Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes

Diabetes-associated metabolites may aid the identification of new risk variants for type 2 diabetes. Using targeted metabolomics within a subsample of the German EPIC-Potsdam study (n = 2500), we tested previously published SNPs for their association with diabetes-associated metabolites and conducted an additional exploratory analysis using data from the exome chip including replication within 2,692 individuals from the German KORA F4 study. We identified a total of 16 loci associated with diabetes-related metabolite traits, including one novel association between rs499974 (MOGAT2) and a diacyl-phosphatidylcholine ratio (PC aa C40:5/PC aa C38:5). Gene-based tests on all exome chip variants revealed associations between GFRAL and PC aa C42:1/PC aa C42:0, BIN1 and SM (OH) C22:2/SM C18:0 and TFRC and SM (OH) C22:2/SM C16:1). Selecting variants for gene-based tests based on functional annotation identified one additional association between OR51Q1 and hexoses. Among single genetic variants consistently associated with diabetes-related metabolites, two (rs174550 (FADS1), rs3204953 (REV3L)) were significantly associated with type 2 diabetes in large-scale meta-analysis for type 2 diabetes. In conclusion, we identified a novel metabolite locus in single variant analyses and four genes within gene-based tests and confirmed two previously known mGWAS loci which might be relevant for the risk of type 2 diabetes

Prevalence and Infant Mortality of Major Congenital Malformations Stratified by Birthweight

Background: Low birthweight and major congenital malformations (MCMs) are key causes of infant mortality. Objectives: The aim of this study was to explore the prevalence of MCMs in infants with low and very low birthweight and analyze the impact of MCMs and birthweight on infant mortality. Methods: We determined prevalence and infant mortality of 28 life-threatening MCMs in very-low-birthweight (75% (10,316) had severe congenital heart disease. The prevalence (per 10,000) of any/cardiac MCM was increased in VLBW (286/176) and LBW (244/143), as compared to NBW infants (38/32). Infant mortality rates were significantly higher in infants with an MCM, as opposed to infants without an MCM, in each birthweight group (VLBW 28.5% vs. 11.5%, LBW 16.7% vs. 0.9%, and NBW 8.6% vs. 0.1%). For most MCMs, observed survival rates in VLBW and LBW infants were lower than expected, as calculated from survival rates of VLBW or LBW infants without an MCM, and NBW infants with an MCM. Conclusions: Infants with an MCM are more often born with LBW or VLBW, as opposed to infants without an MCM. Many MCMs carry significant excess mortality when occurring in VLBW or LBW infants

Advancing Precision Vaccinology by Molecular and Genomic Surveillance of Severe Acute Respiratory Syndrome Coronavirus 2 in Germany, 2021

Background Comprehensive pathogen genomic surveillance represents a powerful tool to complement and advance precision vaccinology. The emergence of the Alpha variant in December 2020 and the resulting efforts to track the spread of this and other severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern led to an expansion of genomic sequencing activities in Germany. Methods At Robert Koch Institute (RKI), the German National Institute of Public Health, we established the Integrated Molecular Surveillance for SARS-CoV-2 (IMS-SC2) network to perform SARS-CoV-2 genomic surveillance at the national scale, SARS-CoV-2–positive samples from laboratories distributed across Germany regularly undergo whole-genome sequencing at RKI. Results We report analyses of 3623 SARS-CoV-2 genomes collected between December 2020 and December 2021, of which 3282 were randomly sampled. All variants of concern were identified in the sequenced sample set, at ratios equivalent to those in the 100-fold larger German GISAID sequence dataset from the same time period. Phylogenetic analysis confirmed variant assignments. Multiple mutations of concern emerged during the observation period. To model vaccine effectiveness in vitro, we employed authentic-virus neutralization assays, confirming that both the Beta and Zeta variants are capable of immune evasion. The IMS-SC2 sequence dataset facilitated an estimate of the SARS-CoV-2 incidence based on genetic evolution rates. Together with modeled vaccine efficacies, Delta-specific incidence estimation indicated that the German vaccination campaign contributed substantially to a deceleration of the nascent German Delta wave. Conclusions SARS-CoV-2 molecular and genomic surveillance may inform public health policies including vaccination strategies and enable a proactive approach to controlling coronavirus disease 2019 spread as the virus evolves.Peer Reviewe

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention

Synopse virologischer Analysen im Nationalen Referenzzentrum für Influenzaviren während der COVID-19-Pandemie

