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

Chen, Xu; Gustafsson, Stefan; Whitington, Thomas; Borné, Yan LU ; Lorentzen, Erik; Sun, Jitong; Almgren, Peter LU ; Su, Jun; Karlsson, Robert and Song, Jie, et al. (2018) In Human Molecular Genetics 27(10). p.1809-1818
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 Europeanancestry 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... (More)

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 Europeanancestry 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 sexmatched 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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Human Molecular Genetics
volume
27
issue
10
pages
10 pages
publisher
Oxford University Press
external identifiers
  • scopus:85047020596
ISSN
0964-6906
DOI
10.1093/hmg/ddy094
language
English
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yes
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6dc51f50-27d7-4c98-b6b9-8a125299b794
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2018-05-29 16:14:59
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2019-03-10 04:47:28
@article{6dc51f50-27d7-4c98-b6b9-8a125299b794,
  abstract     = {<p>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 Europeanancestry 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<sup>-11</sup>). 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<sup>-15</sup>). 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 sexmatched 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.</p>},
  author       = {Chen, Xu and Gustafsson, Stefan and Whitington, Thomas and Borné, Yan and Lorentzen, Erik and Sun, Jitong and Almgren, Peter and Su, Jun and Karlsson, Robert and Song, Jie and Lu, Yi and Zhan, Yiqiang and Hägg, Sara and Svensson, Per and Smedby, Karin E. and Slager, Susan L. and Ingelsson, Erik and Lindgren, Cecilia M. and Morris, Andrew P. and Melander, Olle and Karlsson, Thomas and de Faire, Ulf and Caidahl, Kenneth and Engström, Gunnar and Lind, Lars and Karlsson, Mikael C.I. and Pedersen, Nancy L. and Frostegård, Johan and Magnusson, Patrik K.E.},
  issn         = {0964-6906},
  language     = {eng},
  month        = {05},
  number       = {10},
  pages        = {1809--1818},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {A genome-wide association study of IgM antibody against phosphorylcholine : Shared genetics and phenotypic relationship to chronic lymphocytic leukemia},
  url          = {http://dx.doi.org/10.1093/hmg/ddy094},
  volume       = {27},
  year         = {2018},
}