The association of CD40 polymorphisms with CD40 serum levels and risk of systemic lupus erythematosus

Abstract

BackgroundCurrent evidence shows that the CD40–CD40 ligand (CD40–CD40L) system plays a crucial role in the development, progression and outcome of systemic lupus erythematosus (SLE). The aim of this study was to investigate whether a CD40 gene single nucleotide polymorphism (SNP) is associated with SLE and CD40 expression in the Chinese population. We included controls (n = 220) and patients with either SLE (n =205) in the study.MethodsThe gene polymorphism was measured using Snapshot SNP genotyping assays and confirmed by sequencing. We analyzed three single nucleotide polymorphisms of CD40 gene rs1883832C/T, rs1569723A/C and rs4810485G/T in 205 patients with SLE and 220 age-and sex-matched controls. Soluble CD40 (sCD40) levels were measured by ELISA.ResultsThere were significant differences in the genotype and allele frequencies of CD40 gene rs1883832C/T polymorphism between the group of patients with SLE and the control group (P < 0.05). sCD40 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the CD40 rs1883832 C/T variant allele were associated with increased CD40 levels compared to the homozygous wild-type genotype in patients with SLE. The rs1883832C/T polymorphism of CD40 and its sCD40 levels were associated with SLE in the Chinese population.ConclusionsOur results suggest that CD40 gene may play a role in the development of SLE in the Chinese population.

CD40 functional gene polymorphisms and mRNA expression in rheumatoid arthritis patients from western Mexico

“…For instance, Field et al (2015) found the minor T allele to be associated with reduced CD40 expression in APCs, related to an increased proportion of the short mRNA isoform encoding the secreted form of CD40. This is consistent with the work of Chen et al (2015), who observed elevated levels of soluble CD40 in SLE patients carrying the T allele. On the other hand, Jacobson et al (2005) showed that the rs1883832 SNP does not affect transcription, but can influence translation efficiency.…”

“…The CD40 SNPs rs1883832 and rs4810485 have been identified as susceptibility markers for this and other autoimmune diseases, such as GD (Tomer et al, 2002;Kim et al, 2003;Li et al, 2012), MS (Blanco-Kelly et al, 2010;Sokolova et al, 2013), and SLE (Vazgiourakis et al, 2011;Chen et al, 2015;Lee et al, 2015). In addition, several studies suggest that these polymorphisms affect CD40 expression at the mRNA and protein level (Jacobson et al, 2005;Vazgiourakis et al, 2011;Field et al, 2015;Wagner et al, 2015).…”

“…The former is located at position -1 in the Kozak sequence, and it has been proposed that the major allele of this SNP enhances the efficiency of CD40 mRNA translation, resulting in up to 32% more CD40 protein (Jacobson et al, 2005). Moreover, some studies have reported that the minor T allele is associated to decreased CD40 mRNA and increased soluble CD40 levels (Chen et al, 2015;Field et al, 2015;Wagner et al, 2015). Although the T allele of rs1883832 has been associated with increased susceptibility to MS and SLE among Russian and Chinese individuals, respectively (Sokolova et al, 2013;Chen et al, 2015), it has also been reported to have a protective effect for RA in the Spanish population (García-Bermúdez et al, 2012).…”

“…Moreover, some studies have reported that the minor T allele is associated to decreased CD40 mRNA and increased soluble CD40 levels (Chen et al, 2015;Field et al, 2015;Wagner et al, 2015). Although the T allele of rs1883832 has been associated with increased susceptibility to MS and SLE among Russian and Chinese individuals, respectively (Sokolova et al, 2013;Chen et al, 2015), it has also been reported to have a protective effect for RA in the Spanish population (García-Bermúdez et al, 2012). Meanwhile, rs4810485, located in the second intron of CD40, is thought to affect CD40 mRNA and protein expression in B cells and monocytes (Vazgiourakis et al, 2011).…”

B cells from African American lupus patients exhibit an activated phenotype

“…In mice, B cells lacking A20 had an increase response to activation with different stimuli, including anti-CD40 (43). Polymorphisms in the CD40 locus in Chinese, Turkish, and Greek populations have been linked to SLE (44,45), but it is unknown if these SNPs confer any altered risk of SLE to African American individuals. In fact, we could not find any evidence in our cohort of an intrinsic propensity of B cells from African American patients to respond differently to CD40L stimulation.…”