Autoimmune disorders share molecular mechanisms and pathways, suggesting that some genetic effects will be selectively concentrated between them. To identify genetic effects potentially shared between SLE and AITD we selected families from the Oklahoma collection of pedigrees multiplex for SLE that contained a member with AITD, either Graves' disease or Hashimoto's thyroiditis.
Methods We identified a total of 35 pedigrees (25 European-American, 6 Hispanic, 2 Native American and 2 Asian-American) containing at least one SLE patient with autoimmune thyroid disease (AITD). Nineteen pedigrees were used in the initial genome scan while an independent sample of sixteen was used to replicate findings. Phenotypic characterization included a diagnosis of Graves' disease or Hashimoto's thyroiditis by a physician in the medical records with at least two of the following: presence of antimicrosomal antibodies, a consistent thyroid biopsy report, radioiodine ablation therapy, hormone replacement therapy, or the expected abnormalities in the serum levels of TSH.
Results We identified a strong, robust, and reproducible linkage effect in chromosome 5 (5q14.3-q15) at D5S1462. The first 19 pedigrees produced a two-point parametric LOD = 4.97, which was later confirmed in the replication sample (LOD = 2.89). All 35 pedigrees together produce LOD = 7.86 under a dominant model with 90% penetrance and a disease allele frequency of 10% (NPL = 0.00003). Multipoint LOD scores and heterogeneity LOD scores (HLOD) were computed using the same models described above. The 35 pedigrees produced LOD (HLOD) = 6.90 at 5q14.3-15 between D5S1725 and D5S1453, a 12 cM interval, with the peak at D5S1462 at 96.64 cM (NPL = 2.31, p = .01, α = 1.00). Fine mapping further confirms the genetic linkage effect and narrows the region likely to contain the gene to ˜ 5 Mb. The SLE pedigrees selected for AITD in affecteds suggest that the gene responsible for the 5q14.3 effect contributes to both of these autoimmune diseases. 5q14.3-15 has already been linked to AITDs in another linkage study.
Conclusion These results suggest that stratifying SLE pedigrees by other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3-15 harbors a susceptibility gene shared by SLE and AITD.
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