Progression to multifactorial diseases is determined jointly by genes and environment. A valid approach for the prediction and prevention of such diseases might be to define at birth, or at an early age, the population at increased genetic risk by analysing the risk genes or risk alleles, the subsequent follow-up of those at risk, and the appropriate implementation of preventive measures at optimum time, if available. The feasibility and acceptance of population-wide genetic tests aimed at an early recognition of the risk of common multifactorial diseases with clinical presentation later in life is not known.The Type I Diabetes Prediction and Prevention project (DIPP) is an effort to predict and search for means to delay or prevent the disease in a large population-based cohort of children in Finland. The case of Type I diabetes is probably a useful model for the prediction and prevention of chronic, multifactorial Diabetologia (2001) AbstractAims/hypothesis. Population-wide genetic screening of susceptibility to multifactorial diseases will become relevant as knowledge of the pathogenesis of these diseases increases and preventive interventions are identified. Methods. Feasibility and acceptance of neonatal genetic screening for Type I (insulin-dependent) diabetes mellitus susceptibility and adherence of the atrisk children to frequent autoantibody follow-up were studied. Screening was offered to all families. The infants with HLA-DQB1 genotypes *02/*0302 and *0302/x (x¹*02, *0301, *0602) were invited to autoantibody follow-up. The children who developed signs of b-cell autoimmunity were invited to a separate prevention trial. Results. The parents of 31 526 babies born between November 1994 and April 1999 (94.4 % of those eligible) agreed to genetic screening. We found that 4651 infants (14.8 %) had increased genetic risk (2.5 to 15 times that of the general population) for Type I (insulin-dependent) diabetes mellitus, and 80 % of them joined the autoantibody surveillance. At the age of 1, 2, 3 and 4 years, 74, 69, 68 and 76 % of the at-risk children, respectively, attended the follow-up. A total of 17 of the 22 children (77 %) who were born during the study period and have developed diabetes carry the risk genotypes we currently use for screening. Conclusions/interpretation. Population-based screening of genetic susceptibility for Type I diabetes, linked with a possibility to participate later in a prevention trial, is highly accepted in Finland and identifies about 75 % of those developing diabetes at an early age. Families adhere well to the frequent measurement of signs of b-cell autoimmunity in the children at-risk. [Diabetologia (2001) 44: 290±297]
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.Describing aspects of biology as "heterogeneous" often has a negative connotation. It is a term that is used when we do not understand a measured or observed aspect of disease or when we need to explain data that are not consistent. However, it is evident that recognizing that there are "different kinds" of cells, genes, types of response, and severity of disease could offer a set of opportunities for therapies to work and biomarkers to be meaningful. Thus, it may be time to exploit heterogeneity rather than curse it and to use the opportunity to carve out endotypes of type 1 diabetes that have traction both in the clinic and in the laboratory.The introduction of the term "endotype" can largely be attributed to developments in the field of asthma (1) when it became apparent in the late 1990s that different pathogenic mechanisms induce a similar symptom cluster and manifest as a
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.