Das Nationale Referenzzentrum für Influenzaviren gewinnt durch die fortlaufende Untersuchung von Proben aus den Sentinelpraxen der Arbeitsgemeinschaft Influenza einen umfassenden Überblick über die zirkulierenden respiratorischen Erreger in Deutschland. Dazu gehören neben SARS-CoV-2 und den Influenzaviren auch das Respiratorische Synzytialvirus, Parainfluenzaviren, humane Metapneumoviren, humane saisonale Coronaviren und humane Rhinoviren. Die Analyseergebnisse von 15.660 Sentinelproben sowie weiteren Isolaten im Zeitraum von Kalenderwoche 5/2020 bis 21/2022 werden im Epidemiologischen Bulletin 22/2022 vorgestellt. Beschrieben werden außerdem die Zirkulation respiratorischer Erreger im Vergleich zu vorpandemischen Saisons, die molekulare Charakterisierung und phylogenetische Analysen, die Überprüfung der Passgenauigkeit der eingesetzten Influenzaimpfstoffe und die Resistenzprüfung von Influenzaviren

A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study.

BACKGROUND: Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated. METHODS AND FINDINGS: We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991-1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19-0.29) adjusted for potential confounders and 0.37 (95% CI 0.27-0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding. CONCLUSIONS: A combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors

Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study.

BACKGROUND: Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations. METHODS AND FINDINGS: Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs. CONCLUSIONS: These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following sources: Medical Research Council Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5, and Medical Research Council Human Nutrition Research MC_UP_A090_1006 and Cambridge Lipidomics Biomarker Research Initiative G0800783; FLC and TJK: Cancer Research UK; JMH and MJT: Health Research Fund of the Spanish Ministry of Health; Murcia Regional Government (Nº 6236); MG: Regional Government of Navarre; -IS, DLvdA, AMWS, YTvdS: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands; Verification of diabetes cases in EPIC-NL was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; PWF: Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation; RK: German Cancer Aid, German Ministry of Research (BMBF); KTK: Medical Research Council UK, Cancer Research UK; PMN: Swedish Research Council; KO and AT: Danish Cancer Society; JRQ: Asturias Regional Government; OR: The Västerboten County Council; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; ER: Imperial College Biomedical Research Centre

Association between plasma phospholipid saturated fatty acids and metabolic markers of lipid, hepatic, inflammation and glycaemic pathways in eight European countries: a cross-sectional analysis in the EPIC-InterAct study.

BACKGROUND: Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. METHODS: We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. RESULTS: Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. CONCLUSIONS: Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake

Examination of the relation of dietary fatty acid intake and fatty acid status in erythrocytes to the risk of type 2 diabetes in the EPIC-Potsdam study

