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HLA on Chromosome 6: The Story Gets Longer and Longer

¹ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
² Children's Hospital Oakland Research Institute, Oakland, Calrifornia

Address correspondence and reprint requests to Jerome Rotter, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California. E-mail: jerome.rotter@cshs.org

Abbreviations: HLA, human leukocyte antigen; LD, linkage disequilibrium; MHC, major histocompatibility complex

The first 20% of the full text of this article appears below.

Over the past three decades, substantial progress has been made in understanding the genetic basis for diabetes. One of the important first steps that allowed this progress to occur was realizing that diabetes is heterogeneous, and, therefore, separation of clinically distinct forms of the disorder (i.e., type 1 vs. type 2 diabetes) improves the ability to detect genetic associations. The key points that allowed type 1 diabetes to be separated from type 2 diabetes included realization of the clinical differences (typically childhood onset, thin, ketosis-prone versus adult onset, obese, nonketosis prone); family and twin studies that demonstrated that the two forms of diabetes usually segregate separately and, while both demonstrate substantial monozygotic twin concordance, the concordance rate in type 2 diabetes is at least double that in type 1 diabetes; and appreciation that there is automimmune β-cell destruction in type 1 diabetes that does not occur in type 2 diabetes (rev. in 1). The confirmation that these clinical observations truly represented genetic differences came from the early studies of the human leukocyte antigen (HLA) region, which we now know plays an important role in type 1 but not in type 2 diabetes susceptibility.

HLA, the human form of the major histocompatibility complex (MHC), has indeed long been recognized as the major genetic region influencing risk for type 1 diabetes. The fact that it was the first genetic susceptibility region identified was, in part, serendipitous, as the emerging ability to distinguish a variety of HLA-A and -B serotypes made HLA one of . . . [Full Text of this Article]

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