Chen, Xu, Gustafsson, Stefan, Whitington, Thomas, Borne, Yan, Lorentzen, Erik, Sun, Jitong, Almgren, Peter, Su, Jun, Karlsson, Robert, Song, Jie et al (show 19 more authors)
(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).
pp. 1809-1818.
ISSN 0964-6906, 1460-2083
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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.
Item Type: | Article |
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Uncontrolled Keywords: | Macrophages, Humans, Phosphorylcholine, Lipoproteins, LDL, Immunoglobulin M, Antibodies, Epitopes, Apoptosis, Haplotypes, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Core Binding Factor Alpha 3 Subunit, Leukemia, Lymphocytic, Chronic, B-Cell, Genome-Wide Association Study |
Depositing User: | Symplectic Admin |
Date Deposited: | 23 Mar 2018 11:28 |
Last Modified: | 07 Dec 2024 09:09 |
DOI: | 10.1093/hmg/ddy094 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3019381 |