| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Peden, John F., et al.
(författare)
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A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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| 3. |
- Hooft, Ferdinand M van't
(författare)
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Functional characterisation of polymorphisms in candidate genes for coronary heart disease
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Coronary heart disease (CHD) is a multifactorial disorder. Several important risk factors, in particular cigarette smoking, hypertension, hypercholesterolaemia, reduced high density lipoprotein (HDL) cholesterol concentration and hyperglycaemia, have been defined. It appears that most risk factors are influenced by genetic components, suggesting that genetic variants in candidate genes play an important role in the development of CHD. In view of the importance of transcriptional regulation in protein synthesis, it seems appropriate to analyse the promoter region of candidate genes for mutations affecting the basal rate of transcription. The objective of this thesis was therefore to analyse the physiological significance of common polymorphisms in the promoters of candidate genes for CHD. The proximal promoters of the genes for ß-fibrinogen, coagulation factor VII (FVII), apolipoprotein (apo) B, hepatic lipase (HL) and angiotensinogen (AGT) were sequenced in both directions, and in each of these genes one or more common polymorphisms were discovered. Electromobility shift assays were used to determine whether the mutations introduced a change in the binding pattern of nuclear factors. Significant changes were observed for the -455G/A and -854G/A polymorphisms of the ß-fibrinogen gene, the -401G/T and -402G/A polymorphisms of the FVII gene, the -516C/T polymorphism of the apo B gene, the -71OT/C polymorphism of the HL gene, and the -829T/A polymorphism of the AGT gene. The nature of these polymorphisms were subsequently analysed in transient transfection studies in HepG2 cells. It was found that all polymorphisms, with the exception of the -71OT/C polymorphism in the HL gene, influence the basal rate of transcription of the respective genes in vitro. The physiological significance of the promoter polymorphisms in the genes for ß-fibrinogen, FVII, apo B, and AGT was further evaluated in association studies in apparently healthy, middle-aged men. Both the -455G/A and the -854G/A polymorphisms of the ß-fibrinogen gene were associated with an increased plasma fibrinogen concentration. The -40IG/T polymorphism of the FVII gene was related to reduced plasma concentrations of total FVII and fully activated FVII molecules, while the -402G/A polymorphism was associated with increased plasma FVII levels. The -516C/T polymorphism in the apo B gene was associated with an increased level of low density lipoprotein (LDL) cholesterol in plasma. The rare allele of the -829T/A polymorphism of the AGT gene was related to increases in both systolic and diastolic blood pressure. It is concluded that the -455G/A and -854G/A polymorphisms of the p41brinogen gene, the -401G/T and -402G/A polymorphisms of the FVII gene, the -516C/T polymorphism of the apo B gene, and the -829T/A polymorphism of the AGT gene are physiologically relevant mutations with a significant impact on the plasma concentrations of fibrinogen, FVII and LDL cholesterol and blood pressure, respectively, in healthy middle-aged men.
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| 4. |
- Nastase Mannila, Maria, et al.
(författare)
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Identification of a Functional Apolipoprotein E Promoter Polymorphism Regulating Plasma Apolipoprotein E Concentration
- 2013
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 33:5, s. 1063-1069
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:There is compelling evidence that the plasma apolipoprotein E (APOE) concentration, in addition to the APOE ε2/ε3/ε4 genotype, influences plasma lipoprotein levels, but the functional genetic variants influencing the plasma APOE concentration have not been identified.APPROACH AND RESULTSGenome-wide association studies in 2 cohorts of healthy, middle-aged subjects identified the APOE locus as the only genetic locus showing robust associations with the plasma APOE concentration. Fine-mapping of the APOE locus confirmed that the rs7412 ε2-allele is the primary genetic variant responsible for the relationship with plasma APOE concentration. Further mapping of the APOE locus uncovered that rs769446 (-427T/C) in the APOE promoter is independently associated with the plasma APOE concentration. Expression studies in 199 human liver samples demonstrated that the rs769446 C-allele is associated with increased APOE mRNA levels (P=0.015). Transient transfection studies and electrophoretic mobility shift assays in human hepatoma HepG2 cells corroborated the role of rs769446 in transcriptional regulation of APOE. However, no relationships were found between rs769446 genotype and plasma lipoprotein levels in 2 cohorts (n=1648 and n=1039) of healthy middle-aged carriers of the APOE ε3/ε3 genotype.CONCLUSIONS:rs769446 is a functional polymorphism involved in the regulation of the plasma APOE concentration.
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