Identification Of Unique Susceptible Genes Of Early-onset Graves' Disease

Diffuse toxic goiter with hypothyroidism,known as Graves' disease(GD),is a common tissue specific autoimmune thyroid disease(AITD)and its prevalence is about 1%~2%.The genetic predisposition to AITD was found by familial aggregation,such as a high recurrence rate in family members,a high occurrence rate of autoantibodies and 30% prevalence in monozygotic twins.Graves' disease is caused by genetic and environmental factors,and 79% susceptibility can be attributed to genetic factors.Through candidate gene analysis,genome wide association study and some functional studies,researchers had identified several susceptible genes of GD,such as HLA,CTLA4,PTPN22,FCRL3,RNASET2,TSHR,etc.Graves' disease can occur at any age,but the cutoff age of early-onset GD has not been clear defined(most researchers chose patients less or equal to 30 years old as early-onset GD).Researches about unique loci of early-onset GD were reported several years ago,but considered their insufficient sample size and deficient analysis methods,these loci should be verified in more studies.A study did genotyping of 196,524 polymorphisms in 106 earlyonset patients(onset < 30 y)and 855 healthy subjects through Illumina Infinium Immunochip and performed case-control association analyses,finally found 30 specific SNPs in early-onset patients(these SNPs were located in genes of HLA-I,HLA-II,BTNL2,NOTCH4,TNFAIP3 and CXCR4).Another study had reported FOXP3 in X chromosome was a unique gene of early-onset patients(onset ? 30 y).We tempted to validate their results in Chinese Han population(the cutoff age is also 30 years old).In addition,whether early-onset GD can be treated as a subset of GD still needs to be confirmed,thus we speculated early-onset GD may not be an independent classification.The susceptible genes of GD probably only have a stronger effect on them because their less exposure time of environment.Finally we chose twenty susceptible loci of Chinese GD to study their specificity in early-onset patients,these loci were identified previously by our group.Besides the association analyses of above loci and early,we also analyzed the heterogeneity between early-onset GD patients and non-early-onset patients.Subsequently,we classified GD patients into other groups according to different cutoff ages(20y,25 y,30y)and performed the same analyses of significant loci in the first stage.In the second stage,we genotyped significant loci in a larger samples and did the same in the combined stage.Finally,we also did the detailed heterogeneity analyses of each groups classified by distinct cutoff ages(from 15 y to 45y),and we gave a more accurate definition of early-onset GD.Our research did not confirm the previously reported unique loci and gene of earlyonset GD in Chinese Han population,but proved that one GD susceptible locus rs4947296 had a stronger effect on early-onset GD patients.In addition,we redefined the early-onset patients should be ones whose onset age were ? 20 years old through the heterogeneity analysis.