Variation in mitochondrial genes in obesity

Nach Angaben der WHO, waren im Jahre 2008 mehr als 35 % aller Erwachsenen übergewichtig (BMI ≥ 25 kg/m^2) und 11 % adipös (BMI ≥ 30 kg/m^2). Obwohl in den letzten fünf bis zehn Jahren ein stabilisierender Trend in der Prävalenz zu verzeichnen war, stellt Adipositas wegen gesundheitlicher Konsequenzen im späteren Leben wie z.B. Type 2 Diabetes Mellitus (T2DM) immer noch ein globales Gesundheitsproblem dar. Sowohl Umwelt- als auch genetische Faktoren sind für die globale Adipositasepidemie verantwortlich. In empirischen Studien wurde die Erblichkeit der Varianz des BMI auf 40 % bis 70 % geschätzt. Interessanterweise wurden größere Korrelationen zwischen mütterlichem und kindlichem BMI, als zwischen väterlichem und kindlichem gefunden. Mitochondrien sind als Kraftwerke der Zelle bekannt und besitzen eine ausschließlich mütterlich vererbte zirkuläre DNA (mtDNA) von 16.569 bp. Diese kodiert 37 Gene; 13 dieser Gene stellen proteinkodierende Untereinheiten des oxidativen Phosphorylierungssystems (OXPHOS) dar. Auf der anderen Seite werden ~1.000 bis 1.500 kernkodierte Gene benötigt, um die mitochondriale Biogenese aufrechtzuerhalten. Änderungen der mitochondrialen Funktion wurden in ädipösen Individuen gefunden. Im Rahmen dieser Doktorarbeit wurden Variationen in der mtDNA sowie in kernkodierten mitochondrialen Genen in Assoziation mit Adipositas analysiert, aufgrund (1) der zentralen Rolle der Mitochondrien im Energiemetabolismus, (2) von Hinweisen auf eine veränderte mitochondriale Funktion bei Adipösen und (3) des elterlichen Effekts höherer mütterlicher-kindlicher BMI Korrelationen, zu diesem genetische Variationen der ausschließlich mütterlich vererbten mtDNA beitragen könnten. Zur Analyse der Variation in der mtDNA wurde zunächst eine Assoziationsstudie von bis zu 40 chipbasierten mtDNA SNPs (welche bis auf einen in der kodierenden Region der mtDNA zu finden sind) in einem Fall-Kontroll-Kollektiv von 1.158 (extrem-) adipösen Kindern und Jugendlichen und 435 schlanken erwachsenen Kontrollen durchgeführt. Die SNPs wurden als einzelne SNPs und Haplogruppen, welche mittels HaploGrep bestimmt wurden, analysiert. Die Analysen wurden (a) in allen Individuen und (b) geschlechtsgetrennt durchgeführt. Zur unabhängigen Bestätigung wurden nominal assoziierte SNPs in Erwachsenen aus drei populationsbasierten Kohorten weiterverfolgt, wobei nur die insgesamt 1.697 adipösen Fälle den 2.373 normalgewichtigen Kontrollen gegenübergestellt wurden. Zur Identifizierung weiterer Varianten wurde die mitochondriale Kontrollregion (D-loop) von je 192 Fällen und Kontrollen re-sequenziert (Sanger). Ein zwei-seitiger exakter Fisher Test wurde als Assoziationstest verwendet. Fünf SNPs (m.4769A/G, m.8994G/A, m.11674C/T, m.12612A/G und m.13708G/A) und zwei Haplogruppen (W, J) waren initial nominal mit Adipositas (a) in allen Individuen (m.8994G/A, W) oder (b) geschlechtsgetrennt assoziiert. Jedoch konnte keiner dieser SNPs bzw. Haplogruppen im unabhängigen Kollektiv bestätigt werden. Durch Re-Sequenzierung wurden 252 Varianten gefunden. Die Frequenzen zweier Varianten unterschieden sich nominal zwischen Fällen und Kontrollen (m.16189T/C, m.16292C/T). m.16189T/C war häufiger in den Fällen (17 % vs. 9 %; p=0,048), wohingegen 16292T nur in acht Kontrollen zu finden war. Zur Analyse der kernkodierten mitochondrialen Gene wurde eine „gene set enrichment analysis“ (GSEA) durchgeführt und drei Gensets, die im Vorfeld in Assoziation mit T2DM analysiert wurden, verwendet: (1) 16 kernkodierte Regulatoren der mitochondrialen Gene, (2) 91 OXPHOS