Hintergrund: Die langfristige Rolle von Fettsäuren (FS) in der Ätiologie des Typ-2-Diabetes ist noch nicht ausreichend erforscht. Aufgrund der bekannten Limitationen traditioneller Ernährungserhebungsinstrumente erfährt der Einsatz von FS-Biomarkern seit einiger Zeit zunehmendes Interesse. FS-Biomarker reflektieren zudem das biologisch relevante FS-Profil an der Schnittstelle zwischen der Ernährung und metabolischen Prozessen. Ziel: Das Ziel dieser Arbeit war, den Zusammenhang der FS-Zufuhr, der FS-Zusammensetzung von Erythrozytenmembranen und der Aktivitäten von FS-Desaturasen mit der Inzidenz des Typ-2-Diabetes zu untersuchen. Design: Für die vorliegende Arbeit wurden die Daten der European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam-Studie ausgewertet, einer prospektiven Kohortenstudie mit 27 548 Studienteilnehmern. Für die Analysen zur FS-Zufuhr fand ein Kohortendesign (n=25 069) Anwendung, während für Auswertungen zu biologischen Markern das Design einer eingebetteten Fall-Kohorten-Studie (n=2 724) gewählt wurde. Die Bestimmung der Zufuhr von FS mit der Nahrung (Erhebung mit einem Verzehrshäufigkeitenfragebogen (FFQ), FS-Zufuhr ausgedrückt als % der Energiezufuhr) und der Proportionen von FS in Erythrozytenmembranen (Bestimmung durch Gaschromatographie, FS ausgedrückt als % aller FS) erfolgte zur Basis. Ärztlich verifizierte Fälle einer inzidenten Erkrankung an Typ-2-Diabetes (n=849) wurden während einer mittleren Nachbeobachtungszeit von 7,0 Jahren identifiziert. Die Aktivitäten der Δ5-Desaturase (D5D) und Δ6-Desaturase (D6D) wurden zum einen anhand von FS-Verhältnissen in den Erythrozyten (traditioneller Ansatz) und zum anderen anhand von genetischen Varianten in den FADS1- und FADS2-Genen evaluiert, welche für diese beiden Desaturasen kodieren (Ansatz der Mendelschen Randomisierung). Zur Analyse der Zusammenhänge mit dem Diabetes-Risiko fand das proportionale Hazard-Modell nach Cox Anwendung unter Einbeziehung verschiedener Kovariate. Ergebnisse: Das FS-Profil von Erythrozytenmembranen stellte sich als starker Prädiktor des Diabetes-Risikos heraus. Die stärksten direkten Assoziationen mit dem Risiko wurden für Proportionen von γ-Linolensäure, Dihomo-γ-Linolensäure und Palmitoleinsäure beobachtet, während für die Proportion von Linolsäure die stärkste inverse Assoziation mit dem Risiko detektiert wurde. Zudem standen FS-Verhältnisse, die als geschätzte Aktivitäten von Desaturasen interpretiert werden, in einem sehr starken Zusammenhang mit dem Diabetes-Risiko. So wurde eine klare direkte Risikobeziehung für die geschätzten Aktivitäten der SCD und D6D und eine starke inverse Risikobeziehung für die geschätzte Aktivität der D5D beobachtet (traditioneller Ansatz). Unter Verwendung von Genotypinformationen für die FADS1- und FADS2-Gene konnte in der vorliegenden Arbeit die direkte Risikobeziehung für die D6D bekräftigt werden und die inverse Risikobeziehung für die D5D tendenziell auch bestätigt werden (Ansatz der Mendelschen Randomisierung). Die Nahrungszufuhr von FS laut FFQ korrelierte nur moderat bis schwach mit den entsprechenden FS-Proportionen in Erythrozyten und war, wenn überhaupt, nur schwach mit dem Diabetes-Risiko assoziiert. Schlussfolgerung: Das FS-Profil von Erythrozytenmembranen und die Aktivitäten von Desaturasen stehen in einem starken Zusammenhang mit dem Risiko für Typ-2-Diabetes. Die Beziehungen der D5D- und D6D-Aktivitäten mit dem Diabetes-Risiko sind nicht durch umgekehrte Kausalität erklärbar und können wahrscheinlich auch nicht auf Confounding zurückgeführt werden.Background: The long-term role of fatty acids (FAs) in the etiology of type 2 diabetes remains largely unclear. Given the well-known limitations of traditional dietary assessment methods, the use of FA biomarkers has received particular interest. FA biomarkers may be measurable more accurately than dietary FAs and reflect the biologically relevant FA profile. Objective: The aim of this thesis was to investigate dietary FAs, erythrocyte membrane FAs, and activities of FA desaturases in relation to the incidence of type 2 diabetes. Design: The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study involves 27,548 subjects. A cohort design (n=25,069) was applied for dietary studies and a nested case-cohort design (n=2,724) for biomarker studies. FA intake (assessed with a food frequency questionnaire (FFQ), FA intake expressed as % of total energy intake) and erythrocyte membrane FAs (determined by gas chromatography, FAs expressed as % of total FAs) were measured at baseline and physician-confirmed incident type 2 diabetes (n=849) was assessed during a mean follow-up of 7.0 years. Δ5 desaturase (D5D) and Δ6 desaturase (D6D) activities were evaluated by using FA product-to-precursor ratios in erythrocytes (traditional approach) and by investigating variants in FADS1 and FADS2 genes that encode these desaturases (Mendelian randomization approach). Cox proportional hazards analysis with multivariable adjustments was applied to study relations to the incidence of type 2 diabetes. Results: The FA profile of erythrocyte membranes was clearly associated with diabetes risk. The strongest direct relations with risk were observed for proportions of γ-linolenic acid, dihomo-γ-linolenic acid, and palmitoleic acid, whereas the strongest inverse relation was detected for linoleic acid. Furthermore, ratios of erythrocyte FAs that reflect desaturase activities were strongly associated with diabetes incidence. FA ratios that estimate stearoyl CoA desaturase (SCD) and D6D activity were clearly positively associated with risk, whereas the FA ratio that reflects D5D activity showed a strong negative risk relation (traditional approach). The Mendelian randomization approach corroborated the direct risk relation for D6D activity and tended to support the inverse relation for D5D activity. Dietary FAs as assessed with the FFQ showed only modest to low correlations with erythrocyte FAs and were, if at all, only weakly associated with diabetes risk. Conclusions: The FA profile of erythrocyte membranes and activities of desaturases are strongly linked to the risk of type 2 diabetes. The relations of D5D and D6D activity to diabetes risk are not subject to reverse causation and are not likely to be explainable by confounding