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Abstract: SA-PO564

Genome-Wide Association Study (GWAS) Uncovers Novel Mechanisms and Potential Therapeutic Targets for IgA Vasculitis

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Liu, Lili, Columbia University Irving Medical Center, New York, New York, United States
  • Zhu, Li, Peking University First Hospital, Beijing, Beijing, China
  • Monteiro-Martins, Sara, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Zanoni, Francesca, Columbia University Irving Medical Center, New York, New York, United States
  • Lugani, Francesca, The Giannina Gaslini Children's Hospital, Genova, Italy
  • Mucha, Krzysztof, Warsaw University Medical Center, Warsaw, Poland
  • Mizerska-wasiak, Malgorzata, Warsaw University Medical Center, Warsaw, Poland
  • Berthelot, Laureline, INSERM, Paris, Île-de-France, France
  • Novak, Jan, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Wyatt, Robert J., The University of Memphis, Memphis, Tennessee, United States
  • Nelson, Raoul D., University of Utah Health, Salt Lake City, Utah, United States
  • Kottgen, Anna, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
  • Zhang, Hong, Peking University First Hospital, Beijing, Beijing, China
  • Kiryluk, Krzysztof, Columbia University Irving Medical Center, New York, New York, United States
Background

IgA vasculitis (IgAV) is an immune complex-mediated leukocytoclastic vasculitis characterized by vascular deposition of IgA-containing immune complexes in the skin, gastrointestinal and glomerular capillaries. The exact pathogenic mechanisms of IgAV remain unclear and thus there are presently no targeted treatments.

Methods

We conducted a GWAS for IgAV in 8,098 individuals of European and East Asian ancestries including 2,170 IgAV cases and 5,928 controls. We performed meta-analysis with dense imputation and fine-mapping of significant loci, followed by proteome-wide association studies (PWAS) and transcriptome-wide association studies. Whole blood RNA-seq data from 255 IgAV cases with matched genotype data were used for genome-wide expression QTL (eQTL) mapping. By integrative analysis of genetic and transcriptomic data, we investigated the consequences of IgAV risk alleles on gene function and regulation.

Results

In GWAS, we detected 3 genome-wide significant loci for IgAV. We confirmed a strong effect of the HLA locus (OR=1.55, P= 1.1x10-25) and we identified two novel non-HLA loci at chr.19q13.42 (OR=1.51, P=1.0x10-20) and chr.2q37.1 (OR=1.34, P= 2.2x10-09) loci. The HLA fine-mapping identified HLA-DRB1 as the most likely culprit gene, with amino-acid position 11 conveying the greatest risk. The chr.19q13.42 locus colocalized with the eQTL for FCAR (PP4=0.95), encoding the Fc α IgA receptor (CD89), with the risk allele being associated with increased FCAR expression in myeloid cells (Pfdr-adjusted =1.6x10-09). Blood mRNA levels of FCAR in IgAV patients were 1.5-fold higher vs. controls (P=5.1x10-09). Four upstream regulators for FCAR differentially activated in IgAV cases vs. controls were identified using ARACNe3-based master regulator analysis. By PWAS, we additionally identified a distinct proteome-wide significant signal at the 1q21.3 locus that was suggestive in GWAS, and for which the risk allele was associated with increased blood levels of soluble IL6R.

Conclusion

Our genetic findings implicate roles for CD89 and IL6R in the pathogenesis of IgAV and nominate these genes and related pathways for future therapeutic targeting.