HSP was considered as a polygenic and multifactorial disorder. There were extensive evidences suggested the genetic components were involved in the susceptibility and progression of HSP. The pathogenesis of HSP was still unclear, as far as we knew. Recently, more and more evidences suggested that deficient β1,3 galactosylation of hinge region of IgA1 molecule played an important role in the pathogenesis of HSP [11
]. The galactosylation of GalNAcα1-R in hinge region of IgA1 molecule depended on the activity of C1GALT1 gene and C1GALT1C1 gene [13
]. Furthermore, diseases resulted from deficiency of β1,3 galactose, such as Tn syndrome, weren't a result of decreased expression of C1GALT1 gene, but resulted from the mutations of C1GALT1C1 gene [6
]. These results suggested that it was rather the variants of C1GALT1C1 gene in influencing the galactosylation of IgA1 hinge-region than the variants of C1GALT1 gene. It implies that the variants of C1GALT1C1 gene could contribute to susceptibility of HSP by influencing β1,3 galactosylation of IgA1 molecule. One previous study revealed that there was only one SNP, c.393T>A (rs17261572), in coding region of C1GALT1C1 [14
]. It was a nonsynonymous SNP. The MAF of c.393T>A was only 0.069. A previous study revealed that the mutations in C1GALT1C1 gene were not important for the European IgAN patients [15
]. We performed this study to investigate whether the mutations (including somatic mutation) in the promoter region of C1GALT1C1 important in the pathogenesis of HSP in China.
We firstly screened the polymorphisms of C1GALT1C1 gene. Three SNPs with high minor allele frequency (MAF) were identified, including rs5957424, rs3810744, and rs17261572. Therefore, association between these SNPs and HSP risk was explored in a case-control association study in a large population sampled from the Northern Chinese. The association analysis revealed that there was significant difference of the alleles (rs17261572) between the controls and the HSP patients. These results suggested that polymorphisms of C1GALT1C1 gene might be related to the susceptibility of HSP.
In present study, we further analyzed the association between the SNP of C1GALT1C1 gene and clinical parameters of HSP. The results revealed that there was no significant difference of blood pressure, proteinuria, and renal function among the HSP patients with different genotypes. These data suggested that the genotypes of the C1GALT1C1 gene did not influence the clinical manifestations of HSP.
In previous studies of Tn syndrome, three somatic mutations of C1GALT1C1 gene were identified in two patients. The three somatic mutations, c.202C>T, c.393T>A and c.454G>A, were all in the coding region of C1GALT1C1 [6
]. Except the c.393T>A mutation, both of the other two somatic mutations could impressively inhibit chaperone activity and lead to inactivation of C1β3Gal-T, and the expression of autoimmune Tn antigen on blood cells of all lineages [6
]. Galactosylation deficiency was already proved in patients with HSP. Therefore, we tested whether somatic mutations exist in C1GALT1C1 gene in patient with HSP.
We performed a somatic mutation screening in the patients with HSP. DNAs from B lymphocytes
where IgA molecule was produced were isolated from 20 individuals. And then the coding region of C1GALT1C1 gene was amplified, cloned and sequenced. Except the c.393T>A, no other mutations were detected. The mutation, c.393T>A, was only found in the patients whose mutations were demonstrated in genomic DNA by routinely sequencing. Furthermore, c.393T>A was proved not to be a somatic mutation in these HSP patients. The result indicated that the variation of coding region of C1GALT1C1 gene might be of little importance in the processing of aberrant glycosylation
of IgA1 molecule in patients with HSP. Mutations in other regions of C1GALT1C1 gene, which may influence the glycosylation process of IgA1 molecule, were needed to be clarified in patients with HSP. In fact, in a recent study, Malycha et al. [15
] detected mutations in whole blood DNA and in B cell DNA separately in a relative small European sample. They didn't found any important mutations of C1GALT1C1 gene in patients with IgAN. These results suggested that the C1GALT1C1 gene might influence the susceptibility to HSP by pathways other than mutation.
Our results suggested that the SNP rs17261572 was significantly associated with the risk of HSP, while the mutation (including somatic mutation) of C1GALT1C1 gene did not significantly contribute to the genetic susceptibility or clinical manifestations of HSP in Chinese population. Further studies are warranted to investigate into the mechanism of the association, which may shed light on the etiology of HSP.
This study was supported by Heilongjiang Provincial Health Research Project (No. 2013180) and the National Natural & Science Foundation of China (No. 81202263).