Homozygous parent affected sib pair method for detecting disease predisposing variants: Application to insulin dependent diabetes mellitus

Abstract

For complex genetic diseases involving incomplete penetrance, genetic heterogeneity, and multiple disease genes, it is often difficult to determine the molecular variant(s) responsible for the disease pathogenesis. Linkage and association studies may help identify genetic regions and molecular variants suspected of being directly responsible for disease predisposition or protection, but, especially for complex diseases, they are less useful for determining when a predisposing molecular variant has been identified. In this paper, we expand upon the simple concept that if a genetic factor predisposing to disease has been fully identified, then a parent homozygous for this factor should transmit either of his/her copies at random to any affected children. Closely linked markers are used to determine identity by descent values in affected sib pairs from a parent homozygous for a putative disease predisposing factor. The expected deviation of haplotype sharing from 50%, when not all haplotypes carrying this factor are in fact equally predisposing, has been algebraically determined for a single locus general disease model. Equations to determine expected sharing for multiple disease alleles or multiple disease locus models have been formulated. The recessive case is in practice limiting and therefore can be used to estimate the maximum proportion of putative susceptibility haplotypes which are in fact predisposing to disease when the mode of inheritance of a disease is unknown. This method has been applied to 27 DR3/DR3 parents and 50 DR4/DR4 parents who have at least 2 children affected with insulin dependent diabetes mellitus (IDDM). The transmission of both DR3 and DR4 haplotypes is statistically different from 50% (P < 0.05 and P < 0.001, respectively). An upper estimate for the proportion of DR3 haplotypes associated with a high IDDM susceptibility is 49%, and for DR4 haplotypes 38%. Our results show that the joint presence of non-Asp at DQ beta position 57 and Arg at DQ alpha position 52, which has been proposed as a strong IDDM predisposing factor, is insufficient to explain the HLA component of IDDM predisposition.

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

“…Because the estimated "control" frequencies are low, the CIs are broad, and a statistically significant hierarchy of risk for all diplotypes cannot be established from these data, but clearly, the DR3/4, the DR4/4, and DR4/8 diplotypes (excluding DRB1*0404) have the highest risk. The estimated risk for the DR3/3 diplotype is somewhat lower than in other studies (31); this difference may reflect the well-known risk heterogeneity of the DR3 haplotype (32,33), which implicates loci other than DRB1, DQA1, and DQB1 in determining the extent of risk on DR3 haplotypes. Type 1 diabetes risk in closely related DR-DQ haplotypes.…”

Linkage Disequilibrium With Predisposing DR3 Haplotypes Accounts for Apparent Effects of Tumor Necrosis Factor and Lymphotoxin-α Polymorphisms on Type 1 Diabetes Susceptibility

“…This demonstrates risk heterogeneity of DR3 haplotypes and is consistent with the hypothesis that this polymorphism, or another locus in LD with it, may affect T1D susceptibility independently of HLA class II loci. However, risk heterogeneity of DR3 haplotypes has been previously demonstrated, with those DR3 haplotypes that carry B18 alleles having higher T1D risk than those DR3 haplotypes that carry B8 alleles [20]. We found that the putative predisposing allele "A" of the TNF G(-238)A SNP is found on B18-DR3 haplotypes in this data set but is absent from B8-DR3 haplotypes.…”

Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: Association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls

“…Previous reports have indicated that this DR3 haplotype has a somewhat lower risk for type 1 diabetes than other DR3 haplotypes [19], although one study concluded that the type 1 diabetes risk for the 8.1 haplotype was not different than that of other DR3 haplotypes [20]. These data suggest that the 8.1 haplotype may contain protective alleles at loci near or identical to HLA-A*0101 as well as near or identical to DPB1*0101.…”