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- Ali, Ashfaq, et al.
(författare)
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Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia? : Findings From the GLACIER and the MDC Studies
- 2016
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Ingår i: Circulation. - 1942-325X .- 1942-3268. ; 9:2, s. 162-171
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability.Methods and Results We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmo Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS(TG)) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS(TG) were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4x10(-84)) higher triglyceride concentration and each additional WGRS(TG) unit with 2% (P=7.6x10(-48)) higher triglyceride concentration. Each unit of the WGRS(TG) was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (P-interaction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS(TG)xBMI interaction effect (P-interaction=6.0x10(-4)), which was strengthened by including data from the Danish cohorts (P-interaction=6.5x10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS(TG)xBMIxsex) was observed (P-interaction=0.03), where the WGRS(TG)xBMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci.Conclusions Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.
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| 2. |
- Ericson, Ulrika, et al.
(författare)
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Sex-specific interactions between the IRS1 polymorphism and intakes of carbohydrates and fat on incident type 2 diabetes.
- 2012
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Ingår i: The American journal of clinical nutrition. - : Elsevier BV. - 1938-3207 .- 0002-9165.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The minor T allele of rs2943641 near the gene encoding for insulin receptor substrate 1 (IRS1) has been associated with decreased risk of type 2 diabetes (T2D) and adiposity in genome-wide association studies. Dietary intake can influence the regulation of IRS1, and studies have indicated sex-specific associations between IRS1 and adiposity. OBJECTIVE: The objective was to examine the interaction between IRS1 rs2943641 and macronutrient intakes on incident T2D and percentage body fat in the Malmö Diet and Cancer cohort. DESIGN: The study included 15,227 women and 9614 men aged 45-74 y without prevalent diabetes. Dietary data were collected with a modified diet history method. During 12 y follow-up, 1567 incident T2D cases were identified. RESULTS: The T allele was associated with lower incidence of T2D (P-trend = 0.003) and, in men, with higher percentage body fat (P-trend = 0.00002). We observed 3-way interactions between sex, rs2943641, and carbohydrate intake (P = 0.01) as well as between sex, rs2943641, and fat intake (P = 0.01) on incident T2D. Among women, the T allele was associated with decreased risk only in the lower tertiles of carbohydrate intake (P-trend = 0.01, P-interaction = 0.01). In contrast, among men, the T allele was associated with decreased risk in the lowest tertile of fat intake (P-trend = 0.01, P-interaction = 0.02). No interaction was observed between macronutrient intakes and rs2943641 on percentage body fat. CONCLUSIONS: Our results indicate that IRS1 rs2943641 interacts with carbohydrate and fat intakes on incident T2D in a sex-specific fashion. A protective association between the rs2943641 T allele and T2D was restricted to women with low carbohydrate intake and to men with low fat intake.
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| 3. |
- Hyysalo, Jenni, et al.
(författare)
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Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease
- 2012
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Ingår i: Journal of Gastroenterology and Hepatology. - : Wiley. - 0815-9319. ; 27:5, s. 951-956
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T-455C at rs2854116 and C-482T at rs2854117) to contribute to non-alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort. Methods: Atotal of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) influencing liver fat. Plasma apoC3 concentration was measured enzymatically, and liver fat by proton magnetic resonance spectroscopy. Results: APOC3 wild-type homozygotes and variant allele (T-455C or C-482T or both) carriers did not differ with regard to liver fat, apoC3 concentrations, triglyceride-, high density lipoprotein-, fasting plasma glucose, insulin-, alanine aminotransferase-and aspartate aminotransferase-concentrations, nor was there a difference in prevalence of NAFLD. In contrast, carriers of the PNPLA3 GG genotype at rs738409 had a 2.7-fold (median 11.3%) higher liver fat than those with the CC (median 4.2%) genotype. The PNPLA3 rs738409 was also an independent predictor of liver fat, together with age, gender, and body mass index. Conclusion: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD.
