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

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 European-ancestry 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 sex-matched 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.

• Authors: 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 Melander, Thomas Karlsson, Ulf de Faire, Kenneth Caidahl, Gunnar Engström, Lars Lind, Mikael C I Karlsson, Nancy L Pedersen, Johan Frostegård, Patrik K E Magnusson
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 27 Issue 10 Pg. 1809-1818 (05 15 2018) ISSN: 1460-2083 [Electronic] England
• PMID: 29547969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Core Binding Factor Alpha 3 Subunit
• Epitopes
• Immunoglobulin M
• Lipoproteins, LDL
• Runx3 protein, human
• oxidized low density lipoprotein
• Phosphorylcholine

Topics

• Adult
• Aged
• Antibodies (blood, genetics)
• Apoptosis (genetics)
• Core Binding Factor Alpha 3 Subunit (genetics)
• Epitopes (blood, genetics, immunology)
• Female
• Genome-Wide Association Study
• Haplotypes
• Humans
• Immunoglobulin M (blood, genetics, immunology)
• Leukemia, Lymphocytic, Chronic, B-Cell (blood, genetics, immunology)
• Lipoproteins, LDL (blood, genetics, immunology)
• Macrophages (immunology)
• Male
• Middle Aged
• Phosphorylcholine (blood, immunology)
• Polymorphism, Single Nucleotide (genetics)