Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study.

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. CONCLUSIONS: Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.

Epidemiology, risk factors, and prediction score of carbapenem resistance among inpatients colonized or infected with 3rd generation cephalosporin resistant Enterobacterales.

In this study, we determined the incidence and risk factors of Carbapenem-resistant Enterobacterales (CRE) acquisition in inpatients with 3rd generation cephalosporin-resistant (3GCR) Enterobacterales at a tertiary-care hospital in Lebanon, and suggested a risk prediction score for it. This is a retrospective matched case-control study of inpatients with 3GCR Enterobacterales that are carbapenem resistant (cases) versus those with carbapenem-sensitive isolates (controls). Data analysis was performed on IBM SPSS program, version 23.0 (Armonk, NY, USA: IBM Corp.). Categorical variables were compared between cases and controls through bivariate analysis and those with statistical significance (P < 0.05) were included in the forward stepwise multiple logistic regression analysis. To develop the CRE acquisition risk score, variables that maintained statistical significance in the multivariate model were assigned a point value corresponding to the odds ratio (OR) divided by the smallest OR identified in the regression model, and the resulting quotient was multiplied by two and rounded to the nearest whole number. Summation of the points generated by the calculated risk factors resulted in a quantitative score that was assigned to each patient in the database. Predictive performance was determined by assessing discrimination and calibration. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for different cutoffs of the score. The incidence of CRE acquisition significantly increased with time from 0.21 cases/1000 patient-days (PD) in 2015 to 1.89 cases/1000PD in 2019 (r2 = 0.789, P = 0.041). Multivariate analysis of matched data revealed that the history of cerebrovascular disease (OR 1.96; 95% CI 1.04-3.70; P = 0.039), hematopoietic cells transplantation (OR 7.75; 95% CI 1.52-39.36; P = 0.014), presence of a chronic wound (OR 3.38; 95% CI 1.73-6.50; P < 0.001), endoscopy done during the 3 months preceding the index hospitalization (OR 2.96; 95% CI 1.51-4.73; P = 0.01), nosocomial site of acquisition of the organism in question (OR 2.68; 95% CI 1.51-4.73; P = 0.001), and the prior use of meropenem within 3 months of CRE acquisition (OR 5.70; 95% CI 2.61-12.43; P < 0.001) were independent risk factors for CRE acquisition. A risk score ranging from 0 to 25 was developed based on these independent variables. At a cut-off of ≥ 5 points, the model exhibited a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 64.5%, 85.8%, 82%, 70.7% and 75%, respectively. We also showed that only meropenem consumption intensity and CRE acquisition incidence density showed a strong positive correlation(r = 0.798, P = 0.106), unlike imipenem (r = - 0.868, P = 0.056) and ertapenem (r = 0.385, P = 0.522). Patients with a score of ≥ 5 points in our model were likely to acquire CRE. Only meropenem was associated with CRE carriage. Our proposed risk prediction score would help target surveillance screening for CRE amongst inpatients at the time of hospital admission and properly guide clinicians on using anti-CRE therapy.

A critical evaluation of results from genome-wide association studies of micronutrient status and their utility in the practice of precision nutrition.

Rapid advances in 'omics' technologies have paved the way forward to an era where more 'precise' approaches - 'precision' nutrition - which leverage data on genetic variability alongside the traditional indices, have been put forth as the state-of-the-art solution to redress the effects of malnutrition across the life course. We purport that this inference is premature and that it is imperative to first review and critique the existing evidence from large-scale epidemiological findings. We set out to provide a critical evaluation of findings from genome-wide association studies (GWAS) in the roadmap to precision nutrition, focusing on GWAS of micronutrient disposition. We found that a large number of loci associated with biomarkers of micronutrient status have been identified. Mean estimates of heritability of micronutrient status ranged between 20 and 35 % for minerals, 56-59 % for water-soluble and 30-70 % for fat-soluble vitamins. With some exceptions, the majority of the identified genetic variants explained little of the overall variance in status for each micronutrient, ranging between 1·3 and 8 % (minerals), <0·1-12 % (water-soluble) and 1·7-2·3 % for (fat-soluble) vitamins. However, GWAS have provided some novel insight into mechanisms that underpin variability in micronutrient status. Our findings highlight obvious gaps that need to be addressed if the full scope of precision nutrition is ever to be realised, including research aimed at (i) dissecting the genetic basis of micronutrient deficiencies or 'response' to intake/supplementation (ii) identifying trans-ethnic and ethnic-specific effects (iii) identifying gene-nutrient interactions for the purpose of unravelling molecular 'behaviour' in a range of environmental contexts.

Interaction between plasma homocysteine and the MTHFR c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans.

One-carbon metabolism provides a direct link among dietary folate/vitamin B12 exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR), and epigenetic regulation of the genome via DNA methylation. Previously, it has been shown that the common c.677C > T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with total homocysteine (tHcy) levels. To build on that and other more recent observations that have further highlighted associations among MTHFR c.677C > T, tHcy, and aberrations in DNA methylation, we investigated whether the interaction between mildly elevated plasma tHcy and the c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. We used data on plasma tHcy levels, c.677C > T polymorphism, and site-specific DNA methylation levels for a total of 915 white women and 335 men from the TwinsUK registry ( n = 610) and the Rotterdam study ( n = 670). We performed methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C > T genotypes on DNA methylation ß values. Our meta-analysis identified 13 probes significantly associated with rs1801133 × tHcy levels [false-discovery rate (FDR) < 0.05]. The most significant associations were with a cluster of probes at the AGTRAP-MTHFR-NPPA/B gene locus on chromosome 1 (FDR = 1.3E-04), with additional probes on chromosomes 2, 3, 4, 7, 12, 16, and 19. Our top 2 hits on chromosome 1 were functionally associated with variability in expression of the TNF receptor superfamily member 8 ( TNFRSF8) gene/locus on that chromosome. This is the first study, to our knowledge, to provide a direct link between perturbations in 1-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.-Nash, A. J., Mandaviya, P. R., Dib, M.-J., Uitterlinden, A. G., van Meurs, J., Heil, S. G., Andrew, T., Ahmadi, K. R. Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans.