Experimental Study On Linkage And Association Between Polymorphisms Within TPO And TSHR Genes And Inherited Thyroid Diseases

Inherited thyroid diseases, which result from an interaction between predisposing genes and environmental triggers, provide an informative model for dissecting the molecular genetics of multi-stage human tumorigenesis and heterogeneity. Genome scans have identified many genomic regions that may harbor putative susceptibility genes for thyroid diseases. Evidence for most regions, however, varies in different datasets. The aim of this study was 1) to dissect the genetic predisposition to these diseases in Chinese populations and families with multiple members affected with MNG, PTC, FTA and GD and 2) to identify and characterize genetic polymorphisms, which could explain phenotypic variation of the thyroid diseases.Adopting a set of 119 microsatellite markers, we performed a genome-wide GeneScan in three Chinese pedigrees. After conducting linkage analysis, we identified that two candidate regions, which were on chromosome 10 and 15 respectively, show significant linkage to MNG with P values of 0.015; while another three candidate regions on chromosome 8, 14 and 22 respectively, show significant linkage to MNG/PTC with P values of 0.03, 0.007 and 0.03, respectively. These findings indicated that the Chinese families harbored susceptibility loci for MNG and PTC, which were distinct from those previously found in the Caucasian population. Our result suggested that different susceptibility loci existed between different ethnic groups. Furthermore, even within a single family from a genetically homogenous population, more than one gene was involved in the genetic susceptibility to thyroid diseases, supporting the notion that thyroid diseases were caused by multiple genes of varying influences.Meanwhile, a systematic polymorphism screening was performed in the coding regions of thyroid peroxidase (TPO) and thyroid stimulating hormone receptor (TSHR) genes. Association between the detected polymorphisms and thyroid diseases was analyzed in 256 Chinese including 142 unrelated normal individuals and 114 patients affected with thyroid diseases using case-control approach. Ten single nucleotide polymorphisms (SNPs) in coding sequences and two SNPs around the exons were detected. Haplotypes based on all or parts of the SNPs were predicted and were evaluated for their association with the assumed disease allele. The analysis showed diverse degree of association of haplotypes based on various combinations of these polymorphic sites. Among them, the haplotype constructed from the mutant sites G859T and G1207T within TPO gene displayed highly and consistently significantassociation over various models in regarding to genetic control of the disease. To investigate the effect of case and control size on statistical power of the haplotype-based association study, distribution of the significance level was explored. The mode of the distribution was found to be mainly related with the control sample size while the variance of the distribution largely determined by the case sample size.Our results suggested that some chromosome regions might be susceptibility to MNG/PTC diseases, and that variants of TPO gene and the specific haplotype may act as low penetrance alleles in the predisposition to thyroid tumors. These findings laid a foundation for further fine mapping and finally positional cloning the associated genes for thyroid diseases. Characterizing the functional and clinical significance of the haplotypes requires further study.