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| 4. |
- Stojkovic, Ivana
(författare)
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Genetic variants for liver fat accumulation and circulating triglyceride levels
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-alcoholic fatty liver disease (NAFLD), obesity and type 2 diabetes(T2D) are strongly associated and today their prevalence reaches epidemic proportions. NAFLD has a multi-factorial aetiology, both genetic and environmental factors are equally important. The aim of this thesis was to investigate genetic factors associating with NAFLD and circulating triglyceride (TG) levels in overweight or obesity and their interaction with diet, as well as their association with lipid and glucose traits, and incidence of T2D and CVD. In total 417 obese Finnish subjects and >5000 subjects from the population-based prospective Malmö Diet and Cancer Study (MDCS), with data on genotypes, lipid traits and diet, were included. Two apolipoprotein c3 (APOC3) variants did not associate with liver fat content or apoc3 concentrations among Finns, which was in contrast to results in a previous study. Overweight modified the association between the PNPLA3 rs738409 and TG and ALAT levels (Pinteraction=0.003 and 0.03, respectively) and we additionally observed that carbohydrate (CHO) and fat intakes, in particular sucrose among normal-weight individuals, and possibly the ω-6: ω-3 PUFA ratio in overweight individuals, may modify association with TG levels (Pinteraction=0.03 and 0.08, respectively). Importantly, our results suggest that the mechanism by which PNPLA3 variant increases liver fat accumulation may depend on BMI status and dietary intake. The variants in MLXIPL and GCKR genes, were associated with lower TG and higher glucose traits in MDCS-CC study, and a combination of TG lowering alleles in MLXIPL and GCKR was strongly associated with lower TG levels (P=2.4-12) and higher fasting glucose and HbA1c levels (P=0.009, for both). The same alleles associated with lower risk of hypertriglyceridemia at the baseline (P=0.015 for MLXIPL, P=0.00025 for GCKR and P=0.000012 for combined alleles), and the MLXIPL T-allele was associated with lower incidence of hypertriglyceridemia in the prospective analysis (OR: 0.37; 95%CI: 0.20-0.70; P=0.002).These loci did not associate with the risk of T2D, although a nominally significant interactions between total CHO intake and MLXIPL and between fiber intake and GCKR on T2D risk was observed (Pinteraction=0.043, Pinteraction=0.007, respectively). Analysis of combined genotypes reflected the results observed in the interaction analyses for the individual genotypes. Additionally, five NAFLD susceptibility loci did not show any association with T2D, CVD or total mortality, except for that nominally significant associations between the GRS and increased incidence of T2D (P=0.03) and death (P=0.048) was observed among severely obese (BMI≥35kg/m2) individuals. In conclusion, this thesis suggests putative role of obesity and dietary CHOs in modifying the genetic susceptibility to NAFLD, which may facilitate further studies to elucidate the mechanisms and factors behind increased liver fat accumulation and potential new therapeutic approaches.
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| 6. |
- Stojkovic, Ivana, et al.
(författare)
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The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels
- 2014
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Ingår i: Genes and Nutrition. - : Springer Science and Business Media LLC. - 1555-8932 .- 1865-3499. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- The Ile148Met (rs738409, G-allele) in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) associates with liver fat content and may lead to loss-of-function (hydrolysis) or gain-of-function (CoA-dependent lysophosphatidic acid acyltransferase) defects. PNPLA3 is up-regulated by dietary carbohydrates, and interactions between rs738409 and carbohydrates, and sugar and omega 6:omega 3-polyunsaturated fatty acid (PUFA) ratio on hepatic fat accumulation have been reported. We examined interaction between rs738409 and overweight, and between rs738409 and dietary intakes (carbohydrates, sucrose and omega 6:omega 3-PUFA ratio), on fasting triglyceride levels. From the Malmo Diet and Cancer Study-Cardiovascular Cohort, 4,827 individuals without diabetes aged 58 +/- 6 years, 2,346 with BMI <= 25 kg/m(2) and 2,478 with BMI > 25 kg/m(2), were included in cross-sectional analyses. Dietary data were collected by a modified diet history method. Overweight modified the association between rs738409 and fasting triglyceride levels (P-interaction = 0.003). G-allele associated with lower triglycerides only among overweight individuals (P = 0.01). Nominally, significant interaction on triglyceride levels was observed between rs738409 and sucrose among normal-weight individuals (P-interaction = 0.03). G-allele associated with lower triglycerides among overweight individuals in the lowest tertiles of carbohydrate and omega 6:omega 3-PUFA ratio (P = 0.04 and P = 0.001) and with higher triglycerides among normal-weight individuals in the highest tertile of sucrose (P = 0.001). We conclude that overweight and dietary sucrose may modify the association between rs738409 and fasting triglyceride levels.
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