terminaalisen munuaissairauden paras hoitomuoto on munuaissiirto. Immuunivastetta heikentävää lääkitystä (immunosuppressiivit) annetaan estämään siirteen immunologinen hyljintä. Toisaalta immunosuppressiivit ovat haitallisia munuaisille ja lisäävät infektioiden ja syövän vaaraa. Tärkeimmät siirteen immunologiseen hyväksyntään vaikuttavat geenit ovat ihmisen valkosoluantigeeneja koodaavat geenit (HLA). Muut HLA:n ulkopuolisten geenien eri muodot voivat ennustaa ennen siirtoa hoidon sivuvaikutuksia ehkä mahdollistaen yksilöllisen immunosuppressiivisen lääkityksen. Siirron jälkeen siirteen toimintaa seurataan yleisluontoisten sairauden oireiden ja laboratoriokokeiden avulla. Siirteen hyljintä määritetään ottamalla neulakoepala siirteestä. Äkillisen hyljinnän määritykseen tarvitaan koepalan oton sijaan helposti toistettava ja yksinkertainen menetelmä säännölliseen seurantaan, mikä voi parantaa siirteen pitkäaikaistoimintaa. Väitöskirjassa tutkittiin sytokiinigeeneistä ja laskimotukokseen liittyvistä geeneistä eri geenimuotoja ja näiden vaikutusta munuaissiirteen ennusteeseen. Hyljinnän määrityksen avuksi tutkittiin myös soluille myrkyllisiä ja soluja ärsyttäviä T-imusolumolekyyligeenien ilmentymisbiomerkkejä. Sytokiinigeenien TNF ja IL10 tietyt muodot siirteen saajissa vaikuttivat hyljintäriskiin pienessä aineistossa. Lisäksi IL10 geenin tietyt muodot siirteen luovuttajissa vaikuttivat sytomegaloviruksen lisääntymiseen tietyissä siirteen saajissa. Toisaalta emme löytäneet laskimotukokselle, infarktille, hyljintään sairastuvuudelle tai siirteen elinikää lyhentäville altistavia sytokiini- tai tukosgeenimuotoja. Hyljinnän biomerkkejä tutkittaessa reaaliaikaisella kvantitatiivisella polymeraasiketjureaktiolla CD154- ja ICOS-geenien ilmentyminen oli erilaista hyljintäpotilaiden ja normaalien potilaiden välillä muttei muiden hyljinnänkaltaisia oireita ilmentäneiden potilaiden ja hyljintäpotilaiden välillä. Tutkittaessa kliinisesti oireettomien mutta koepalan perusteella hyljintätautimäärityksen saaneita lapsipotilaita hyljintäpotilaita ei pystytty erottamaan normaalipotilaista tutkimalla ehdokasgeenien ilmentymistä tai koko genomin ilmentymistä. Munuaissiirtoa voidaan pitää kompleksitautina, jossa useat ympäristö- ja geneettiset tekijät vaikuttavat siirron jälkeiseen aikaan. Suuri joukko tällä hetkellä tuntemattomia geneettisiä tekijöitä vaikuttavat mahdollisesti siirron onnistumiseen.
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