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Article ; Online: A polygenic and family risk score are both independently associated with risk of type 2 diabetes in a population-based study.

Duschek, Elena / Forer, Lukas / Schönherr, Sebastian / Gieger, Christian / Peters, Annette / Kronenberg, Florian / Grallert, Harald / Lamina, Claudia

Scientific reports

2023 Volume 13, Issue 1, Page(s) 4805

Abstract: The availability of polygenic scores for type 2 diabetes (T2D) raises the question, whether assessing family history might become redundant. However, family history not only involves shared genetics, but also shared environment. It was the aim of this ... ...

Abstract	The availability of polygenic scores for type 2 diabetes (T2D) raises the question, whether assessing family history might become redundant. However, family history not only involves shared genetics, but also shared environment. It was the aim of this study to assess the independent and combined effects of one family risk score (FamRS) and a polygenic score (PGS) on prevalent and incident T2D risk in a population-based study from Germany (n = 3071). The study was conducted in 2004/2005 with up to 12 years of follow-up. The FamRS takes into account not only the number of diseased first grade relatives, but also age at onset of the relatives and age of participants. 256 prevalent and additional 163 incident T2D cases were recorded. Prevalence of T2D increased sharply for those within the top quantile of the PGS distribution resulting in an OR of 19.16 (p < 2 × 10
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/genetics ; Risk Factors ; Germany/epidemiology
Language	English
Publishing date	2023-03-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-31496-w
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Article ; Online: Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

Schaefer, Benedikt / Pammer, Lorenz M / Pfeifer, Bernhard / Neururer, Sabrina / Troppmair, Maria R / Panzer, Marlene / Wagner, Sonja / Pertler, Elke / Gieger, Christian / Kronenberg, Florian / Lamina, Claudia / Tilg, Herbert / Zoller, Heinz

Liver international : official journal of the International Association for the Study of the Liver

2024 Volume 44, Issue 3, Page(s) 838–847

Abstract: Background and aims: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of ... ...

Abstract	Background and aims: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. Methods: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. Results: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. Conclusion: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.
MeSH term(s)	Female ; Humans ; Male ; Middle Aged ; Hemochromatosis/epidemiology ; Hemochromatosis/genetics ; Hemochromatosis/complications ; Penetrance ; Carcinoma, Hepatocellular/epidemiology ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/complications ; Cohort Studies ; Incidence ; Histocompatibility Antigens Class I/genetics ; Hemochromatosis Protein/genetics ; Iron Overload/complications ; Homozygote ; Liver Cirrhosis/complications ; Liver Neoplasms/epidemiology ; Liver Neoplasms/genetics ; Liver Neoplasms/complications ; Mutation
Chemical Substances	Histocompatibility Antigens Class I ; Hemochromatosis Protein ; HFE protein, human
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.15797
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Article ; Online: Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity.

Harrer, Philip / Inderhees, Julica / Zhao, Chen / Schormair, Barbara / Tilch, Erik / Gieger, Christian / Peters, Annette / Jöhren, Olaf / Fleming, Thomas / Nawroth, Peter P / Berger, Klaus / Hermesdorf, Marco / Winkelmann, Juliane / Schwaninger, Markus / Oexle, Konrad

EBioMedicine

2024 Volume 101, Page(s) 105007

Abstract: Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, ... ...

Abstract	Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. Methods: MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n = 482; BiDirect, n = 822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. Findings: Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ = 0.6) than between 3-DG and MG or GO (ρ = 0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p = 2.3 × 10 Interpretation: This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. Funding: Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).
MeSH term(s)	Humans ; Genome-Wide Association Study ; gamma-Glutamyltransferase ; Glomerular Filtration Rate ; Pyruvaldehyde/metabolism ; Glyoxal/metabolism ; Glucose ; Polymorphism, Single Nucleotide
Chemical Substances	gamma-Glutamyltransferase (EC 2.3.2.2) ; Pyruvaldehyde (722KLD7415) ; Glyoxal (50NP6JJ975) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2024-02-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2024.105007
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Article ; Online: Common electrocardiogram measures are not associated with telomere length.

von Falkenhausen, Aenne S / Freudling, Rebecca / Waldenberger, Melanie / Gieger, Christian / Peters, Annette / Müller-Nurasyid, Martina / Kääb, Stefan / Sinner, Moritz F

Aging

2022 Volume 14, Issue 14, Page(s) 5620–5627

Abstract: Aims: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, ... ...

