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Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

ABSTRACT: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

SUBMITTER: Versmissen J

PROVIDER: S-EPMC4326701 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Versmissen Jorie J Oosterveer Daniëlla M DM Yazdanpanah Mojgan M Dehghan Abbas A Hólm Hilma H Erdman Jeanette J Aulchenko Yurii S YS Thorleifsson Gudmar G Schunkert Heribert H Huijgen Roeland R Vongpromek Ranitha R Uitterlinden André G AG Defesche Joep C JC van Duijn Cornelia M CM Mulder Monique M Dadd Tony T Karlsson Hróbjartur D HD Ordovas Jose J Kindt Iris I Jarman Amelia A Hofman Albert A van Vark-van der Zee Leonie L Blommesteijn-Touw Adriana C AC Kwekkeboom Jaap J Liem Anho H AH van der Ouderaa Frans J FJ Calandra Sebastiano S Bertolini Stefano S Averna Maurizio M Langslet Gisle G Ose Leiv L Ros Emilio E Almagro Fátima F de Leeuw Peter W PW Civeira Fernando F Masana Luis L Pintó Xavier X Simoons Maarten L ML Schinkel Arend F L AF Green Martin R MR Zwinderman Aeilko H AH Johnson Keith J KJ Schaefer Arne A Neil Andrew A Witteman Jacqueline C M JC Humphries Steve E SE Kastelein John J P JJ Sijbrands Eric J G EJ

European journal of human genetics : EJHG 20140611 3

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. ...[more]

PMID: 24916650

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Project description:BackgroundHeterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment.Materials and methodsA retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study's participants for the occurrence of ASCVD.ResultsA causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305-4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017-1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899-3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523).ConclusionIn this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.

Dataset Information

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Publications

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

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