葛瑞夫茲氏病 ( Graves' disease )遺傳研究新進展

1 ( Graves' disease ) Graves' disease Autoimmune thyroid disease Animal model Genetic study Linkage analysis ( Graves' disease von Basedow's disease )

2 1 ( Hashimoto's thyroiditis ) ( organ specific autoimmune diseases ) ( genome project ) 1:10 ( diffuse goiter ) ( hyperthyroidism ) ( infiltrative orbitopathy ) ( infiltrative dermopathy ) 2 ( T3, T4, free T4 ) TSH ( thyroid-stimulating hormone ) anti-TSHRAb ( anti-TSH receptor antibodies ) anti-hTgAb ( anti-human thyroglobulin antibodies, or ATA ) anti-hTPOAb ( anti-human thyroid peroxidase antibodies AMA, anti-microsomal antibodies ) anti-TSHRAb ( )

3 ( non-homogeneous infiltration ) ( follicles ) T ( T lymphocytes ) T 2,3 ( ) T T B ( TSH receptor antibody ) T 2-5 T molecular mimicry ( ) bystander hypothesis ( intra-thyroidal insult ) T T HLA class I molecules HLA class II molecules 2 obese strain chicken BB rat non-obese diabetic(NOD ) mice ( destructive thyroiditis ) thyroglobulin ( chicken rat )

4 Thyroid peroxidase ( mouse ) ( ) chromosome 14q31 60 kilobases exons mRNA 4 kilobases 9 exons 10 exon 743 LH/CG receptor homology G-protein extracellular domain mRNA adipocytes or preadipocytes 4,5 TSH-binding and immunoreactivity ( ) 6 ( 1 )

5 Thyroxine ( ) TSH ( 2 ) ( 3 ) ( 4 ) ( 5 ) ( 6 ) ( 7 ) ( pretibial skin ) peptides or fragments of the receptor ( ) immunological adjuvants Genetic immunization of inbred mice ( DNA ) ( in vitro ) T 7 non-obese diabetic ( NOD ) mice BALBc mice ( 17/25 ) BALBc mice in vitro mice fibroblast ( MHC class II ) AKR/N mice "inbred" mouse strains NMR outbred strain genetic immunization 30 female mice 4 8 type 1 DM ( non-obese diabetes mice ) ( )

6 50% 9 10 ( ) 6 9 ( mean Mother = , mean Sisters = , mean Siblings = ) 11 ( 1000 ) ( twin study ) 1876 Sir Francis Galton ( MZ twin ) ( HZ twin ) 1950 probandwise concordance rate 86% 40% concordance rate 64% 6% Brix 1998 12 concordance rate 36% 0% ( )

7 NMR outbred strain multifactorial disease ( susceptibility genes ) multifactorial polygenic disease ( ) multifactorial disease polygenic disease genome project Type 1 DM 13 2,14,15 ( experimental cross ) ( population-based case-control studies ) ( ) alleles ( candidate genes ) class II MHC region (chromosome 6p ) CTLA-4 ( chromosome 2q33 )

8 Family based study candidate gene whole genome study family based data set ( classical linkage analysis ) ( gold standard ) cosegregation, linkage, disequilibrium, allele-sharing, polymorphism, and microsatellites DNA ( "non-parametric" linkage analysis ) DNA identical by descent identical by state linkage analysis ( "parametric" linkage analysis ) ( multigenerational pedigrees ) ( mode of inheritance and likely penetrance ) classical linkage analysis locus LOD( logarithm of odds ) score 3 ( ) type 1 DM multiple sclerosis linkage study candidate genes mar-kers ( microsatellites, or single nucleotide polymorphism, SNP )

9 Whole genome study locus 2 400 intrafamilial linkage disequilibrium TDT ( transmission disequilibrium test ) the transmission of alleles from a heterozygous parent to one or more offspring classical linkage analysis candidate genes polymorphism genome project markers multifactorial polygenic disease Type 1 DM candidate genes population-based case-control study candidate genes HLA CTLA-4 ( cytotoxic T-lymphocyte associated 4 ) gene IL-1RA ( interleukin 1 )

10 TNF- HLA region CTLA-4 HLA ( ) linkage analysis whole genome analysis 17-24 ( ) Barbesino Tomer ( ) genome microsatellites parametric linkage analysis 25 6 markers ( linkage ) 1 locus ( AITD-1 3 loci ( GD-1, GD-2, and GD-3 ) 2 loci ( HT-1 and HT-2 ) ( ))