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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Xu Chen
  • Stefan Gustafsson
  • Thomas Whitington
  • 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
  • Thomas Karlsson
  • Ulf de Faire
  • Kenneth Caidahl
  • Lars Lind
  • Mikael C.I. Karlsson
  • Nancy L. Pedersen
  • Johan Frostegård
  • Patrik K.E. Magnusson
Organisations
External organisations
  • Karolinska Institutet
  • Uppsala University
  • University of Gothenburg
  • QIMR Berghofer Medical Research Institute
  • Södersjukhuset
  • Mayo Clinic Minnesota
  • Stanford University
  • Wellcome Trust Centre for Human Genetics
  • Broad Institute
  • University of Liverpool
  • Sahlgrenska Academy
  • Karolinska University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)1809-1818
Number of pages10
JournalHuman Molecular Genetics
Volume27
Issue number10
Publication statusPublished - 2018 May 15
Publication categoryResearch
Peer-reviewedYes