Polyclonal human antibodies against glycans bearing red meat-derived non-human sialic acid N-glycolylneuraminic acid are stable, reproducible, complex and vary between individuals: Total antibody levels are associated with colorectal cancer risk
Samraj AN, Bertrand KA, Luben R, Khedri Z, Yu H, Nguyen D, Gregg CJ, Diaz SL, Sawyer S, Chen X, Eliassen H, Padler-Karavani V, Wu K, Khaw KT, Willett W, Varki A
PloS one · 45 citations
Review labels
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How it was studied
- Design
- Case-control study (classified by our AI screen)
- Studied in
- People
- Main outcome
- Clinical events such as disease or death
- Intake measured by
- Not stated
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Cancer Research UK
- Government
- National Institute for Health and Care Research
- Government
- National Institutes of Health
- Government
- Medical Research Council
- Government
- National Cancer Institute
- Government
- National Institute of General Medical Sciences
- Government
- National Institute for Health Research (NIHR)
- Government
- NIGMS NIH HHS
- Government
- NCI NIH HHS
- Grants
- National Cancer Institute (UM1 CA186107); National Cancer Institute (UM1 CA176726); National Institute of General Medical Sciences (R01GM032373); Cancer Research UK (14136); National Institute for Health and Care Research (NF-SI-0512-10114); Medical Research Council (MR/N003284/1); National Institutes of Health (UM1 CA 176726); National Institutes of Health (R01 GM32373); National Institutes of Health (UM1‐CA‐186107)
Based on 9 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2018-06-18 · PLoS One · vol. 13 · issue 6 · p. e0197464
- Publisher
- Public Library of Science
- Cited
- 52 citations · more than 97% of similar papers · 6.5× the field average
- Impact
- Top 10% most cited in its field
- References
- 98 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Xenotransplantation and immune response · Glycosylation and Glycoproteins Research · Atherosclerosis and Cardiovascular Diseases
- Keywords
- Antibody, Epitope, Sialic acid, Immunology, Glycan, Colorectal cancer, Cancer, Medicine, Biology, Molecular biology, Internal medicine, Biochemistry
- MeSH
- humans, colorectal neoplasms, diabetes mellitus, type 2, neuraminic acids, n-acetylneuraminic acid, polysaccharides, antibodies, autoantigens, epitopes, risk factors, adult, aged, middle aged, female, atherosclerosis, red meat
16 authors
From US, GB
- Annie N. SamrajUniversity of California San Diego
- Kimberly A. BertrandBoston University
- Robert LubenUniversity of Cambridge
- Zahra KhedriUniversity of California San Diego
- Hai YuUniversity of California, Davis
- Dzung NguyenUniversity of California San Diego
Abstract
Background
N-glycolylneuraminic acid (Neu5Gc) is a non-human red-meat-derived sialic acid immunogenic to humans. Neu5Gc can be metabolically incorporated into glycan chains on human endothelial and epithelial surfaces. This represents the first example of a "xeno-autoantigen", against which circulating human "xeno-autoantibodies" can react. The resulting inflammation ("xenosialitis") has been demonstrated in human-like Neu5Gc-deficient mice and contributed to carcinoma progression via antibody-mediated inflammation. Anti-Neu5Gc antibodies have potential as biomarkers for diseases associated with red meat consumption such as carcinomas, atherosclerosis, and type 2 diabetes.
Methods
ELISA assays measured antibodies against Neu5Gc or Neu5Gc-glycans in plasma or serum samples from the Nurses' Health Studies, the Health Professionals Follow-up Study, and the European Prospective Investigation into Cancer and Nutrition, including inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over 1-3 years in archived samples. We also assessed associations between antibody levels and coronary artery disease risk (CAD) or red meat intake. A glycan microarray was used to detected antibodies against multiple Neu5Gc-glycan epitopes. A nested case-control study design assessed the association between total anti-Neu5Gc antibodies detected in the glycan array assay and the risk of colorectal cancer (CRC).
Results
ELISA assays showed a wide range of anti-Neu5Gc responses and good inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over time, but these antibody levels did not correlate with CAD risk or red meat intake. Antibodies against Neu5Gc alone or against individual Neu5Gc-bearing epitopes were also not associated with colorectal cancer (CRC) risk. However, a sialoglycan microarray study demonstrated positive association with CRC risk when the total antibody responses against all Neu5Gc-glycans were combined. Individuals in the top quartile of total anti-Neu5Gc IgG antibody concentrations had nearly three times the risk compared to those in the bottom quartile (Multivariate Odds Ratio comparing top to bottom quartile: 2.98, 95% CI: 0.80, 11.1; P for trend = 0.02).
Conclusions
Further work harnessing the utility of these anti-Neu5Gc antibodies as biomarkers in red meat-associated diseases must consider diversity in individual antibody profiles against different Neu5Gc-bearing glycans. Traditional ELISA assays for antibodies directed against Neu5Gc alone, or against specific Neu5Gc-glycans may not be adequate to define risk associations. Our finding of a positive association of total anti-Neu5Gc antibodies with CRC risk also warrants confirmation in larger prospective studies.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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