Article Abstract:
Results of genomewide linkage studies of type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) indicate that in mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is valuable. Both predisposing and nonpredisposing alleles should be anticipated. The studies show that several unlinked susceptibility loci can explain clustering of the disease in families. One locus maps to chromosome 11p13. After 707 affected sib pairs were analyzed a peak multipoint maximum LOD score was found to be 2.7 with linkage over a 15-cM region. To fine map the locus for structural analysis of positional candidate genes was a challenge. Analysis of another 1,702 families have support for negative transmission of D11S1917 (ital) allele 3 to affected offspring and transmission to unaffected siblings.
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Article Abstract:
A much-used measure of familial aggregation is the sibling recurrence-risk ratio or lambda sub S. It is defined as the ratio of risk of disease manifestation, given a sibling's being affected, vs prevalence of the disease in the overall population. The ratio lambda sub S can be greatly inflated because of misunderstanding of the original definition and of ascertainment bias and of overreporting. Like segregation analysis, the estimation of lambda sub S is likely to be affected by ascertainment bias. It should be estimated with great care. If it is used for discrimination between different genetic models, for exclusion mapping and for association studies even more care should be taken.
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Article Abstract:
An approach has been developed to get around the confounding effects of disequilibrium between class II alleles and alleles at other major histocompatibility complex (MHC) loci. The human leukocyte antigen (HLA) complex comprises 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21. It encodes a major part of the genetic predisposition to develop type 1 diabetes (IDDM1) Predisposition to type 1 diabetes has been linked to the human leukocyte antigen complex. It includes at least one non-class II gene.
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