| 21. |
- van de Vegte, Yordi, et al.
(författare)
-
Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
|
|
| 22. |
- de las Fuentes, Lisa, et al.
(författare)
-
Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
-
Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
-
Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
|
|
| 23. |
- Hellsten, Sofie, et al.
(författare)
-
Abating N in Nordic agriculture – policy, measures and way forward
- 2019
-
Ingår i: Journal of Environmental Management. - 0301-4797 .- 1095-8630. ; 236, s. 674-686
-
Tidskriftsartikel (refereegranskat)abstract
- During the past twenty years, the Nordic countries (Denmark, Sweden, Finland and Norway) have introduced a range of measures to reduce losses of nitrogen (N) to air and to aquatic environment by leaching and runoff. However, the agricultural sector is still an important N source to the environment, and projections indicate relatively small emission reductions in the coming years. The four Nordic countries have different priorities and strategies regarding agricultural N flows and mitigation measures, and therefore they are facing different challenges and barriers. In Norway farm subsidies are used to encourage measures, but these are mainly focused on phosphorus (P). In contrast, Denmark targets N and uses control regulations to reduce losses. In Sweden and Finland, both voluntary actions combined with subsidies help to mitigate both N and P. The aim of this study was to compare the present situation pertaining to agricultural N in the Nordic countries as well as to provide recommendations for policy instruments to achieve cost effective abatement of reactive N from agriculture in the Nordic countries, and to provide guidance to other countries. To further reduce N losses from agriculture, the four countries will have to continue to take different routes. In particular, some countries will need new actions if 2020 and 2030 National Emissions Ceilings Directive (NECD) targets are to be met. Many options are possible, including voluntary action, regulation, taxation and subsidies, but the difficulty is finding the right balance between these policy options for each country. The governments in the Nordic countries should put more attention to the NECD and consult with relevant stakeholders, researchers and farmer's associations on which measures to prioritize to achieve these goals on time. It is important to pick remaining low hanging fruits through use of the most cost effective mitigation measures. We suggest that N application rate and its timing should be in accordance with the crop need and carrying capacity of environmental recipients. Also, the choice of application technology can further reduce the risk of N losses into air and waters. This may require more region-specific solutions and knowledge-based support with tailored information in combination with further targeted subsidies or regulations.
|
|
| 24. |
- Kilpeläinen, Tuomas O, et al.
(författare)
-
Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
|
|
| 25. |
- Qi, Qibin, et al.
(författare)
-
FTO genetic variants, dietary intake and body mass index : insights from 177 330 individuals
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:25, s. 6961-6972
-
Tidskriftsartikel (refereegranskat)abstract
- FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
|
|
| 26. |
|
|
| 27. |
- Sarzynski, M. A., et al.
(författare)
-
Changes in Uric Acid Levels following Bariatric Surgery Are Not Associated with SLC2A9 Variants in the Swedish Obese Subjects Study
- 2012
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
-
Tidskriftsartikel (refereegranskat)abstract
- Context and Objective: Obesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study. Methods: SNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance. Results: Overall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R-2 = 3.725.2%, 3.9 x 10-(22)<= p <= 7.7 x 10(-11)). One SNP (rs737267) showed a significant association (R-2 = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (-61.4 mu mol/L) compared to minor allele carriers (A/X: -51.7 mu mol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10. Conclusions: SNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes. Citation: Sarzynski MA, Jacobson P, Rankinen T, Carlsson B, Sjostrom L, et al. (2012) Changes in Uric Acid Levels following Bariatric Surgery Are Not Associated with SLC2A9 Variants in the Swedish Obese Subjects Study.
|
|
| 28. |
|
|
| 29. |
- Sarzynski, MA, et al.
(författare)
-
Associations of markers in 11 obesity candidate genes with maximal weight loss and weight regain in the SOS bariatric surgery cases
- 2011
-
Ingår i: INTERNATIONAL JOURNAL OF OBESITY. - 0307-0565. ; 35:5, s. 676-683
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract: Purpose: To test whether DNA sequence variation in 11 obesity genes is associated with maximum weight loss and weight regain over 6 years of follow-up in bariatric surgery patients of the Swedish obese subjects (SOS) intervention study. Methods: A total of 1443 subjects were available for analysis (vertical banded gastroplasty: n = 966, banding: n = 293 and gastric bypass: n 184). Single-nucleotide polymorphisms (SNPs) from the following 11 genes were included: ADIPOQ, BDNF, FTO, GNB3, LEP, LEPR, MC4R, NR3C1, PPARG, PPARGC1A and TNF. General linear models were used to analyze associations between the SNPs and maximum weight loss and weight regain. Results: The average maximum weight loss was 33.7 kg (s.d. 13.3; min -95.5 kg, max + 2.0 kg), which was reached 2.2 (s.d. 1.6) years after the surgery. Subjects regained approximately 12 kg (range 0.0-51.4 kg) by year 6. After correcting for multiple testing, the FTO SNP rs16945088 remained significantly associated with maximum weight loss (P = 0.0002), as minor allele carriers lost approximately 3 kg less compared with common allele homozygotes. This association was particularly evident in the banding surgery patients (P < 0.0001), whereas no significant association was found in the gastric bypass subjects. No other SNPs were associated with maximum weight loss. Furthermore, no SNPs were significantly associated with weight regain. Conclusion: The FTO SNP rs16945088 was associated with maximum weight loss after banding surgery. We found no evidence that obesity-risk SNPs in FTO or other obesity candidate genes derived from genome-wide association studies are associated with maximum weight loss or weight regain over 6 years of follow-up in bariatric surgery patients. The potential role of other obesity genes remains to be investigated. International Journal of Obesity (2011) 35, 676-683; doi: 10.1038/ijo.2010.166; published online 24 August 2010
|
|
