Challenges and Strategies for Investigating the Genetic Complexity of Common Human Diseases

Abstract

There is substantial interest in the identification of genes underlying susceptibility to complex human diseases because of the potential utility of such genes in disease prediction or therapy. Type 1 diabetes is an example of one such disorder and is presumed to arise from the effect of multiple genes and environmental factors. One identified locus has a major effect on type 1 diabetes susceptibility (IDDM1), whereas other loci have significant, yet small, individual effects (IDDM2, IDDM15). It is unclear whether susceptibility for type 1 diabetes arises because of the effects of loci acting independently or whether there are important interactions between loci. Although genetic tools are continuing to be developed to enable examination of candidate regions, the means to identify and narrow "true" susceptibility regions continues to be limited by the lack of statistical power resulting from inadequately sized collections of families. This report provides an evaluation of the approaches for identification of regions harboring type 1 diabetes genes, methods to identify the gene regions that interact to define the risk for type 1 diabetes, and efforts to fine-map the variants responsible. Diabetes 51 (Suppl. 3):S288 -S294, 2002 T he primary goal of modern human genetics is to identify genes that control pathways that lead to disease. Such genetic information is expected to facilitate development of new drugs that can target the disease-relevant biochemical pathways involved in pathogenesis and thereby reduce the genetic burden of disease. Genetic data can also potentially enhance the identification and understanding of environmental agents and their roles in triggering the cascade of events leading to disease. It is only through the combination of environmental risk factor aversion and application of novel pharmaceuticals to therapeutic targets in genetically "at risk" individuals that public health benefit can accrue.Type 1 diabetes provides a useful paradigm for genetically complex human diseases. Type 1 diabetes arises from autoimmune destruction of the pancreatic ␤-cells, which are the sole source of insulin. This loss of ␤-cells ultimately results in an inability to regulate blood glucose levels without the administration of exogenous insulin. Type 1 diabetes is the third most prevalent chronic disease of childhood, affecting 0.3% of the general population by age 20 years and has a lifetime risk of nearly 1% (1). It is estimated that ϳ1.4 million people in the U.S. (10 -20 million people worldwide) have type 1 diabetes (2,3). In most cases, a preclinical period marked by the presence of autoantibodies to pancreatic ␤-cell antigens (GAD65, insulin, or tyrosine phosphatase-like protein IA-2) precedes the onset of overt hyperglycemia. This preclinical period provides a theoretical opportunity for preventive intervention in individuals recognized as "susceptible." The availability of an effective replacement therapy (insulin) that can be used after the onset of disease means that disease prediction in this precli...

A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families

“…1,2 Considerable effort has been expended in attempting to identify genetic risk factors for T1D with the potential goals of developing predictive tools and better understanding the underlying etiology of the disorder, particularly during the preclinical phase. 3,4 More than 1000 multiplex T1D families have been studied by genome scans for evidence of linkage to T1D. [5][6][7][8][9] Although these linkage approaches have detected loci with demonstrable effects on familial clustering of T1D, the modest sibling risk ratios (eg, lsr1.3) predicted for several of these loci suggest that prohibitively large numbers of families may be required to derive a complete description of genetic risk for T1D from linkage studies alone.…”

Type 1 Diabetes

“…This underlying complexity would also increase the difficulty to obtain convincing results in future fine-mapping association studies. Both development of novel analytical approaches and increased sample size will be necessary to resolve this apparent complexity (54,55). Through the efforts of consortia (such as our international effort), it will be possible to increase the number of families for type 1 diabetes (http://www.t1dgc.org), which would increase power and allow exclusion of loci s Ն 1.2, as well as provide standardized samples and reagents for future fine-mapping studies.…”

Polymorphic variation in the CBLB gene in human type 1 diabetes

“…In T1D, considerable effort has been expended on linkage studies in affected sib pairs as an approach to identify genetic risk factors. [2][3][4][5][6] However, most successes in the identification of susceptibility loci have come from the testing of candidate genes for allelic association with the disease. Two regions, the HLA region on chromosome 6p and the insulin gene region on 11p, are generally accepted as containing T1D susceptibility loci, designated IDDM1 and IDDM2, respectively.…”