A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relation to chronic lymphocytic leukemia.
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 KE., Slager SL., Ingelsson E., Lindgren CM., Morris AP., Melander O., Karlsson T., de Faire U., Caidahl K., Engström G., Lind L., Karlsson MCI., Pedersen NL., Frostegård J., Magnusson PKE.
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 (GWAS) in four European-ancestry cohorts, six 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 beta=0.19, 95% CI 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 based on 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 (RUNX3), 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 relation 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.