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Premature coronary heart disease and autosomal dominant hypercholesterolemia: Increased risk in women with LDLR mutations.

ABSTRACT: For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations.This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mutations (unexplained ADH), stratified by sex.Comparative study of premature CHD in a multiethnic cohort of 111 men and 165 women meeting adult Simon-Broome criteria for ADH.Women with FH (n = 51) had an increased risk of premature CHD compared with unexplained ADH women (n = 111; hazard ratio [HR], 2.74; 95% confidence interval, 1.40-5.34; P = .003) even after adjustment for lipid levels and traditional CHD risk factors (HR, 2.53 [1.10-5.83]; P = .005). Men with FH (n = 42), in contrast, had a similar risk of premature CHD when compared with unexplained ADH men (n = 66; unadjusted: HR, 1.48 [0.84-2.63]; P = .18; adjusted: HR, 1.04 [0.46-2.37]; P = .72). To address whether mutation status provides additional information beyond LDL-cholesterol level, we analyzed premature CHD risk for FH vs unexplained ADH at various percentiles of LDL-cholesterol: the risk ratios were significant for women at 25th percentile (HR, 4.90 [1.69-14.19]) and 50th percentile (HR, 3.44 [1.42-8.32]) but not at 75th percentile (HR, 1.99 [0.95-4.17]), and were not significant for men at any percentile.Our findings suggest that genetic confirmation of ADH may be important to identify patient's risk of CHD, especially for female LDLR mutation carriers.

SUBMITTER: Ahmad Z

PROVIDER: S-EPMC4761103 | biostudies-literature | 2016 Jan-Feb

REPOSITORIES: biostudies-literature

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Premature coronary heart disease and autosomal dominant hypercholesterolemia: Increased risk in women with LDLR mutations.

Ahmad Zahid Z Li Xilong X Wosik Jedrek J Mani Preethi P Petr Joye J McLeod George G Murad Shatha S Song Li L Adams-Huet Beverley B Garg Abhimanyu A

Journal of clinical lipidology 20150925 1

<h4>Background</h4>For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations.<h4>Objective</h4>This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mut ...[more]

PMID: 26892126

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Project description:Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the LDLR and PCSK9 genes, as well as a part of the APOB gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon-intron boundaries of the LDLR and PCSK9 genes and the main parts of their introns, together with exon 26 of the APOB gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs∗72) in LDLR and a double mutation (p.Asp172His and p.Ala53Val) in both LDLR and PCSK9 genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C > G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of LDLR and PCSK9 variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.

Dataset Information

Premature coronary heart disease and autosomal dominant hypercholesterolemia: Increased risk in women with LDLR mutations.

Publications

Premature coronary heart disease and autosomal dominant hypercholesterolemia: Increased risk in women with LDLR mutations.

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