Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population

Engert, James C.; Lemire, Mathieu; Faith, Janet; Brisson, Diane; Fujiwara, Takuya; Roslin, Nicole M.; Brewer, Carl G.; Montpetit, Alexandre; Darmond-Zwaig, Corinne; Renaud, Yannick; Doré, Carole; Bailey, Swneke D.; Verner, Andrei; Tremblay, G; St‐Pierre, Julie; Bétard, Christine; Platko, Jill; Rioux, John D.; Morgan, Kenneth; Hudson, Thomas J.; Gaudet, Daniel

doi:10.1038/sj.ejhg.5201920

Cited by 18 publications

(13 citation statements)

References 74 publications

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“…A total of 2 out of 7 SNPs in the squalene synthase gene that we discovered by sequencing [Engert et al, 2008] were also tSNPs for squalene synthase [Paré et al, 2007]. In addition, two other SNPs were effectively captured by one of the tSNPs (r 2 40.8) (Fig.…”

Section: Snp Selectionmentioning

confidence: 93%

“…Probands for CHD were identified through angiography using a criteria of stenosis of at least 50% in two or more blood vessels. CHD status for siblings in the family-based sample was the same but also included revascularization or a clinical diagnosis of either myocardial infarction, or angina (see Engert et al [2008] for details). The family-based sample consisted of 887 individuals from 149 families.…”

Section: Patients and Methods Study Population And Clinical Phenotypesmentioning

confidence: 99%

“…We first analyzed rs9205 and K45R for association with TC, LDL-C, HDL-C, and TG in a subset of 263 individuals that were successfully genotyped from 50 families that had a LOD score of 3.53 [Engert et al, 2008]. Using the QTDT software and an orthogonal model with age, sex, and BMI as covariates, K45R was associated with LDL-C under both an additive and dominant model (P 5 0.034 for both), while no association was found for rs9205:G4C.…”

Section: Quantitativetrait Analysismentioning

confidence: 99%

“…Previously, we performed a genome-wide linkage scan on a Saguenay-Lac St. Jean (SLSJ) study sample and identified a susceptibility loci for CHD on chromosome 8p.23 (nonparametric linkage score 5 3.53, p 5 0.00033) [Engert et al, 2008]. Within this loci, we sequenced several candidate genes including the squalene synthase gene.…”

Section: Introductionmentioning

confidence: 99%

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K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population

Paré

Montpetit

et al. 2008

Hum. Mutat.

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Squalene synthase is an important component of the cholesterol biosynthetic pathway, and inhibitors of this enzyme have been shown to lower plasma cholesterol levels. Previously, we sequenced the squalene synthase gene, FDFT1 (farnesyl-diphosphate farnesyltransferase), and identified several SNPs, including a nonsynonymous variant, rs11549147:A>G (K45R). To examine the possible association of K45R with plasma lipid traits, we tested 887 individuals from 149 families from the founder population of Saguenay-Lac St. Jean (SLSJ), Quebec. K45R was associated with increased total cholesterol (TC) (P=0.035) and non-high-density lipoprotein cholesterol (non-HDL-C) (P=0.01). These results were replicated in an independent sample of unrelated individuals (P=0.0008 for TC, P=0.004 for non-HDL-C). This SNP also influenced low-density lipoprotein cholesterol (P=0.042) and HDL-C (P=0.025) in the family-based sample, and triglycerides (TG) (P=0.007) in the unrelated subjects. The lysine (K) in codon 45 is conserved across 11 mammals and lies in a potential exonic splicing enhancer (ESE) site. These results suggest that this coding variant in the squalene synthase gene influences plasma cholesterol levels, possibly by affecting the intracellular production of cholesterol.

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Section: Snp Selectionmentioning

confidence: 93%

Section: Patients and Methods Study Population And Clinical Phenotypesmentioning

confidence: 99%

Section: Quantitativetrait Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population

Paré

Montpetit

et al. 2008

Hum. Mutat.

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“…Although it is often perceived as a particularly homogeneous sub-population of founders, there is some genetic heterogeneity at a sub-regional level [14] . It is estimated that the current population of 300,000 is descended from perhaps as few as 400 effective founders [15] . In Quebec, and especially Saguenay-Lac St Jean, a number of genetic disorders occur with high frequency, exhibit particular characteristics, or were first reported in these populations [11] .…”

Section: Population Historymentioning

confidence: 99%

Canada: Public Health Genomics

Little

Potter²,

Allanson³

et al. 2008

Public Health Genomics

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Canada has a diverse population of 32 million people and a universal, publicly funded health care system provided through provincial and territorial health insurance plans. Public health activities are resourced at provincial/territorial level with strategic coordination from national bodies. Canada has one of the longest-standing genetics professional specialty organizations and is one of the few countries offering master’s level training designed specifically for genetic counselors. Prenatal screening is offered as part of routine clinical prenatal services with variable uptake. Surveillance of the effect of prenatal screening and diagnosis on the birth prevalence of congenital anomalies is limited by gaps and variations in surveillance systems. Newborn screening programs vary between provinces and territories in terms of organization and conditions screened for. The last decade has witnessed a four-fold increase in requests for genetic testing, especially for late onset diseases. Tests are performed in provincial laboratories or outside Canada. There is wide variation in participation in laboratory quality assurance schemes, and there are few regulatory frameworks in Canada that are directly relevant to genetics testing services or population genetics. Health technology assessment in Canada is conducted by a diverse range of organizations, several of which have produced reports related to genetics. Several large-scale population cohort studies are underway or planned, with initiatives to harmonize their conduct and the management of ethical issues, both within Canada and with similar projects in other countries.

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Genomics and Proteomics: The Role of Contemporary Biomolecular Analysis in Advancing the Knowledge of Atherosclerotic Coronary Artery Disease

Foster¹,

Ahmadi

2010

Asymptomatic Atherosclerosis

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Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population

Cited by 18 publications

References 74 publications

K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population

K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population

Canada: Public Health Genomics

Genomics and Proteomics: The Role of Contemporary Biomolecular Analysis in Advancing the Knowledge of Atherosclerotic Coronary Artery Disease

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