Abstract	Aims: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, conduction, and repolarization. ECG measures also prolong with aging and are associated with cardiac pathologies including atrial fibrillation. As premature prolongation of ECG measures is observed, we hypothesized that such prolongation may be associated with telomere length. Methods and results: We studied the large, community-based KORA F4 Study. Of 3,080 participants enrolled between 2006 and 2007 with detailed information on demographic, anthropometric, clinical, and ECG characteristics, 2,575 presented with available data on leukocyte telomere length. Telomere length was determined by real-time quantitative PCR and expressed relative to a single copy gene. We fitted multivariable adjusted linear regression models to associate the ECG measures RR-interval, PR-interval, QRS-duration, and heart rate corrected QTc with telomere length. In our cohort, the mean age was 54.9±12.9 years and 46.6% were men. Increased age was associated with shorter telomere length (p<0.01), and men had shorter telomere length than women (p<0.05). In unadjusted models, heart rate (p=0.023), PR-interval (p<0.01), and QTc-interval (p<0.01) were significantly associated with shorter telomere length. However, no significant associations remained after accounting for age, sex, and covariates. Conclusions: ECG measures are age-dependent, but not associated with shortened telomere length as a marker of biological aging. Further research is warranted to clarify if shortened telomeres are associated with clinical cardiac pathologies including atrial fibrillation.
MeSH term(s)	Aged ; Aging/genetics ; Atrial Fibrillation/diagnosis ; Atrial Fibrillation/genetics ; Electrocardiography ; Female ; Humans ; Leukocytes ; Male ; Telomere/genetics ; Telomere Shortening
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.204149
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Article ; Online: Association between a polygenic and family risk score on the prevalence and incidence of myocardial infarction in the KORA-F3 study.

Schnitzer, Florian / Forer, Lukas / Schönherr, Sebastian / Gieger, Christian / Grallert, Harald / Kronenberg, Florian / Peters, Annette / Lamina, Claudia

Atherosclerosis

2022 Volume 352, Page(s) 10–17

Abstract: Background and aims: Genetic risk scores for common diseases as myocardial infarction (MI) gain increasing attention for individual's risk prediction. One might wonder if assessing family history becomes redundant. It was the aim of this study to ... ...

Abstract	Background and aims: Genetic risk scores for common diseases as myocardial infarction (MI) gain increasing attention for individual's risk prediction. One might wonder if assessing family history becomes redundant. It was the aim of this study to evaluate the amount of shared information between family history and genetic risk scores and to assess their independent and combined effects on prevalent and incident MI risk. Methods: A genome wide polygenic risk score (PGS) and one family risk score (FamRS) were calculated in a population-based study from Southern Germany (n = 3071) with up to 11 years of follow-up. Logistic and Cox Regression models were used adjusting for lifestyle and classical risk factors. Results: A right shift in MI risk for increasing values of PGS was found, with. considerably increasing ORs along the top quantiles of PGS (OR = 3.03 for top 10%; OR = 5.55 for top 2.5%). The PGS was not associated with incident MI cases, though. The FamRS was significantly associated with both prevalent and incident MI cases with an OR of 2.9 for participants with a strong positive family history compared to average. ORs and HRs did hardly change in a combined model including both measures, indicating independent contribution to MI risk. The simultaneous addition of PGS and FamRS to a model including classical risk factors significantly enhanced prediction for prevalent cases and non-cases (p = 3.28 × 10 Conclusions: These findings emphasize that both genetic information and family history are relevant for the determination of MI risk and that neither of them can replace the other.
MeSH term(s)	Humans ; Incidence ; Multifactorial Inheritance ; Myocardial Infarction/diagnosis ; Myocardial Infarction/epidemiology ; Myocardial Infarction/genetics ; Prevalence ; Risk Factors
Language	English
Publishing date	2022-05-21
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2022.05.014
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Article: Validation of the 30-Year Framingham Risk Score in a German Population-Based Cohort.

