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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Available from: Marta Gwinn, Jan 22, 2014
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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: Meta-analysis offers the opportunity to combine evidence from retrospectively accumulated or prospectively generated data. Meta-analyses may provide summary estimates and can help in detecting and addressing potential inconsistency between the combined datasets. Application of meta-analysis in genetic associations presents considerable potential and several pitfalls. In this review, we present basic principles of meta-analytic methods, adapted for human genome epidemiology. We describe issues that arise in the retrospective or the prospective collection of relevant data through various sources, common traps to consider in the appraisal of evidence and potential biases that may interfere. We describe the relative merits and caveats for common methods used to trace inconsistency across studies along with possible reasons for non-replication of proposed associations. Different statistical models may be employed to combine data and some common misconceptions may arise in the process. Several meta-analysis diagnostics are often applied or misapplied in the literature, and we comment on their use and limitations. An alternative to overcome limitations arising from retrospective combination of data from published studies is to create networks of research teams working in the same field and perform collaborative meta-analyses of individual participant data, ideally on a prospective basis. We discuss the advantages and the challenges inherent in such collaborative approaches. Meta-analysis can be a useful tool in dissecting the genetics of complex diseases and traits, provided its methods are properly applied and interpreted.
    Human Genetics 03/2008; 123(1):1-14. DOI:10.1007/s00439-007-0445-9 · 4.52 Impact Factor
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    • "This assumption is seldom likely to be true as environmental context, indexed by variables such as age, gender, and body size, nearly always plays a role in determining the influence of genetic variation on measures of health that have a complex multifactorial etiology. As an alternative to population-based single model risk stratification schemes [Conroy et al., 2003;Anderson et al., 1990] and population-based marginal genetic effects [Smith et al., 2006], the PRIM makes possible a more personalized risk prediction strategy that incorporates both rare and common environmental and genetic risk factors, an objective that has been the goal of medical genetics in particular, and clinical practice in general. "
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    ABSTRACT: Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions.
    Genetic Epidemiology 09/2007; 31(6):515-27. DOI:10.1002/gepi.20225 · 2.95 Impact Factor
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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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