A genome-wide association study of IgM antibody against phosphorylcholine: Shared genetics and phenotypic relationship to chronic lymphocytic leukemia

Xu Chen, Stefan Gustafsson, Thomas Whitington, Yan Borné, Erik Lorentzen, Jitong Sun, Peter Almgren, Jun Su, Robert Karlsson, Jie Song, Yi Lu, Yiqiang Zhan, Sara Hägg, Per Svensson, Karin E. Smedby, Susan L. Slager, Erik Ingelsson, Cecilia M. Lindgren, Andrew P. Morris, Olle MelanderThomas Karlsson, Ulf de Faire, Kenneth Caidahl, Gunnar Engström, Lars Lind, Mikael C.I. Karlsson, Nancy L. Pedersen, Johan Frostegård, Patrik K.E. Magnusson

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four Europeanancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined β=0.19, 95% confidence interval 0.13-0.24, P=4.3×10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P=1.2×10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sexmatched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.

Original languageEnglish (US)
Pages (from-to)1809-1818
Number of pages10
JournalHuman molecular genetics
Volume27
Issue number10
DOIs
StatePublished - May 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'A genome-wide association study of IgM antibody against phosphorylcholine: Shared genetics and phenotypic relationship to chronic lymphocytic leukemia'. Together they form a unique fingerprint.

  • Cite this

    Chen, X., Gustafsson, S., Whitington, T., Borné, Y., Lorentzen, E., Sun, J., Almgren, P., Su, J., Karlsson, R., Song, J., Lu, Y., Zhan, Y., Hägg, S., Svensson, P., Smedby, K. E., Slager, S. L., Ingelsson, E., Lindgren, C. M., Morris, A. P., ... Magnusson, P. K. E. (2018). A genome-wide association study of IgM antibody against phosphorylcholine: Shared genetics and phenotypic relationship to chronic lymphocytic leukemia. Human molecular genetics, 27(10), 1809-1818. https://doi.org/10.1093/hmg/ddy094