Abstract
We analyzed the mechanism by which a Graves' disease-associated C/T polymorphism in the Kozak sequence of CD40 affects CD40 expression. CD40 expression levels on B cells in individuals with CT and TT genotypes were decreased by 13.3 and 39.4%, respectively, compared with the levels in CC genotypes (P = 0.012). Similarly, Rat-2 fibroblasts transfected with T-allele cDNA expressed 32.2% less CD40 compared with their C-allele-transfected counterparts (P = 0.004). Additionally, an in vitro transcription/translation system showed that the T-allele makes 15.5% less CD40 than the C-allele (P <0.001), demonstrating that the effect of the single-nucleotide polymorphism (SNP) on CD40 expression is at the level of translation. However, the SNP did not affect transcription, because the mRNA levels of CD40, as measured by quantitative RT-PCR, were independent of genotype. Therefore, our results may suggest that the C allele of the CD40 Kozak SNP, which is associated with Graves' disease, could predispose to disease by increasing the efficiency of translation of CD40 mRNA.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2684-2691 |
| Number of pages | 8 |
| Journal | Endocrinology |
| Volume | 146 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2005 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Endocrinology
- Endocrinology, Diabetes and Metabolism
Cite this
A graves' disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation : A case for translational pathophysiology. / Jacobson, Eric M.; Concepcion, Erlinda; Oashi, Taiji; Tomer, Yaron.
In: Endocrinology, Vol. 146, No. 6, 06.2005, p. 2684-2691.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A graves' disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation
T2 - A case for translational pathophysiology
AU - Jacobson, Eric M.
AU - Concepcion, Erlinda
AU - Oashi, Taiji
AU - Tomer, Yaron
PY - 2005/6
Y1 - 2005/6
N2 - We analyzed the mechanism by which a Graves' disease-associated C/T polymorphism in the Kozak sequence of CD40 affects CD40 expression. CD40 expression levels on B cells in individuals with CT and TT genotypes were decreased by 13.3 and 39.4%, respectively, compared with the levels in CC genotypes (P = 0.012). Similarly, Rat-2 fibroblasts transfected with T-allele cDNA expressed 32.2% less CD40 compared with their C-allele-transfected counterparts (P = 0.004). Additionally, an in vitro transcription/translation system showed that the T-allele makes 15.5% less CD40 than the C-allele (P <0.001), demonstrating that the effect of the single-nucleotide polymorphism (SNP) on CD40 expression is at the level of translation. However, the SNP did not affect transcription, because the mRNA levels of CD40, as measured by quantitative RT-PCR, were independent of genotype. Therefore, our results may suggest that the C allele of the CD40 Kozak SNP, which is associated with Graves' disease, could predispose to disease by increasing the efficiency of translation of CD40 mRNA.
AB - We analyzed the mechanism by which a Graves' disease-associated C/T polymorphism in the Kozak sequence of CD40 affects CD40 expression. CD40 expression levels on B cells in individuals with CT and TT genotypes were decreased by 13.3 and 39.4%, respectively, compared with the levels in CC genotypes (P = 0.012). Similarly, Rat-2 fibroblasts transfected with T-allele cDNA expressed 32.2% less CD40 compared with their C-allele-transfected counterparts (P = 0.004). Additionally, an in vitro transcription/translation system showed that the T-allele makes 15.5% less CD40 than the C-allele (P <0.001), demonstrating that the effect of the single-nucleotide polymorphism (SNP) on CD40 expression is at the level of translation. However, the SNP did not affect transcription, because the mRNA levels of CD40, as measured by quantitative RT-PCR, were independent of genotype. Therefore, our results may suggest that the C allele of the CD40 Kozak SNP, which is associated with Graves' disease, could predispose to disease by increasing the efficiency of translation of CD40 mRNA.
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UR - http://www.scopus.com/inward/citedby.url?scp=18844421908&partnerID=8YFLogxK
U2 - 10.1210/en.2004-1617
DO - 10.1210/en.2004-1617
M3 - Article
C2 - 15731360
AN - SCOPUS:18844421908
VL - 146
SP - 2684
EP - 2691
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 6
ER -