The Type of LDLR Gene Mutation Predicts Cardiovascular Risk in Children with Familial Hypercholesterolemia

Guardamagna, Ornella; Restagno, Gabriella; Rolfo, E.; Pederiva, Cristina; Martini, S.; Abello, Francesca; Baracco, V.; Pisciotta, Livia; Pino, E.; Calandra, Sebastiano

doi:10.1016/j.jpeds.2009.02.022

Cited by 65 publications

(36 citation statements)

References 24 publications

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“…Although hypertriglyceridemia has been shown to be associated with atherosclerotic lesions in children and young adults (5), LDL is considered by many to be the major lipid risk factor for atherosclerosis. In fact, many studies in children with familial hypercholesterolemia have not only described this association, but have also shown that pharmacological lowering of LDL can effectively decrease cIMT (34,(36)(37)(38). Interestingly, hypertriglyceridemia was the most highly prevalent lipid abnormality among our cohort.…”

Section: Discussionmentioning

confidence: 57%

Carotid Intima-Media Thickness in Children with CKD

Brady¹,

Schneider²,

Flynn³

et al. 2012

Clinical Journal of the American Society of Nephrology

103

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SummaryBackground and objectives In adults, increased carotid intima-media thickness (cIMT) as assessed by ultrasonography is a valid predictor of cardiovascular events. Children with CKD are known to be at increased cardiovascular risk. This study sought to identify cardiovascular risk factors associated with increased cIMT in children with CKD. Results The median cIMT was 0.43 mm (interquartile range, 0.38-0.48) compared with 0.41 mm in healthy controls (P=0.03 for difference). After multivariable adjustment, the median cIMT was 0.02 mm (95% confidence interval [CI], 0.01-0.05) larger than that of the healthy controls. In a multivariable linear regression analysis, dyslipidemia and hypertension were associated with 0.05 mm (95% CI, 0.01-0.08) and 0.04 mm (95% CI, 0.003-0.08) greater mean cIMT, respectively. Body mass index, CKD etiology, GFR, birth weight, pubertal status, calcium, phosphorus, sex, and race were not associated with cIMT.Conclusions cIMT is significantly elevated among children with CKD, as is the prevalence of other cardiovascular risk factors. Of these risk factors, hypertension and dyslipidemia are significantly associated with increased cIMT.

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Section: Discussionmentioning

confidence: 57%

Carotid Intima-Media Thickness in Children with CKD

Brady¹,

Schneider²,

Flynn³

et al. 2012

Clinical Journal of the American Society of Nephrology

103

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“…The severity of the phenotype in ADH varies genetically with the type of mutation and the gene affected ( 8,9 ). LDLR is the gene most frequently associated with ADH and is also the best characterized.…”

Section: Supplementary Abstractmentioning

confidence: 99%

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Wintjens

Bozon²,

Belabbas

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function. Abstract Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB , and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR , 3.1% in APOB , and 1.7% in PCSK9 . We identifi ed 18 new variants in LDLR and 2 in PCSK9 . Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a

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“…The basis of FH lies in impaired function of the LDL receptor, as recognized by Goldstein and Brown, in their pivotal, Nobel-prize winning work [8]. Over 1200 different mutations in the LDL receptor gene have been identified [9]. The mutations at the LDL receptor locus have been characterized multiple classes (Table 1), or more simply into two groups: LDL receptor-deficient mutations (i.e., null alleles that do not produce LDL receptor The genes (no shading: by classical genetic or biochemical methods; orange: by resequencing; blue: by genome-wide association study) that determine lipoprotein concentrations in specific segments of the distribution are shown below the respective graphs.…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

Genetics of Dyslipidemia and Ischemic Heart Disease

Sharma¹,

Baliga

2017

Curr Cardiol Rep

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This review includes new knowledge of these disorders including description of these disorders, their method of diagnosis, their prevalence, their genetic underpinnings, and their effect on the development of cardiovascular disease. In addition, it discusses major advances in genetic technology, including the completion of the human genome sequence, next-generation sequencing, and genome-wide association studies. Also discussed are rare variant studies with specific genetic mechanisms involved in inherited dyslipidemias, such as in the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. The field of genetics of dyslipidemia and cardiovascular disease is rapidly growing, which will result in a bright future of novel mechanisms of action and new therapeutics.

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The Type of LDLR Gene Mutation Predicts Cardiovascular Risk in Children with Familial Hypercholesterolemia

Cited by 65 publications

References 24 publications

Carotid Intima-Media Thickness in Children with CKD

Carotid Intima-Media Thickness in Children with CKD

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Genetics of Dyslipidemia and Ischemic Heart Disease

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