Hengstenberg C

References (3)

Title : A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease - Wild_2011_Circ.Cardiovasc.Genet_4_403
Author(s) : Wild PS , Zeller T , Schillert A , Szymczak S , Sinning CR , Deiseroth A , Schnabel RB , Lubos E , Keller T , Eleftheriadis MS , Bickel C , Rupprecht HJ , Wilde S , Rossmann H , Diemert P , Cupples LA , Perret C , Erdmann J , Stark K , Kleber ME , Epstein SE , Voight BF , Kuulasmaa K , Li M , Schafer AS , Klopp N , Braund PS , Sager HB , Demissie S , Proust C , Konig IR , Wichmann HE , Reinhard W , Hoffmann MM , Virtamo J , Burnett MS , Siscovick D , Wiklund PG , Qu L , El Mokthari NE , Thompson JR , Peters A , Smith AV , Yon E , Baumert J , Hengstenberg C , Marz W , Amouyel P , Devaney J , Schwartz SM , Saarela O , Mehta NN , Rubin D , Silander K , Hall AS , Ferrieres J , Harris TB , Melander O , Kee F , Hakonarson H , Schrezenmeir J , Gudnason V , Elosua R , Arveiler D , Evans A , Rader DJ , Illig T , Schreiber S , Bis JC , Altshuler D , Kavousi M , Witteman JC , Uitterlinden AG , Hofman A , Folsom AR , Barbalic M , Boerwinkle E , Kathiresan S , Reilly MP , O'Donnell CJ , Samani NJ , Schunkert H , Cambien F , Lackner KJ , Tiret L , Salomaa V , Munzel T , Ziegler A , Blankenberg S
Ref : Circ Cardiovasc Genet , 4 :403 , 2011
Abstract : BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7x10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3x10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4x10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
ESTHER : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedSearch : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedID: 21606135
Gene_locus related to this paper: human-LIPA

Title : [Genetic factors in myocardial infarction--Results from a candidate gene and a genome-wide approach between beta blockers] - Hengstenberg_2002_Herz_27_649
Author(s) : Hengstenberg C , Brockel U , Holmer S , Mayer B , Fischer M , Baessler A , Erdmann J , Lieb W , Lowel H , Riegger G , Schunkert H
Ref : Herz , 27 :649 , 2002
Abstract : BACKGROUND: Coronary artery disease and myocardial infarction are the most frequent causes of death in the Western societies. Even nowadays, every second myocardial infarction is lethal and hits the patients unexpectedly without previous signs or symptoms. In order to install preventive measures most efficiently, it is necessary to have a detailed knowledge on the pathophysiology of the disease. The identification of patients who are at high risk for suffering from myocardial infarction can be done with epidemiological methods, such as the determination of "traditional" risk factors, like arterial hypertension, hypercholesterolemia, diabetes mellitus or smoking), or eventually in the future using molecular genetic testing. This is of great importance especially for asymptomatic siblings and children from myocardial infarction patients. POLYMORPHISMS: Although traditional risk factors occur frequently in families, they explain only in part the familial accumulation of coronary artery disease. Furthermore, stron genetic effects on the development of coronary artery disease and myocardial infarction have been demonstrated in several studies. These genetic effects can be examined by 1. a candidate gene approach, or 2. a systematic screening of the whole genome. In the first step, several polymorphisms (sequence variations) wee examined in several candidate genes in which a significant influence on a cardiovascular risk factor or intermediate phenotype (such as atherogeneic lipid profile or arterial hypertension) has been shown in the literature. We thus examined in a large population of patients with myocardial infarction and a sample of the general population the effects of the HindIII polymorphism in the lipoproteinlipase gene, of the -344T/C promoter polymorphism in the aldosterone synthase gene and of the 825C/T polymorphism in the gene of the beta3 subunit of the G protein gene (GNB3). In the general population, we could show an association with unfavorable lipid levels in men and in postmenopausal (but not premenopausal) women for the H2H2 genotype of the HindIII lipoproteinlipase polymorphism. However, the theoretical increase in risk for this genotype is not large enough to demonstrate a significant association with myocardial infarction in the population examined. With the promoter polymorphism in the aldosterone synthase gene, anthropometrical and echocardiographical data did not suggest that the polymorphism is a risk factor for myocardial infarction nor for left ventricular remodeling after myocardial infarction, which was observed in earlier studies. Furthermore, we could show an association with arterial hypertension in our general population sample with the polymorphism in the GNB3 gene. However, no association could be demonstrated for this polymorphism with myocardial infarction. AFFECTED SIB-PAIR APPROACH: In a systematic screening of the genome for genes that are relevant in the pathogenesis of coronary artery disease or myocardial infarction, an affected sib-pair approach was followed. 1,261 families were identified in which at least two brothers or sisters were affected with myocardial infarction or severe coronary artery disease, such as percutaneous coronary intervention or coronary after bypass grafting. In a subpopulation of 513 families and 1,407 individuals, we performed a total genome screening. The analyses using the variance component method and the SOLAR program revealed a susceptibility locus for myocardial infarction of chromosome 14q32 with a lod score of 3.89 (genome-wide p < 0.05). This locus comprises a region of about seven centi-Morgan and contains approximately 150 genes. Furthermore, a comprehensive analysis including the cardiovascular risk factors showed that 1. this myocardial infarction locus is unique and does not overlap with chromosomal loci for well-established risk factors, 2. cardiovascular risk factors, such as Lp(a), diabetes mellitus, serum lipids, or arterial hypertension have strong genetic components. CONCLUSION: These findings do not exclude a role of cardiovascular s do not exclude a role of cardiovascular risk factors or candidate genes in the pathogenesis of myocardial infarction, but rather demonstrate that risk factors may act as surrogates of specific underlying disease mechanisms. It is thus necessary to perform a comprehensive analysis of complex polygenic diseases, such as myocardial infarction, including both, established cardiovascular risk factors and genomic data.
ESTHER : Hengstenberg_2002_Herz_27_649
PubMedSearch : Hengstenberg_2002_Herz_27_649
PubMedID: 12439636

Title : Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population - Holmer_2000_Cardiovasc.Res_47_806
Author(s) : Holmer SR , Hengstenberg C , Mayer B , Doring A , Lowel H , Engel S , Hense HW , Wolf M , Klein G , Riegger GA , Schunkert H
Ref : Cardiovascular Research , 47 :806 , 2000
Abstract : OBJECTIVE: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups.
METHODS: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age).
RESULTS: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19-25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P=0.63). CONCLUSION: This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.
ESTHER : Holmer_2000_Cardiovasc.Res_47_806
PubMedSearch : Holmer_2000_Cardiovasc.Res_47_806
PubMedID: 10974229