| ObjectiveGraves'disease (GD) is an autoimmune condition of the thyroid. Genetic factors play an important role in the etiology of the disease. However, GD does not exhibit a simple Mendelian inheritance, its susceptibility may be determined by several genes with different penetrances, and affected by environmental factors. This makes the identification of the susceptibility genes for GD especially difficult! Although many efforts have been put into characterization of the genetic basis for GD, the genes responsible for GD remain unknown. The majority are association studies, which target in the genes that may be involved in the autoimmune process of GD. Interestingly, only Human leukocyte antigen (HLA) and Cytotoxic T lymphocyte associated antigen - 4 ( CTLA - 4 ) have been consistently associated with GD. However, the genes associated with GD may have only a minor role in the overall genetic susceptibility to GD. Linkage analysis provides a powerful approach for detecting genes of major influence. Whether HLA and CTLA - 4 genes are linked to GD has been controversial. Some studies found positive results, others had not. This inconsistency may reflect the existence of genetic heterogeneity. An investigation in whites demonstrated evidence for linkage of GD to chromosome 20q11, suggesting that this region may harbor a major gene for GD. To identify the major locus for GD in Chinese, and to determine whether chromosome 2q31 - q33, which contains the gene for CTLA -4, chromosome 6p21, which contains the genes for HLA, and chromosome 20q are also linked to GD in Chinese, we performed a genome - wide scan in 54 Chinese Han pedigrees, and screened chromosome 2q31 - q33, 6p21, and 20q in detail. Iodine is a kind of microelement necessary for human bodies, and alsothe major material for thyroid hormone synthesis. Some epidemiological studies demonstrated clear correlation between iodine intake and the incidence of autoimmune thyroid diseases ( AITD) , and between iodine intake and the production of thyroid antibodies. Excess iodine intake affects clinical outcomes of AITD. Animal studies showed that increased iodine intake can promote the development of AITD in genetically predisposed strains. However, there has not been a study investigating the effect of varying amounts of iodine intake on the development of AITD in genetically predisposing populations, and little is known about the occurrence rates of thyroid dysfunction and antibody positivity in members from multiplex families ( more than one affected) , which may have even larger inherited susceptibility. To answer these questions, we performed a study investigating the prevalence of thyroid dysfunction and thyroid autoantibodies in members from multiplex families with GD. The effects of increased iodine intake on the occurrence of thyroid antibodies and the incidence of Graves'disease were also investigated.Methods1. Genome - wide scan. A genome - wide scan was performed in 54 pedigrees (322 individuals, 139 GD patients) using 277 microsatellite markers (cover all 22 autosomes and X chromosome) , with an average interval between markers of 13. 4 centimorgan (cM) , and average heterozygosity of 71%. All markers were selected from Genethon maps. Blood samples were collected from all the participants, and genomic DNAs were isolated using standard procedures. Microsatellite markers were amplified using multiplex PCR, and the PCR products were separated on a MegaBASE 1000 DNA sequencer. Allele railing was performed by using Genetic Profiler software. Linkage analysis was performed by using both model - free ( nonparametric ) and model - based ( parametric) methods of linkage analysis. In parametric linkage analysis, two -point LOD scores were calculated using the LINKAGE software, assuming both dominant and recessive models. For the dominant model, three levels of penetrancewere tested (30% , 60% , and 90% ) ; and for the recessive model, four levels of penetrance were evaluated (30% , 60% , 90% , and 100% ). A population prevalence of 1% for GD was...
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