Gene und (3) 966 kernkodierte mitochondriale Gene. Im Discovery-Schritt wurde eine GSEA in einem Fall-Kontroll-Kollektiv von 453 (extrem-) adipösen Kindern und Jugendlichen und 435 schlanken erwachsenen Kontrollen durchgeführt. Zur unabhängigen Bestätigung wurden 705 Adipositastrios sowie ein populationsbasiertes Erwachsenenkollektiv, welches als Fall-Kontroll-Kollektiv analysiert wurde (463 adipöse Fälle vs. 483 normalgewichtige Kontrollen, KORA-CC), verwendet. Zudem wurde eine Metaanalyse aus allen drei Kollektiven durchgeführt. Die Verteilung der Assoziationssignale (d.h. Gen-korrigierte p-Werte Pg) zwischen einem Gensets und dem Genset aller Gene wurden mittels leading-edge-fraction-comparison Test verglichen. Dafür wurden Cut-offs zwischen der 50. und 75. Perzentile des Sets aller Pg verwendet. Zudem wurden alternative Tests wie z.B. der Wilcoxon-Mann-Whitney-Test durchgeführt. Im Discovery-Schritt war Genset 1 signifikant für moderate bis schwache Assoziationssignale oberhalb der 50. Perzentile angereichert (pGSEA,50=0.0103). Diese Anreicherung wurde nicht in den Adipositastrios bestätigt, jedoch in KORA-CC. In der Metaanalyse wurde keine Anreicherung oberhalb der 50., jedoch oberhalb der 75. Perzentile gefunden. Schlussfolgernd lässt sich sagen, dass bei der Analyse der bis zu 40 Chipbasierten häufigen mtDNA SNPs weder ein einzelner SNP noch eine Haplogruppe robust mit Adipositas assoziiert war. Bezüglich der D-loop SNPs erscheint m.16189T/C vielversprechend, in einem unabhängigen Kollektiv weiterverfolgt zu werden, wohingegen m.16292C/T eher falsch positiv sein könnte, da fünf der acht Träger des T-Allels zur Haplogruppe W gehörten, deren Assoziation nicht unabhängig bestätigt werden konnte. Im Hinblick auf die kernkodierten mitochondrialen Gene konnten im Genset der 16 kernkodierten Regulatoren der mitochondrialen Gene durch eine GSEA eine Anreicherung moderater bis schwacher Assoziationssignale ermittelt werden. Die Ergebnisse der vorliegenden Doktorarbeit liefern zwar nur einen kleinen Beitrag, tragen jedoch dazu bei, die Erblichkeit der Varianz des BMI auf molekulargentischer Ebene zu entschlüsseln.In 2008, more than 35 % of the world’s adult population were overweight (BMI ≥ 25 kg/m^2) and 11 % were obese (BMI ≥ 30 kg/m^2). Although in the last five to ten years a stabilizing trend in prevalence had been observed, obesity still is a major global health problem, because of health consequences in later life such as type 2 diabetes mellitus (T2DM). Both environmental and genetic factors were shown to contribute to the global obesity epidemic. In empirical studies, the heritability of the BMI variance was estimated to 40 % to 70 %. Interestingly, larger correlations in BMI between mothers and their offspring than between fathers and their offspring were found. Mitochondria are well known as cellular power plants and contain an exclusively maternally inherited circular DNA (mtDNA) of 16,569 bp with 37 genes of which 13 are protein coding subunits of the oxidative phosphorylation system (OXPHOS). On the other hand, ~1,000 to 1,500 nuclear-encoded genes are required to maintain mitochondrial biogenesis. Alterations in mitochondrial function were found in obese individuals. Both variation of mtDNA and nuclear-encoded mitochondrial genes have been analyzed in association with obesity within the present PhD thesis, because of (1) the central role of mitochondria in the energy metabolism, (2) hints of altered mitochondrial function in obese individuals, and (3) the parental effect of correlations in BMI to which genetic variation in the exclusively