Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10

Narverud, Ingunn; Ueland, Thor; Nenseter, Marit S.; Retterstøl, Kjetil; Telle-Hansen, Vibeke H.; Halvorsen, Bente; Ose, Leiv; Aukrust, Pål; Holven, Kirsten B.

doi:10.1016/j.atherosclerosis.2010.10.002

Cited by 46 publications

(25 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Supporting the finding of no strong relationship between C-reactive protein and LDL cholesterol, patients with heterozygous familial hypercholesterolemia and genetically high levels of LDL cholesterol as a result of a defect in the LDL receptor found either no difference in C-reactive protein levels between patients and controls [116][117][118][119] or only slightly higher levels of C-reactive protein in patients when compared with controls. [120][121][122] Furthermore, patients with homozygous familial hypercholesterolemia, who have extremely high levels of LDL cholesterol and therefore have a high risk of early atherosclerosis, only had slightly increased levels of C-reactive protein when compared with controls.…”

Section: Biologymentioning

confidence: 49%

Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

Nordestgaard

2016

Circulation Research

798

602

View full text Add to dashboard Cite

Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need to reduce levels to no advice on treatment. New insight in epidemiology now suggests that these lipoproteins, marked by high triglycerides, are strong and independent predictors of ASCVD and all-cause mortality, and that their cholesterol content or remnant cholesterol likewise are strong predictors of ASCVD. Of all adults, 27% have triglycerides >2 mmol/L (176 mg/dL), and 21% have remnant cholesterol >1 mmol/L (39 mg/dL). For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) compared with individuals with levels of 0.8 mmol/L (70 mg/dL), the risks were 5.1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate that triglyceriderich lipoproteins are causally associated with ASCVD and all-cause mortality. Finally, genetic evidence also demonstrates that high concentrations of triglyceride-rich lipoproteins are causally associated with low-grade inflammation. This suggests that an important part of inflammation in atherosclerosis and ASCVD is because of

show abstract

Section: Biologymentioning

confidence: 49%

Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

Nordestgaard

2016

Circulation Research

798

602

View full text Add to dashboard Cite

show abstract

“…Therefore, the simplest explanation is that elevated LDL cholesterol does not cause low-grade inflammation. In favor of such an interpretation, studies of patients with heterozygous familial hypercholesterolemia, which is an inherited condition with very high levels of LDL cholesterol caused by a defect in the LDL receptor, found either no difference in CRP levels between patients and control subjects [18][19][20][21] or only slightly higher levels of CRP in patients compared with control subjects. [22][23][24] Even patients with homozygous familial hypercholesterolemia, who have extremely high levels of LDL cholesterol and therefore have a very high risk of early atherosclerosis, had only slightly increased levels of CRP compared with control subjects.…”

Section: Discussionmentioning

confidence: 99%

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

et al. 2013

View full text Add to dashboard Cite

Background-Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown. Methods and Results-We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. Conclusions-Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation. (Circulation. 2013;128:1298-1309.)

show abstract

“…Therefore, investigating inflammatory markers in children and young adults with FH provides a suitable approach to study inflammation in early atherosclerosis. We have previously shown an inflammatory imbalance between TNFa and interleukin (IL)-10 in children and young adults with FH [14]. Because of the potential role of several TNF-related molecules in atherogenesis, in the present study we have investigated the gene expression of members of the TNFSF/TNFRSF in peripheral blood mononuclear cells (PBMCs) in children and young adults with FH and matched healthy controls.…”

Section: Introductionmentioning

confidence: 99%

Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

et al. 2012

View full text Add to dashboard Cite

Objective. Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis. Inflammation is a key event in atherogenesis, and we have previously reported an inflammatory imbalance between tumour necrosis factor (TNF)a and interleukin-10 in children with FH. Based on the potential role of TNF-related molecules in inflammation, we investigated the regulation of other members of the TNF superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) in children and young adults with FH and matched healthy controls.Methods. Expression of TNFSF/TNFRSF genes in peripheral blood mononuclear cells (PBMCs) was quantified in children and young adults with FH prior to (n = 42) and after statin treatment (n = 10) and in controls (n = 25) by quantitative real-time polymerase chain reaction.Results. First we found that, compared with controls, the mRNA levels of OX40L, BAFFR and TRAILR1 were significantly higher, whereas TRAIL and TRAILR3 were significantly lower in children and young adults with FH. Secondly, levels of oxidized low-density lipoprotein (oxLDL) were significantly raised in the FH group, and correlated with the expression of OX40L, BAFFR and TRAILR1. Thirdly, oxLDL increased mRNA levels of BAFFR, TRAILR1 and TRAILR4 in PBMCs ex vivo from individuals with FH. Fourthly, OX40, acting through OX40L, enhanced the oxLDL-induced expression of matrix metalloproteinase-9 in THP-1 monocytes in vitro. Finally, after statin treatment in children with FH (n = 10), mRNA levels of OX40L and TRAILR1 decreased, whereas levels BAFF, TRAIL and TRAILR3 increased.Conclusion. Our findings suggest the involvement of some TNFSF/TNFRSF members and oxLDL in the early stages of atherogenesis; this may potentially contribute to the accelerated rate of atherosclerosis observed in individuals with FH.

show abstract

Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10

Cited by 46 publications

References 36 publications

Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

Contact Info

Product

Resources

About