| 1. |
- Tabassum, R, et al.
(författare)
-
Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
|
|
| 2. |
- Cederberg, H., et al.
(författare)
-
Non-Cholesterol Sterol Levels Predict Hyperglycemia and Conversion to Type 2 Diabetes in Finnish Men
- 2013
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.
|
|
| 3. |
|
|
| 4. |
- Dongiovanni, P, et al.
(författare)
-
Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.
- 2018
-
Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 1365-2796 .- 0954-6820. ; 283:4, s. 356-370
-
Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance.We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS).Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.
|
|
| 5. |
|
|
| 6. |
- Stancakova, A., et al.
(författare)
-
Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance
- 2008
-
Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:5, s. 1924-30
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: CDKAL1 is a recently discovered susceptibility gene for type 2 diabetes. OBJECTIVE: Our objective was to investigate the impact of rs7754840 of CDKAL1 on insulin secretion, insulin sensitivity, and risk of type 2 diabetes. DESIGN AND SETTINGS: Study 1 (the EUGENE2 study) was a cross-sectional study including subjects from five white populations in Europe (Denmark, Finland, Germany, Italy, and Sweden). Study 2 is an ongoing prospective study of Finnish men. PARTICIPANTS: In study 1, 846 nondiabetic offspring of type 2 diabetic patients (age 40 +/- 10 yr; body mass index 26.7 +/- 5.0 kg/m(2)) participated. In study 2, subjects included 3900 middle-aged men (533 type 2 diabetic and 3367 nondiabetic subjects). Interventions: Interventions included iv glucose-tolerance test (IVGTT), oral glucose-tolerance test (OGTT), and euglycemic-hyperinsulinemic clamp in study 1 and OGTT in study 2. MAIN OUTCOME MEASURES: Parameters of insulin secretion, insulin resistance, and glucose tolerance status were assessed. RESULTS: In study 1, carriers of the GC and CC genotypes of rs7754840 had 11 and 24% lower first-phase insulin release in an IVGTT compared with that in carriers of the GG genotype (P = 0.002). The C allele was also associated with higher glucose area under the curve in an OGTT (P = 0.016). In study 2, rs7754840 was significantly associated with type 2 diabetes (P = 0.022) and markers of impaired insulin release [insulinogenic index (IGI), P = 0.012] in 2405 men with normal glucose tolerance. CONCLUSIONS: rs7754840 of CDKAL1 was associated with markers of impaired insulin secretion in two independent studies. Furthermore, rs7754840 was associated with type 2 diabetes in Finnish men (study 2). Therefore, CDKAL1 is likely to increase the risk of type 2 diabetes by impairing insulin secretion.
|
|
| 7. |
|
|
| 8. |
- Dongiovanni, P., et al.
(författare)
-
Transmembrane 6 Superfamily Member 2 Gene Variant Disentangles Nonalcoholic Steatohepatitis From Cardiovascular Disease
- 2015
-
Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 61:2, s. 506-514
-
Tidskriftsartikel (refereegranskat)abstract
- Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P<0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P<0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P<0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95). Conclusions: Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver. (Hepatology 2015;61:506-514)
|
|
| 9. |
- Hammarstedt, Ann, 1975, et al.
(författare)
-
High circulating levels of RBP4 and mRNA levels of aP2, PGC-1alpha and UCP-2 predict improvement in insulin sensitivity following pioglitazone treatment of drug-naive type 2 diabetic subjects
- 2008
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 263:4, s. 440-9
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: High levels of circulating retinol-binding protein 4 (RBP4) and baseline expression of adipogenic genes correlate with subsequent improvement in insulin sensitivity following Thiazolidinedione (TZD) treatment. OBJECTIVE: The aim was to identify baseline characteristics and early changes related to TZD treatment that could predict a good treatment response. DESIGN: Subjects were examined with oral glucose tolerance test, intravenous glucose tolerance test, hyperinsulinaemic euglycaemic clamp, body composition and standard blood sampling at baseline and after 4 and 12 weeks treatment. Subcutaneous adipose tissue biopsies were taken from the abdominal region at baseline, after 3 days and 4 weeks treatment to examine the gene expression profile. SETTING: Research laboratory in a University hospital. PARTICIPANTS: Ten newly diagnosed and previously untreated type 2 diabetic subjects were treated with pioglitazone for 3 months. MAIN OUTCOME MEASURES: Baseline characteristics and early changes related to TZD treatment that could predict the response after 3 months. RESULTS: Pioglitazone improved insulin sensitivity after 4 weeks combined with lower glucose and insulin levels without any change in BMI. It was accompanied by lower circulating resistin and plasminogen activator inhibitor-1 levels rapidly increased levels of circulating total and high molecular weight adiponectin as well as adiponectin and adipocyte fatty acid-binding protein (aP2) mRNA expression in the adipose tissue. High levels of circulating RBP4 at baseline and adipose tissue expression of aP2, proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) and uncoupling protein 2 (UCP-2) predicted a good treatment response measured as improvement in insulin-stimulated whole-body glucose uptake after 3 months. CONCLUSIONS: Circulating levels of RBP4 as an index of insulin sensitivity and mRNA levels of adipogenic genes correlate with the subsequent improvement in insulin sensitivity following TZD treatment.
|
|
| 10. |
- Hammarstedt, Ann, 1975, et al.
(författare)
-
Visfatin is an adipokine, but it is not regulated by thiazolidinediones
- 2006
-
Ingår i: J Clin Endocrinol Metab. - : The Endocrine Society. - 0021-972X. ; 91:3, s. 1181-4
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Visfatin was recently reported to be expressed in human adipose tissue and to exert insulin-mimicking effects. OBJECTIVE: The objective of this study was to examine whether visfatin is a true adipokine and is expressed in isolated fat cells. We also examined whether visfatin is regulated by thiazolidinediones and, thus, can contribute to the ability of these agents to improve insulin sensitivity. DESIGN: This was an open-labeled drug therapy trial. SETTING: This study was performed at a university hospital. PATIENTS: Seven newly diagnosed and previously untreated type 2 diabetic patients and six healthy individuals with reduced insulin sensitivity participated in the study. INTERVENTION: Pioglitazone therapy (30-45 mg/d) was given for 3-4 wk. MAIN OUTCOME MEASURES: Serum and adipose tissue mRNA levels of visfatin and adiponectin were the main outcome measures. RESULTS: Visfatin mRNA is expressed in both adipose tissue and isolated adipocytes. Treatment with thiazolidinediones for 3-4 wk did not alter the gene expression or circulating levels of visfatin in either nondiabetic or the diabetic individuals, whereas adiponectin increased significantly. CONCLUSION: The present study shows that visfatin is a true adipokine, but it is not regulated by TZD and, thus, is unlikely to contribute to the insulin-sensitizing actions of these drugs.
|
|
