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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A,POB 281, SE-17177 Stockholm, Sweden.ORCID iD: 0000-0002-7299-3238
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-5894-0351
Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A,POB 281, SE-17177 Stockholm, Sweden.
Lund Univ, Dept Clin Sci, Malmo, Sweden.
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 10, p. 1809-1818Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 27, no 10, p. 1809-1818
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-356866DOI: 10.1093/hmg/ddy094ISI: 000431886200012PubMedID: 29547969OAI: oai:DiVA.org:uu-356866DiVA, id: diva2:1239008
Funder
Swedish Research Council, 2017-00641Swedish Heart Lung Foundation, 20070481Available from: 2018-08-15 Created: 2018-08-15 Last updated: 2018-08-15Bibliographically approved

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Chen, XuGustafsson, StefanIngelsson, ErikLind, LarsMagnusson, Patrik K. E.
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