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Compelling Evidence Linking CD40 Gene With Graves' Disease in the Chinese Han Population
He Jiang1, Fei-Fei Yuan1, Hai-Ning Wang2
1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Insights
The single nucleotide polymorphism rs1883832 in the CD40 gene is strongly linked to Graves' disease (GD) susceptibility. This genetic variation influences CD40 gene expression, impacting thyroid-stimulating hormone receptor antibody levels and contributing to GD development.
Area of Science:
- Genetics
- Immunology
- Endocrinology
Background:
- Mutations in the CD40 gene are recognized risk factors for Graves' disease (GD).
- The CD40 gene and its ligand CD40L play roles in immune and inflammatory responses.
- Rs1883832, a single nucleotide polymorphism (SNP) in the CD40 gene's Kozak sequence, is a known GD risk factor across ethnicities.
Purpose of the Study:
- To identify the most significant SNP associated with Graves' disease in the Han Chinese population.
- To elucidate the pathogenic mechanism linking rs1883832 to Graves' disease.
- To investigate the association of rs1883832 with specific GD subtypes, such as those with positive thyroid-stimulating hormone receptor antibodies (pTRAb+).
Main Methods:
- A two-stage refined genetic study involving 8,171 GD patients and 7,906 controls.
- Genome-wide association study (GWAS) analysis to identify GD-associated SNPs.
- Analysis of cis-expression quantitative trait locus (cis-eQTL) databases and quantitative reverse transcription PCR (qRT-PCR) to assess gene transcription influence.
Main Results:
- Rs1883832 was identified as the most significantly associated SNP with Graves' disease in the studied population (P=9.17×10⁻¹¹, OR=1.18).
- The rs1883832 genotype was found to influence CD40 gene transcription.
- Rs1883832 was confirmed as a susceptibility locus specifically for patients with positive thyroid-stimulating hormone receptor antibodies (pTRAb+) GD.
Conclusions:
- The study provides strong evidence that rs1883832 regulates CD40 gene expression.
- This SNP affects serum TRAb levels, thereby contributing to the pathogenesis of Graves' disease.
- Rs1883832 represents a key genetic factor in the development of GD, particularly in pTRAb+ individuals.
Abstract:
Mutations in CD40 have been widely reported to be risk factors for Graves' disease (GD). The gene, along with its cognate ligand CD40L, may regulate pro-inflammatory and immune responses. Rs1883832, located at the -1 position of the Kozak sequence, is the most well-studied single nucleotide polymorphism (SNP) of CD40, and has been confirmed to predispose those with the alteration to GD, regardless of ethnicity. Our genome-wide association study (GWAS) indicated that several SNPs, including rs1883832 located within the vicinity of CD40 were associated with GD in the Han Chinese population. Aiming at identifying the most consequential SNP and its underlying pathogenic mechanism, we performed a two-stage refined study on 8,171 patients with GD and 7,906 controls, and found rs1883832 was the most significantly GD-associated SNP in the CD40 gene region (PCombined = 9.17×10-11, OR = 1.18). Through searching the cis-expression quantitative trait locus database and using quantitative RT-PCR, we further discovered that the rs1883832 genotype can influence CD40 gene transcription. Furthermore, we demonstrated that rs1883832 is a susceptibility locus for pTRAb+ GD patients. In conclusion, the current study provides robust evidence that rs1883832 can regulate CD40 gene expression and affect serum TRAb levels, which ultimately contributes to the development of GD.
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