maternally inherited mtDNA might contribute. For analysis of variation in mtDNA, first of all, an association study of up to 40 array-based SNPs of mtDNA (all but one of the SNPs located in mtDNA coding region) was performed in a case-control (CC) sample of 1,158 (extremely) obese cases and 435 lean adult controls (discovery). SNPs were analyzed as single SNPs and as haplogroups determined by HaploGrep. Analysis was done (a) in all individuals and (b) stratified by gender. For independent confirmation, nominally associated SNPs were followed-up among adults of three population-based samples analyzed as CC sample of 1,697 obese cases and 2,373 normal weight controls. In addition, the mtDNA control region (D-loop) of each 192 cases and controls was screened for variants by re-sequencing (Sanger). Fisher’s two-sided exact test was used for association testing. Five SNPs (m.4769A/G, m.8994G/A, m.11674C/T, m.12612A/G and m.13708G/A) and two haplogroups (W, J) were initially found to be nominally associated with obesity (a) in the whole sample (m.8994G/A, W) or (b) stratified by gender, but none of these SNPs or haplogroups could be confirmed in the independent sample. By re-sequencing, 252 variants were detected. Frequencies of two of these variants differed nominally between cases and controls (m.16189T/C, m.16292C/T). m.16189C was more frequent among the cases (17 % vs. 9 %; p=0.048), while 16292T was only found in eight controls. For analysis of nuclear-encoded mitochondrial genes, a gene set enrichment analysis (GSEA) was performed using three gene sets previously investigated in association with T2DM: (1) 16 nuclear-encoded regulators of mitochondrial genes, (2) 91 OXPHOS genes, and (3) 966 nuclear-encoded human mitochondrial genes. For discovery, GSEA was performed in a CC sample of 453 (extremely) obese cases and 435 lean adult. Independent confirmation occurred in a family-based sample of 705 obesity trios and an adult population-based analyzed as a CC sample (463 obese cases and 483 normal weight controls, KORA-CC). A meta-analysis of all three samples was performed. The distribution of association signals (i.e. gene-wise corrected p-values Pg) between a gene set and the gene set of all genes was compared using a leading-edge-fraction-comparison test with cut-offs between the 50th and the 95th percentile in the set of all Pg and alternative tests (e.g. Wilcoxon-Mann-Whitney-test). In the discovery, gene set 1 was significantly enriched for modest to weak association signals above the 50th percentile (pGSEA,50=0.0103). This enrichment was not confirmed in the trios, but in KORA-CC. In the meta-analysis, enrichment was not detected above the 50th percentile, but above the 75th. In conclusion, analysis of up to 40 array-based common mtDNA SNPs did not lead to robust association of either a single mtDNA SNP or a haplogroup. Pertaining to D-loop variants, m.16189T/C seems to be promising to be followed-up in a further sample for independent confirmation of the initial association. The results of variant m.16292C/T, by contrast, might be rather spurious as five of the eight controls carrying the variant allele T were of haplogroup W, association of which could not be independently confirmed. Regarding nuclear-encoded mitochondrial genes, GSEA revealed that modest to weak association signals for obesity might be enriched in the gene set of 16 nuclear-encoded regulators of mitochondrial genes. Although the impact is small, the results of the present thesis contribute to elucidate the heritability of the BMI variance on a molecular genetic level

