Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In ...order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis.
Numerous genetic loci have been identified as being associated with circulating fatty acid (FA) levels and/or inflammatory biomarkers of cardiovascular health (e.g., C-reactive protein). Recently, ...using red blood cell (RBC) FA data from the Framingham Offspring Study, we conducted a genome-wide association study of over 2.5 million single nucleotide polymorphisms (SNPs) and 22 RBC FAs (and associated ratios), including the four Omega-3 FAs (ALA, DHA, DPA, and EPA). Our analyses identified numerous causal loci. In this manuscript, we investigate the extent to which polyunsaturated fatty acid (PUFA) levels moderate the relationship of genetics to cardiovascular health biomarkers using a genome-wide interaction study approach. In particular, we test for possible gene-FA interactions on 9 inflammatory biomarkers, with 2.5 million SNPs and 12 FAs, including all Omega-3 PUFAs. We identified eighteen novel loci, including loci which demonstrate strong evidence of modifying the impact of heritable genetics on biomarker levels, and subsequently cardiovascular health. The identified genes provide increased clarity on the biological functioning and role of Omega-3 PUFAs, as well as other common fatty acids, in cardiovascular health, and suggest numerous candidate loci for future replication and biological characterization.
In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored ...with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphate-guanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)-CpG interactions on changes in triglyceride levels. Although we were able to identify numerous loci of interest when using an exploratory significance threshold, we did not identify any significant interactions using a strict genome-wide significance threshold. We were also able to identify numerous loci using the candidate gene approach, in which we focused on 18 genes with prior evidence of association of triglyceride levels. In particular, we identified
loci as containing potential CpG sites that moderate the impact of genetic polymorphisms on triglyceride levels. Further work is needed to provide clear guidance on analytic strategies for testing SNP-CpG interactions, although leveraging prior biological understanding may be needed to improve statistical power in data sets with smaller sample sizes.
Although methylation data continues to rise in popularity, much is still unknown about how to best analyze methylation data in genome-wide analysis contexts. Given continuing interest in gene-based ...tests for next-generation sequencing data, we evaluated the performance of novel gene-based test statistics on simulated data from GAW20. Our analysis suggests that most of the gene-based tests are detecting real signals and maintaining the Type I error rate. The minimum
value and threshold-based tests performed well compared to single-marker tests in many cases, especially when the number of variants was relatively large with few true causal variants in the set.
The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We ...aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.
We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.
Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m
, who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio RR per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I
=53·9%, p
=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I
=63·0%, p
<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all p
≥0·13).
Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.
Funders are shown in the appendix.
Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the ...very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.
We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.
Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.
There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.
Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.
Background
Adult congenital heart disease (CHD) transplant recipients historically experienced worse survival early after transplantation. We aim to review updated trends in adult CHD ...transplantation.
Methods
We performed a single center case series of adult cardiac transplants from January 2013 through July 2020. Outcomes of patients with CHD were compared to non‐CHD. The primary outcome was overall survival. Secondary outcomes included a variety of post‐operative complications.
Results
18/262 (7%) transplants were CHD recipients. CHD patients were younger with median age 41 (32—47) versus 58 (48–65) (P < .001). Fontan circulation for single ventricle physiology was present in 4/18 (22%) of CHD recipients, while 16/18 (89%) had systemic right ventricles. CHD recipients had higher rates of previous cardiovascular operations (94% vs. 51%, P < .001). 9/18 (50%) of CHD patients required reconstructive procedures at the time of transplant. Operative and cardiopulmonary bypass times were longer for the CHD cohort (7.5 h 6.6–8.5 vs. 5.6 h 4.6–7 P < .001) and (197 min 158–240 vs. 130 105–167 P < .001), respectively. There were no differences in operative complications or survival between CHD and non‐CHD recipients.
Conclusions
These data highlight the added technical challenges of performing adult CHD transplants. However, similar outcomes can be achieved as for non‐CHD recipients.
Summary
Modern advances in palliation of congenital heart defects (CHD) has led to increased survival into adulthood. Many of these patients require heart transplantation as adults. There are limited data on adult CHD transplantation. Historically, these patients have had worse perioperative outcomes with improved long‐term survival. We retrospectively analyzed 262 heart transplants at a single center, 18 of which were for adult CHD. Here, we report our series of 18 CHD recipients. We detail the palliative history of all CHD patients and highlight the added technical challenges for each of the 18 patients at transplant. In our analysis, CHD patients had more prior cardiovascular surgeries as well as longer transplant operative and bypass times. Despite this, there were no differences in perioperative and long‐term outcomes. We have added patient and institution specific data for transplanting patients with adult CHD. We hope that our experience will add to the growing body of literature on adult CHD transplantation.
Background
Cerebrovascular accidents (CVA) are a source of postoperative morbidity. Existing data on CVA after lung transplantation (LT) are limited. We aimed to evaluate the impact of CVA on LT ...survival.
Methods
A retrospective analysis of LT recipients at the University of Texas Southwestern Medical Center was performed. Data was obtained from the institutional thoracic transplant database between January 2012 and December 2018, which consisted of 476 patients. Patients were stratified by the presence of a postoperative CVA. Univariate comparisons of baseline characteristics, operative variables, and postoperative outcomes between the cohorts were performed. Survival was analyzed by Kaplan–Meier method. Aalen's additive regression model was utilized to assess mortality hazard over time.
Results
The incidence of CVA was 4.2% (20/476). Lung allocation score was higher in the CVA cohort (46.2 41.7, 57.3 vs. 41.5 35.8, 52.2, p = 0.04). There were no significant differences in operative variables. CVA patients had longer initial intensive care unit (ICU) stays (316 h 251, 557 vs. 124 85, 218, p < 0.001) and longer length of stay (22 days 17, 53 vs. 15 11, 26, p = 0.007). CVA patients required more ICU readmissions (35% vs. 15%, p = 0.02) and had a lower rates of home discharge (35% vs. 71%, p < 0.001). Thirty‐day mortality was higher in the CVA cohort (20% vs. 1.3%, p < 0.001). Overall survival was lower in the CVA cohort (log rank p = 0.044).
Conclusions
Postoperative CVA following LT was associated with longer ICU stays, more ICU readmissions, longer length of stay, and fewer home discharges. Thirty day and long‐term mortality were significantly higher in the CVA group.
PDF