Rospleszcz, Susanne / Starnecker, Fabian / Linkohr, Birgit / von Scheidt, Moritz / Gieger, Christian / Schunkert, Heribert / Peters, Annette

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 4

Abstract: The Framingham Risk Score to predict 30-year risk (FRS30y) of cardiovascular disease (CVD) constitutes an important tool for long-term risk prediction. However, due to its complex statistical properties and the paucity of large population-based cohorts ... ...

Abstract	The Framingham Risk Score to predict 30-year risk (FRS30y) of cardiovascular disease (CVD) constitutes an important tool for long-term risk prediction. However, due to its complex statistical properties and the paucity of large population-based cohorts with appropriate data, validation of the FRS30y is lacking. A population-based cohort from Southern Germany (N = 3110, 1516 (48.7%) women) was followed up for a median time of 29.5 [18.7, 31.2] years. Discrimination and calibration were assessed for the original, recalibrated and refitted FRS30y version. During follow up, 620 incident CVD events (214 in women) occurred. The FRS30y showed adequate discrimination (original and recalibrated version: Area under the curve (AUC): 78.4 for women and 74.9 for men) but overestimated actual CVD risk (original version: discordance 45.4% for women and 37.3% for men, recalibrated version: 37.6% and 28.6%, respectively). Refitting showed substantial improvement in neither discrimination nor calibration. The performance of FRS30y is adequate for long-term CVD risk prediction and could serve as an important tool in risk communication, especially for younger audiences.
Language	English
Publishing date	2022-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12040965
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Article ; Online: A Family and a Genome-Wide Polygenic Risk Score Are Independently Associated With Stroke in a Population-Based Study.

Hämmerle, Michelle / Forer, Lukas / Schönherr, Sebastian / Peters, Annette / Grallert, Harald / Kronenberg, Florian / Gieger, Christian / Lamina, Claudia

Stroke

2022 Volume 53, Issue 7, Page(s) 2331–2339

Abstract: Background: Positive family history and genetic risk scores have been shown to independently capture those individuals with high risk for stroke. The aim of our study was to evaluate the amount of shared information between family history and genetic ... ...

Abstract	Background: Positive family history and genetic risk scores have been shown to independently capture those individuals with high risk for stroke. The aim of our study was to evaluate the amount of shared information between family history and genetic risk and to investigate their combined effect on the association with prevalent and incident stroke cases. Methods: We obtained a family risk score (FamRS), weighted for disease onset and family size as well as genome-wide polygenic risk score (PGS) including over 3.2 million single-nucleotide polymorphisms in the population-based prospective KORA F3 (Cooperative Health Research in the Region of Augsburg) study (n=3071) from Southern Germany. FamRS and PGS were evaluated separately and combined. The measures were once treated as continuous variables but also divided in the highest 20%, 10%, 5%, and 1% percentiles. Odds ratios via logistic regression and hazard ratios via Cox regression were estimated. A stroke event was defined as a hospitalization for stroke that was self-reported in a standardized interview by certified and supervised personnel. Results: The FamRS outperformed other simplified family measures such as affected parents or number of affected family members. FamRS and PGS were not correlated, and no individuals were observed with both very high FamRS and very high PGS (top 1% percentile). In a combined model, both FamRS and PGS were independently from each other associated with risk of stroke, also independent of other traditional risk factors (p [FamRS]=0.02, p [PGS]=0.005). Individuals in the top 1% of either FamRS or PGS were found to have >5-fold risk for stroke (odds ratios, 5.82 [95% CI, 2.08-14]; Conclusions: Our study shows that a family risk score and PGS capture different information concerning individual stroke risk. Combining the risk measures FamRS and PGS increases predictive power, as demonstrated in a population-based study.
MeSH term(s)	Genome-Wide Association Study ; Humans ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide/genetics ; Prospective Studies ; Risk Factors ; Stroke/epidemiology ; Stroke/genetics
Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.121.036551
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Zs.A 448: Show issues

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Article ; Online: Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis.