High content of long-chain n-3 polyunsaturated fatty acids in red blood cells of Kenyan Maasai despite low dietary intake

<p>Abstract</p> <p>Background</p> <p>Increasing land restrictions and a reduced livestock-to-human ratio during the 20th century led the Maasai to lead a more sedentary, market-orientated lifestyle. Although plant-derived food nowadays contributes substantially to their diet, dairy products being high in saturated fatty acids (SFA) and low in polyunsaturated fatty acids (PUFA) still are an important energy source. Since reliable data regarding the Maasai diet date back to the 1980s, the study objective was to document current diet practices in a Kenyan Maasai community and to investigate the fatty acid distribution in diet and red blood cells.</p> <p>Methods</p> <p>A cross-sectional study was conducted among 26 Maasai (20 women, 6 men) from Loodokilani, Kajiado District, Kenya. Food intake was described by the subjects via 24-h recall, and both food and blood samples were analysed.</p> <p>Results</p> <p>Two main foods - milk and <it>ugali </it>- constituted the Maasai diet in this region. A total of 0.9 L of milk and 0.6 kg of <it>ugali </it>were consumed per person and day to yield an energy intake of 7.6 MJ/d per person. A major proportion of ingested food contributing 58.3% to the total dietary energy (en%) was plant-derived, followed by dairy products representing 41.1 en%. Fat consumed (30.5 en%) was high in SFA (63.8%) and low in PUFA (9.2%). Long-chain n-3 PUFA (EPA, DPA and DHA) made up only 0.15% of the ingested fatty acids, but 5.9% of red blood cell fatty acids.</p> <p>Conclusion</p> <p>The study indicates the Maasai diet is rich in SFA and low in PUFA. Nevertheless, red blood cells are composed of comparable proportions of long-chain n-3 PUFA to populations consuming higher amounts of this fatty acid group.</p

Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth: A Randomized Controlled Noninferiority Trial

Objective: A high protein content of nonhydrolyzed infant formula exceeding metabolic requirements can induce rapid weight gain and obesity. Hydrolyzed formula with too low protein (LP) content may result in inadequate growth. The aim of this study was to investigate noninferiority of partial and extensively hydrolyzed formulas (pHF, eHF) with lower hydrolyzed protein content than conventionally, regularly used formulas, with or without synbiotics for normal growth of healthy term infants. Methods: In an European multi-center, parallel, prospective, controlled, double-blind trial, 402 formula-fed infants were randomly assigned to four groups: LP-formulas (1.9 g protein/100 kcal) as pHF with or without synbiotics, LP-eHF formula with synbiotics, or regular protein eHF (2.3 g protein/100 kcal). One hundred and one breast-fed infants served as observational reference group. As primary endpoint, noninferiority of daily weight gain during the first 4 months of life was investigated comparing the LP-group to a regular protein eHF group. Results: A comparison of daily weight gain in infants receiving LPpHF (2.15 g/day CI -0.18 to inf.) with infants receiving regular protein eHF showed noninferior weight gain (-3.5 g/day margin;per protocol [PP] population). Noninferiority was also confirmed for the other tested LP formulas. Likewise, analysis of metabolic parameters and plasma amino acid concentrations demonstrated a safe and balanced nutritional composition. Energetic efficiency for growth (weight) was slightly higher in LPeHF and synbiotics compared with LPpHF and synbiotics. Conclusions: All tested hydrolyzed LP formulas allowed normal weight gain without being inferior to regular protein eHF in the first 4 months of life

Auf Augenhöhe: Wissenstransfer zwischen Forschung und Praxis der ökologischen und nachhaltigen Land- und Lebensmittelwirtschaft (Teilprojekt des FiBL Deutschland e.V.)

Im vom FiBL bearbeiteten Teil des Projektes wurde ein sehr breiter Ansatz gewählt: Unterschiedlichste Akteure der ökologischen Landwirtschaft und Lebensmittelwirtschaft, die sich mit dem Thema Wissenstransfer beschäftigen, wurden angesprochen mit dem Ziel, sie zur Kooperation zu gewinnen und gemeinsam aktuelle Fragestellungen aus dem Bereich Wissenskommunikation zu bearbeiten. Eine Vernetzung mit Kolleg/innen in anderen Organisationen sollte aufgebaut werden, die die Projektlaufzeit überdauert und die Nachhaltigkeit sichert. Als Ergebnisse des Projekts entstanden Leitfäden/Praxishandreichungen zur Konzeption und Organisation von Veranstaltungen und von Videoaufnahmen. Weitere Praxishandreichungen stellen grundlegende Voraussetzungen zur Wissenskommunikation sowie aktuelle Werkzeuge für typische Netzwerkarbeiten im Steckbriefformat vor. Eine Tagung zur Wissenskommunikation wurde durchgeführt und dokumentiert. Die Tagungsdokumentation umfasst neben Videos, Fotos, Graphic Records auch die Präsentationen der Vorträge. Sie bietet einen fundierten Einblick in aktuelle Themen und Methoden der Wissenskommunikation. Zwei Vorhaben zur Praxisforschung wurden umgesetzt. Zum einen wurde der Aufbau des Verbunds zur ökologischen Praxisforschung V.Ö.P durch das Projekt begleitet. Der durch Bioland, Demeter und Naturland getragene Verbund bleibt auch nach Ende der Projektlaufzeit aktiv. Zum anderen wurden in einer Studie die Voraussetzungen für gelingende Praxisforschung in der Landwirtschaft analysiert. Mitarbeitende aus Organisationen der ökologischen Lebensmittelwirtschaft wurden im Rahmen einer Ausbildung im Bereich des Wissensmanagements qualifiziert. Die Teilnehmenden wurden dabei begleitet, Projekte des Wissensmanagements in ihren Organisationen durchzuführen und zu optimieren. Die DLG-Feldtage 2016 und die Öko-Feldtage 2017 dienten wiederum als Plattform für vielfältige Wissenstransfer-Veranstaltungen (Infostand, Vorträge, Diskussionen etc.) für die landwirtschaftliche Praxis

Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity

There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes

Global Landscape Review of Serotype-Specific Invasive Pneumococcal Disease Surveillance among Countries Using PCV10/13: The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) Project.

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon

Evaluation der Leibniz-WissenschaftsCampi. Bericht der ExpertInnenkommission

Evaluation der Leibniz-WissenschaftsCampi. Bericht der ExpertInnenkommissio

Development and Validation of the General Dietary Behavior Inventory (GDBI) in Scope of International Nutrition Guidelines

Unhealthy eating is associated with various diseases, such as cardiovascular, neurodegenerative, or oncological. There are neither economical nor behavior-related questionnaires available in the German language to assess general dietary behavior. Therefore, the aim of this validation study was to develop an instrument considering these aspects and verifying its construct and criterion validity. The new questionnaire is based on the general nutrition recommendations of the World Health Organization and the German Nutrition Society. It consists of 16 items that contrast dietary behaviors on a semantic differential scale. Our German-speaking convenience sample consisted of 428 participants. The construct validity of the General Dietary Behavior Inventory (GDBI) could be confirmed by examining convergent and discriminant validity. Furthermore, criterion validity was confirmed (significant negative correlations with body weight, Body Mass Index, and positive correlations with physical/mental health as well as life satisfaction). A cluster analysis revealed two different dietary behavior clusters representing a rather healthy and a rather unhealthy dietary behavior cluster. The results indicate that the GDBI is a validated and economical instrument to assess general dietary behavior. In practical research, this questionnaire helps to assess dietary behavior and to derive interventions for a healthy dietary behavior in concordance with international nutrition recommendations

Development and Validation of Dietary Behavior Inventory&mdash;Surgery (DBI-S) in the Scope of International Post-Bariatric Surgery Guidelines and Recommendations

(1) Dietary behavior is highly relevant for patients after bariatric surgery. No instrument exists assessing adherence to medical guidelines concerning the dietary behavior of patients after bariatric surgery. The aim of this study was to develop and validate such an instrument. (2) Data from patients after bariatric surgery (n = 543) were collected from March to May 2022. The development of the DBI-S was theory-based and interdisciplinary. Items&rsquo; and content validity of the DBI-S were examined. (3) The final version of the DBI-S consists of 13 items. Convergent validation was confirmed by significant correlations between DBI-S score and attitude towards healthy food (r = 0.26, p = &lt;0.001) and impulsivity (r = &minus;0.26, p = &lt;0.001). Criterion validity was confirmed by significant correlations between DBI-S score and pre-/post-surgery BMI difference (r = &minus;0.14, p = 0.002), pre-/post-surgery weight difference (r = 0.13, p = 0.003), and quality of life (r = 0.19, p = &lt;0.001). Cluster analysis confirmed the ability to distinguish between two dietary behavior clusters (rather healthy and rather unhealthy). (4) The DBI-S is an economic and valid instrument to assess the adherence of post-bariatric surgery patients to the relevant dietary behavior recommendations and guidelines and can distinguish between rather unhealthy and healthy dietary behavior