siRNA knock-down of C1GALT1, COSMC and COSMC+C1GALT1 in IgA1-secreting cell lines increases Gd-IgA1 production.

<p><b>(a)</b> knock-down in IgA1-secreting cell lines from healthy controls; mock-control (n = 5), non-targeting siRNA (n = 7), C1GALT1 siRNA (n = 5), COSMC siRNA (n = 7), and COSMC+C1GALT1 siRNA (n = 2); <b>(b)</b> knock-down in IgA1-secreting cell lines from IgAN patients; mock-control (n = 5), non-targeting siRNA (n = 7), C1GALT1 (n = 5), COSMC siRNA (n = 7), and COSMC+C1GALT1 siRNA (n = 2); <b>(c)</b> relative change in mRNA in IgA1-secreting cell lines after siRNA knock-down of C1GALT1 (n = 5), COSMC (n = 7), and COSMC+C1GALT1 (n = 2) compared to non-targeting siRNA control.</p

Combined results for new significant and suggestive GWAS signals: serum Gd-IgA1 levels were determined using HAA lectin-based ELISA, normalized and adjusted for age, case-control status and serum total IgA levels.

<p>Combined results for new significant and suggestive GWAS signals: serum Gd-IgA1 levels were determined using HAA lectin-based ELISA, normalized and adjusted for age, case-control status and serum total IgA levels.</p

Genotypic effects and worldwide allelic frequency distribution for the two top genome-wide significant loci.

<p><b>(a)</b> Mean trait values (+/- standard errors) by rs13226913 genotype at the <i>C1GALT1</i> locus. (<b>b</b>) The distribution of rs13226913 alleles across the Human Genome Diversity Panel (HGDP) populations. <b>(c)</b> Mean trait values (+/- standard errors) by rs5910940 genotype at the <i>C1GALT1C1</i> locus. <b>(d)</b> The distribution of rs5910940 alleles across HGDP populations. The allelic distribution plots were modified from the HGDP Selection Browser. The trait values were expressed as standard normal residuals of log-transformed serum Gd-IgA1 levels after adjustment for age, serum total IgA levels, case-control status and cohort membership.</p

Study cohorts after implementation of all quality control filters: the final counts of cases and controls by cohort are provided.

<p>Study cohorts after implementation of all quality control filters: the final counts of cases and controls by cohort are provided.</p

Longitudinal measurements of serum immunoglobulin levels and Gd-IgA1 levels over 4 years of follow-up.

<p>Initial and 4-year follow-up levels of <b>(a)</b> serum total IgG, <b>(b)</b> serum total IgA, and <b>(c)</b> serum Gd-IgA1 normalized for serum total IgA. Panels <b>(d, e, f)</b> represent scatter plots of initial (x-axis) versus follow-up (y-axis) values. P-values correspond to the Pearson’s test of correlation; r²: squared correlation coefficient.</p

The best predictive model for IgAN based on all the genotyped SNPs and their pairwise interaction terms.

<p>This model represents the solution of a stepwise logistic regression algorithm (BIC-based stepwise model selection). The coefficients from this model are used to refine the risk score for IgAN.</p

Conditional analysis of the <i>HLA-DQB1, HLA-DQA1, HLA-DRB1</i> locus.

<p>Conditional analysis of the <i>HLA-DQB1, HLA-DQA1, HLA-DRB1</i> locus.</p

Replication Study Results and Combined Meta-Analysis.

<p>Combined association results for 12 SNPs representing 5 independent regions that reached genome-wide significance in the original GWAS. The combined effect estimates (per allele odds ratios) in the replication cohorts were all direction-consistent with the ones in the original GWAS cohorts. Significant heterogeneity was noted only for the second HLA locus represented by rs9357155 and rs2071543.</p><p>Q-test: P-value for the Cochrane's Q statistic for heterogeneity, NS: heterogeneity test not significant,</p>*<p>heterogeneity P<0.05,</p>**<p>heterogeneity P<0.01;</p><p>I²: Heterogeneity Index (0–100%), where <25% corresponds to low, 50%–75% to medium, and >75% to high level of heterogeneity;</p><p>OR: Additive (per-allele) Odds Ratio;</p>#<p>Han and Eskin random effects model.</p

Multiplicative interaction between Chr. 22q12 (rs2412971) and Chr. 1q32 (rs6677604) loci.

<p>The allelic effects of rs2412971-A by genotype class of rs9275596 (top signal in the HLA, no interaction) and rs6677604 (top signal in at <i>CFHR1/R3</i> locus on Chr. 1q32, significant interaction). The protective effect of rs2412971-A allele is reversed in homozygotes for the rs6677604-A allele, which tags a deletion in <i>CFHR3/R1</i>. The allelic effects are expressed on the log-odds scale and correspond to beta coefficients of the logistic regression model. Error bars correspond to 95% confidence intervals.</p

Genetic risk and IgAN–attributable ESRD among major US ethnicities.

<p>The relationship between IgAN risk scores (red line) and IgAN incidence and prevalence (bars) among US ethnicities are shown. The following metrics of IgAN occurrence are depicted: (panel a) the incidence of ESRD due to IgAN per million population by ethnicity, (panel b) the prevalence of ESRD due to IgAN per million population by ethnicity, (panel c) percent of IgAN among the total ESRD population by ethnicity; and (panel d) percent of IgAN among ESRD due to glomerular disease by ethnicity.</p