Genetic study of early‐onset Graves’ disease in the Chinese Han population

Abstract

Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, 11 single nucleotide polymorphisms (SNPs) and their related SNPs (R 2 > .6), SNPs located within a AE1-Mb region of the FOXP3 gene, and 20 validated GD-risk SNPs were selected and screened for genotyping in 3735 GD and 4893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early-onset GD in our Chinese Han population but found that a GD-risk SNP located in the human leukocyte antigen class I region-rs4947296-was more strongly correlated with earlyonset GD than non-early-onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early-onset GD as an onset age ≤20 years.

The Association Between Foxp3 Polymorphisms and Risk of Graves' Disease: A Systematic Review and Meta-Analysis of Observational Studies

“…When stratified by ethnicity, we found a positive association among Asians (OR = 1.31, 95%CI 1.04, 1.64; P = 0.02) but not among Caucasians (OR = 0.96, 95%CI 0.67, 1.37; P = 0.82), as shown in Figure 4. The leave-one-out sensitivity analysis confirmed the statistical robustness of our findings ( Table 3), and the study by Yuan et al (36) was regarded as the major source of heterogeneity, since the intra-study heterogeneity decreased from 75 to 57% after the removal of Yuan's study. No publication bias was detected (Egger's test: t = 0.63, P = 0.554; Begg's test: z = 1.00, P = 1.00).…”

“…Seven studies (30-32, 34-37) investigated the genetic effect of rs3761548 on the risk of GD, however, achieving inconsistent results. Four studies (32,34,35,37) reported significantly higher frequency of A allele in GD groups than control groups, while the other three studies (30,31,36) failed to replicate these positive findings. Under the random-effect model, the variant allele of rs3761548 polymorphism was associated with 25% higher risk of GD compared to reference allele in the overall population (OR = 1.25, 95%CI 1.02, 1.54; P = 0.03).…”

“…All the studies were published between 2006 and 2019, with the sample size ranging from 180 to 2,568. The majority of studies were performed in China (35)(36)(37) and India (31,34), the remaining studies were carried out in Poland (30), UK (33), and Japan (32), respectively. Two widely used techniques for genotyping were used by our included studies, namely TaqMan and polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP).…”

“…Six studies addressed the relationship between rs3761547 and risk of GD, including five studies (32,(34)(35)(36)(37) on Asian population and one study (30) on Caucasian population. The pooled results showed that the minor allele of rs3761547 was not associated with risk of GD in the overall population (OR = 1.09, 95%CI 0.99, 1.20; P = 0.09), no significant heterogeneity was detected (I 2 = 0%, P = 0.60).…”

Paediatric‐onset and adult‐onset Graves' disease share multiple genetic risk factors

“…Several other studies have investigated the genetic background of GD in young adults (defined as age of GD onset lower than 30‐45 years), showing that certain genetic variants, such as HLA‐DRB1 , CTLA4 and PTPN22 polymorphisms, may be associated with age of GD onset . Most recently, based on the results of an analysis performed in a large cohort of GD patients, Yuan et al reported significant genetic heterogeneity between subjects with age of GD onset ≤20 and >20 years, suggesting it is reasonable to reduce the cut‐off value for the definition of early‐onset GD. However, data on the genetic risk factors in POGD are limited .…”