Pott, Janne / Kheirkhah, Azin / Gadin, Jesper R / Kleber, Marcus E / Delgado, Graciela E / Kirsten, Holger / Forer, Lukas / Hauck, Stefanie M / Burkhardt, Ralph / Scharnagl, Hubert / Loeffler, Markus / März, Winfried / Thiery, Joachim / Gieger, Christian / Peters, Annette / Silveira, Angela / Hooft, Ferdinand Van't / Kronenberg, Florian / Scholz, Markus

Biology of sex differences

2024 Volume 15, Issue 1, Page(s) 26

Abstract: Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It ... ...

Abstract	Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. Methods: We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. Results: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10 Conclusions: We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.
MeSH term(s)	Male ; Humans ; Female ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Proprotein Convertase 9/genetics ; Proprotein Convertase 9/metabolism ; Genome-Wide Association Study ; Cholesterol, LDL/genetics ; Oxidoreductases, N-Demethylating ; Jumonji Domain-Containing Histone Demethylases
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Cholesterol, LDL ; JMJD1C protein, human (EC 1.14.11.-) ; Oxidoreductases, N-Demethylating (EC 1.5.-) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-)
Language	English
Publishing date	2024-03-26
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2587352-0
ISSN	2042-6410 ; 2042-6410
ISSN (online)	2042-6410
ISSN	2042-6410
DOI	10.1186/s13293-024-00602-6
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Article ; Online: Epigenome-wide association study of dietary fatty acid intake.

Lange de Luna, Julia / Nounu, Aayah / Neumeyer, Sonja / Sinke, Lucy / Wilson, Rory / Hellbach, Fabian / Matías-García, Pamela R / Delerue, Thomas / Winkelmann, Juliane / Peters, Annette / Thorand, Barbara / Beekman, Marian / Heijmans, Bastiaan T / Slagboom, Eline / Gieger, Christian / Linseisen, Jakob / Waldenberger, Melanie

Clinical epigenetics

2024 Volume 16, Issue 1, Page(s) 29

Abstract: Background: Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with ... ...

Abstract	Background: Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). Results: DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10 Conclusions: Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes.
MeSH term(s)	Humans ; Epigenome ; DNA Methylation ; Fatty Acids, Omega-3 ; Fatty Acids ; Docosahexaenoic Acids ; Repressor Proteins
Chemical Substances	Fatty Acids, Omega-3 ; Fatty Acids ; Docosahexaenoic Acids (25167-62-8) ; CDCA7L protein, human ; Repressor Proteins
Language	English
Publishing date	2024-02-16
Publishing country	Germany
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-024-01643-9
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Article: Metabolic Signatures Elucidate the Effect of Body Mass Index on Type 2 Diabetes.

Dong, Qiuling / Sidra, Sidra / Gieger, Christian / Wang-Sattler, Rui / Rathmann, Wolfgang / Prehn, Cornelia / Adamski, Jerzy / Koenig, Wolfgang / Peters, Annette / Grallert, Harald / Sharma, Sapna

Metabolites

2023 Volume 13, Issue 2

Abstract: Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA ... ...

Abstract	Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA FF4 cohort consisting of 1715 participants and associated them with obesity and type 2 diabetes. In the basic model, 83 and 51 metabolites were significantly associated with body mass index (BMI) and T2D, respectively. Those metabolites are branched-chain amino acids, acylcarnitines, lysophospholipids, or phosphatidylcholines. In the full model, 42 and 3 metabolites were significantly associated with BMI and T2D, respectively, and replicate findings in the previous studies. Sobel mediation testing suggests that the effect of BMI on T2D might be mediated via lipids such as sphingomyelin (SM) C16:1, SM C18:1 and diacylphosphatidylcholine (PC aa) C38:3. Moreover, mendelian randomization suggests a causal relationship that BMI causes the change of SM C16:1 and PC aa C38:3, and the change of SM C16:1, SM C18:1, and PC aa C38:3 contribute to T2D incident. Biological pathway analysis in combination with genetics and mice experiments indicate that downregulation of sphingolipid or upregulation of phosphatidylcholine metabolism is a causal factor in early-stage T2D pathophysiology. Our findings indicate that metabolites like SM C16:1, SM C18:1, and PC aa C38:3 mediate the effect of BMI on T2D and elucidate their role in obesity related T2D pathologies.
Language	English
Publishing date	2023-02-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo13020227
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