Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

Zacho, Jeppe; Tybjærg‐Hansen, Anne; Jensen, Jan Skov; Grande, Peer; Sillesen, Henrik; Nordestgaard, Børge G.

doi:10.1056/nejmoa0707402

Cited by 721 publications

(577 citation statements)

References 36 publications

Supporting

Mentioning

549

Contrasting

Unclassified

Order By: Relevance

“…24,25 All participants were whites of Danish descent and there was no overlap between the studies. Prior to examinations, participants filled out a self-administered questionnaire which was completed by the participant and an investigator on the day of attendance, where a physical examination was performed and blood samples were drawn for immediate biochemical analyses, as well as storage for later DNA and biochemical analyses.…”

Section: Participantsmentioning

confidence: 99%

Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

Kjærgaard

Nordestgaard

Johansen

et al. 2015

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Plasma YKL-40 is high in patients with cancer and in individuals who later develop cancer. Whether YKL-40 is only a marker or indeed a cause of cancer is presently unknown. We tested the hypothesis that observationally and genetically, high plasma YKL-40 is associated with high risk of cancer. For this purpose, we performed cohort and Mendelian randomization studies in 96,099 individuals from the Danish general population. Plasma levels of YKL-40 were measured in 21,643 and CHI3L1 rs4950928 was genotyped in 94,568 individuals. From 1943 through 2011, 2,291 individuals developed gastrointestinal cancer, 913 developed lung cancer, 2,863 women developed breast cancer, 1,557 men developed prostate cancer and 5,146 individuals developed other cancer. Follow-up was 100% complete. Multifactorially and CRP adjusted hazard ratio (HR) for gastrointestinal cancer was 1.82 (95%CI, 1.16-2.86) for 96-100% versus 0-33% YKL-40 percentile category. Corresponding HR were 1.71 (0.95-3.07) for lung cancer, but insignificant for breast cancer, prostate cancer and other cancers. CHI3L1 rs4950928 genotype was associated with plasmaYKL-40 levels, but not with risk of any cancer category. For gastrointestinal cancer, a doubling in YKL-40 was associated with a multifactorially and CRP adjusted observational HR of 1.14(1.05-1.23) for gastrointestinal cancer, but a corresponding genetic odds ratio of 1.06(0.94-1.18). For lung cancer, corresponding risk estimates were 1.11(1.00-1.22) observationally and 1.01(0.84-1.20) genetically. For other cancer categories, observational and genetic findings were insignificant. This study shows that high plasma YKL-40 levels were associated with high risk of gastrointestinal and likely of lung cancer, but genetic high levels were not.Inflammation plays an important role in cancer development and/or progression. 1 Both tumor cells and tumor-associated macrophages produce YKL-40. 2 Plasma YKL-40 is high in patients with gastrointestinal, 3-5 breast, 6 lung, 7 prostate 8 and other cancer, 9-11 and is also associated with tumour burden and prognosis after a cancer diagnosis. 5,[12][13][14][15][16] Furthermore, high plasma YKL-40 predicts high risk of gastrointestinal cancer in the general population. 17 Whether YKL-40 is only a marker of inflammation and cancer or plays a causal role in the development of cancer is presently unknown.A single nucleotide polymorphism in the proximal promoter of chitinase-3-like-1 (same as YKL-40; CHI3L1), rs4950928, accounts for 9.4% of the variance of plasma YKL-40. 18 MYC/MAX transcriptional factors bind better to the major than to the minor allele of rs4950928 in the gene promoter, 19 thereby presumably increasing CHI3L1 transcription and elevating plasma YKL-40 levels in carriers of the major versus minor allele. [20][21][22] We tested the hypothesis that observationally and genetically high plasma YKL-40 is associated with high risk of cancer. For this purpose, we performed cohort and Mendelian randomization studies in 96,099 individuals from the Danish general population...

show abstract

Section: Participantsmentioning

confidence: 99%

Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

Kjærgaard

Nordestgaard

Johansen

et al. 2015

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…In line, a pathway analysis of the CARDIoGRAMplusC4D meta‐analysis has also shown a major role for variants in inflammatory genes (CARDIoGRAMplusC4D Consortium, 2013). By contrast, C‐reactive protein (CRP) appears to be rather a marker than a causal factor, as its genetic variation does not translate to CAD risk (Schunkert & Samani, 2008; Zacho et al , 2008; Elliott et al , 2009; C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) (2011)).…”

Section: Inflammationmentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

View full text Add to dashboard Cite

Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

show abstract

“…Arguments have been presented both supporting and refuting this view (8). Although the evidence cited above suggests that CRP is a reflector, it is still possible that CRP may contribute to the pathogenesis of atherosclerosis, although recent Mendelian randomization studies argue against this possibility (23).…”

Section: Why Does Minor Crp Level Elevation Predict Coronary Events?mentioning

confidence: 99%

A unifying biologic explanation for “high‐sensitivity” C‐reactive protein and “low‐grade” inflammation

Kushner¹,

Samols²,

Magrey³

2010

Arthritis Care & Research

View full text Add to dashboard Cite

Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

Abstract: Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.

Cited by 721 publications

References 36 publications

Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

A unifying biologic explanation for “high‐sensitivity” C‐reactive protein and “low‐grade” inflammation

Contact Info

Product

Resources

About