IgA nephropathy (IgAN [MIM 161950]) is a common form of primary glomerulonephritis characterised by diffuse glomerular mesangial IgA1 deposition that leads to mesangial proliferation and chronic glomerular inflammation. Analysis of serum IgA1 from IgAN patients revealed an abnormally galactosylation of the O-linked carbohydrate moieties of IgA.
It may be hypothesised that the abnormal glycosylation of the hinge region glycans could result from a reduced quantity or enzymatic activity of the Core1 beta 1,3- Galactosyltransferase. Recently, C1GALT1 gene coding for this molecule has been characterised.
In order to evaluate the association between C1GALT1 and IgAN, we performed a case control study among the Italian population. We sequenced C1GALT1 coding and promoter regions in 196 IgAN patients and 234 healthy controls. We identified 8 single nucleotide polymorphisms (SNPs) two of which were never described: 5 were in the promoter region (-796T/C, -784G/T, -511G/A, -392G/T, -353insC) and 3 in the 3’UTR (1365G/A, 1484T/A, 1513T/A).
Comparing allelic frequencies of C1GALT1 SNPs between patients and controls, we evidenced that allele 1365G in 3’UTR was significantly more frequent in IgAN patients than in healthy controls (Chi-square =14.68, p = 0.0001, pc = 0.008, odds ratio 2.47 [95% CI: 1.54-3.97]).
For the linkage disequilibrium analysis, and in order to calculate the haplotype frequencies, we processed genotypes data with Genotype Transposer and Arlequin softwares.
The promoter CGATW haplotype was significantly less frequent in IgAN patients than in healthy controls (Chi-square =6.76, p = 0.009, pc = 0.05 odds ratio 0.564 [95% CI: 0.365-0.872]).
The genotype 1365G/G confers susceptibility to IgAN (Chi-square =12.26, p = 0.0005, pc= 0.004, odds ratio 2.51 [95% CI: 1.48-4.24]) but it is not associated with the progression of the disease. The role of this SNP in the pathogenesis of IgAN has been investigated by Real-time quantitative PCR experiments that have shown reduced expression of C1GALT1 in homozygous 1365 G/G (mean ratio +/-SD: 1,4+/1,46) individuals in respect to those with other genotypes (mean ratio +/- SD: 2,96+/-2,5; unpaired t test p value =0.0295).
The results of this study suggest that C1GALT1 plays a possible role as a pathogenetic factor for IgAN.