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. 2017 Jul;28(7):2158-2166.
doi: 10.1681/ASN.2016091043. Epub 2017 Feb 16.

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Daniel P Gale  1 , Karen Molyneux  2 , David Wimbury  2 , Patricia Higgins  2 , Adam P Levine  3 , Ben Caplin  4 , Anna Ferlin  4 , Peiran Yin  5 , Christopher P Nelson  6 , Horia Stanescu  4 , Nilesh J Samani  6 , Robert Kleta  4 , Xueqing Yu  5 , Jonathan Barratt  2
Affiliations

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Daniel P Gale et al. J Am Soc Nephrol. 2017 Jul.

Abstract

IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h2), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the C1GALT1 gene that strongly associated with Gd-IgA1 level (β=0.26; P=2.35×10-9). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK (P<1.00×10-6) and 622 controls with normal kidney function from the UK (P<1.00×10-10), and in a candidate gene study of 704 Chinese patients with IgAN (P<1.00×10-5). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. C1GALT1 encodes a galactosyltransferase enzyme that is important in O-galactosylation of glycoproteins. These findings demonstrate that common variation at C1GALT1 influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 O-glycosylation may vary between white and Chinese patients with IgAN.

Keywords: Genome Wide Association Study; IgA; IgA nephropathy; SNP; glomerulonephritis; human genetics.

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Figures

Figure 1.
Figure 1.
Gd-IgA1 levels were higher in 379 patients with IgAN compared with 638 healthy control subjects (P<0.0001). Levels were higher in 154 patients with progressive IgAN (defined as doubling of serum creatinine or ESRD) compared with 123 patients with IgAN in whom good renal function remained stable over >5 years (P=0.0011). Gd-IgA1 levels were not significantly elevated in 308 patients with Membranous Nephropathy (MN controls). AU, arbitrary units of optical absorbance.
Figure 2.
Figure 2.
Heritability (h2) of Gd-IgA1 in UK whites is 0.387. This was estimated using 134 complete trios by plotting Gd-IgA1 of patients against their mean parental Gd-IgA1. Values plotted are Gd-IgA1 levels in arbitrary units of optical absorbance standardized to mean of 0 and SD of 1 to allow narrow sense heritability estimation by calculation of the slope.
Figure 3.
Figure 3.
GWAS of Gd-IgA1 levels in 513 unrelated UK individuals showing association with alleles at a single locus on Chromosome 7. Manhattan plot (left panel) showing significance of the association of each SNP allele with Gd-IgA1 level by plotting the negative logarithm to the base 10 of the P value against the genomic position. Horizontal line indicates conventional genome-wide significance (P=5×10−8). Quantile-quantile plot (right panel) is a plot of the observed −log10(P) against the −log10(P) values that would be expected under the null hypothesis of no association. Deviation above the y=x line indicates lower P values than would be expected to occur by chance and implies statistically significant association. The genomic inflation factor was 1.00196.
Figure 4.
Figure 4.
Gd-IgA1 levels were elevated in 704 Han Chinese patients with IgAN compared with 111 healthy Chinese subjects (P=0.015). Levels in both Chinese groups were significantly lower than those in UK healthy subjects and UK patients with IgAN (P<0.0001 for both). Ten percent of Chinese and 24% of UK subjects with IgAN exhibited Gd-IgA1 levels above the 95th percentile of their respective control populations. AU, arbitrary units of optical absorbance.
Figure 5.
Figure 5.
Gd-IgA1 levels increase with copies of the H1 haplotype in Chinese and white populations. In the combined IgA and MN (white) cohort (left panel) haplotype frequency was 0.32 (n=821, R2=0.033, P<0.0001). In Chinese patients with IgAN (right panel) haplotype frequency was 0.04 (n=704, R2=0.019, P<0.001). In multiple regression analysis, Chinese ethnicity was associated with lower Gd-IgA1 levels than in whites, even correcting for haplotype frequency and disease status (P<0.0001). AU, arbitrary units of optical absorbance.
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