Association of Loss-of-Function Mutations in the &lt;emph type="ital"&gt;ABCA1&lt;/emph&gt; Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease

Frikke‐Schmidt, Ruth; Nordestgaard, Børge G.; Stene, Maria C. A.; Sethi, Amar A.; Remaley, Alan T.; Schnohr, Peter; Grande, Peer; Tybjærg‐Hansen, Anne

doi:10.1001/jama.299.21.2524

Cited by 436 publications

(289 citation statements)

References 53 publications

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“…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

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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...

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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

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“…12,14,15 Participants aged 20 years or above were randomly drawn from the Copenhagen Population Register. Data on each participant collected in this study are identical to those in the CCHS.…”

Section: Participantsmentioning

confidence: 99%

“…14,15 Inclusion criteria for cases are characteristic symptomatology of angina pectoris and at least one of the following: previous MI, stenosis/atherosclerosis on coronary angiography or a positive exercise electrocardiography test. We included 5089 cases.…”

Section: Participantsmentioning

confidence: 99%

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

2009

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“…The CGPS was initiated in 2003, and enrollment is on‐going 28, 29, 30. Participants were selected with the use of the Danish Civil Registration System to reflect the adult Danish population aged 20 to 100 + years.…”

Section: Methodsmentioning

confidence: 99%

“…The national Danish Patient Registry has information on all patient contacts with all clinical somatic and psychiatric hospital departments in Denmark since 1977, including emergency wards and outpatient clinics from 1995. The national Danish Causes of Death Registry contains data on the causes of all deaths in Denmark, as reported by hospitals and general practitioners 28, 29, 30…”

Section: Methodsmentioning

confidence: 99%

ABCA7 and risk of dementia and vascular disease in the Danish population

Kjeldsen

Tybjærg‐Hansen

Nordestgaard

et al. 2017

Ann Clin Transl Neurol

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Objective ATP‐binding‐cassette transporter A7(ABCA7) is suggested to be involved in lipid transport as well as in phagocytosis of amyloid‐β in the brain. We tested the hypothesis that a common genetic variant in ABCA7 is associated with dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels in the general population, independent of the common apolipoprotein E(APOE) genotype.MethodsFor this purpose, we genotyped a common genetic variant in ABCA7, identified in genome‐wide‐association‐studies of Alzheimer's disease, in 104,258 individuals from the Danish general population, and also meta‐analyzed our results with publicly available consortia data.ResultsMultifactorially adjusted hazard ratios for Alzheimer's disease were 1.07 (95% confidence interval:0.93–1.23) and 1.72 (1.24–2.40) for GA and AA versus GG genotype. Results were similar after APOE genotype adjustment and when only APOE ɛ33 carriers were studied. Including 178,304 individuals, the meta‐analyzed odds ratio for Alzheimer's disease per one allele ABCA7 rs4147929 increase was 1.15 (1.12–1.18). ABCA7 genotype was not convincingly associated with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, or with lipid levels. Including 288,563 individuals, meta‐analyzed odds ratios for ischemic heart disease per one allele ABCA7 rs4147929 increase was 1.01 (0.99–1.03).InterpretationA common genetic variant in ABCA7 was associated with high risk of Alzheimer's disease independent of APOE genotype. The lack of association with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels suggests that ABCA7 is not important for atherosclerosis. Thus, our findings support the suggested role of ABCA7 in Alzheimer's disease pathology and phagocytic clearance of amyloid‐β in the brain.

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Association of Loss-of-Function Mutations in the <emph type="ital">ABCA1</emph> Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease

Cited by 436 publications

References 53 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

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

ABCA7 and risk of dementia and vascular disease in the Danish population

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