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

Journal article
Authors X. Chen
S. Gustafsson
T. Whitington
Y. Borne
Erik Lorentzen
J. Sun
P. Almgren
J. Su
R. Karlsson
J. Song
Y. Lu
Y. Zhan
S. Hagg
P. Svensson
K. E. Smedby
S. L. Slager
E. Ingelsson
C. M. Lindgren
A. P. Morris
O. Melander
Thomas Karlsson
U. de Faire
Kenneth Caidahl
G. Engstrom
L. Lind
M. C. I. Karlsson
N. L. Pedersen
J. Frostegard
P. K. E. Magnusson
Published in Human Molecular Genetics
Volume 27
Issue 10
Pages 1809-1818
ISSN 0964-6906
Publication year 2018
Published at Core Facilities, Bioinformatics
Institute of Medicine, Department of Molecular and Clinical Medicine
Institute of Medicine, Department of Public Health and Community Medicine, Health Metrics
Pages 1809-1818
Language en
Links https://doi.org/10.1093/hmg/ddy094
Subject categories Molecular medicine, Molecular medicine (genetics and pathology)

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 beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 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 x 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.

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