Aim

Determine the association of circulating ceramides with NAFLD and glycemic impairment.

Methods

Sample: 669 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort aged 40-84 years without cardiovascular disease, cirrhosis, or significant alcohol intake.

Clinical measures

Computed tomography scans at baseline for hepatic attenuation. Fasting serum specimens at baseline and after 5 years. Lipidomics: LC-MS-based analysis of 19 known ceramide signals.

Statistical analysis

Linear and logistic regression models of log-transformed ceramides, hepatic attenuation and glucose adjusted for age, sex, calories, study site, BMI, exercise, diet quality, alcohol, saturated fat, lipid-lowering medications and fasting glucose.

Results

Average age was 55 years, 44% were women, mean BMI was 25.9 kg/m2, and 8% had NAFLD. In adjusted models, Cer(d16:1/20:0) and Cer(d18:1/18:0) were associated with lower mean hepatic attenuation (increased liver fat) (β -4.29; 95% CI [-5.98, -2.59]) and (β -3.40; 95% CI [-5.11, -1.70]), and LacCer(d18:1/16:0) with higher attenuation (β 4.44; 95% CI [2.15, 6.73]). All three ceramides partially mediated the relationship between hepatic attenuation and fasting glucose by 16%, 11% and 5%, respectively, after 5-years.

Conclusions

Three circulating ceramides were strongly associated with NAFLD and fasting glucose after 5 years, and partially mediated this association.

South Asians are at higher risk for diabetes (DM) than many other racial/ethnic groups. Circulating metabolites are measurable products of metabolic processes that may explain the etiology of elevated risk. We characterized metabolites associated with prevalent DM and incident glycemic measures in South Asians. We included 717 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, aged 40-84 years. We used baseline fasting serum for metabolomics and demographic, behavioral, glycemic data from baseline and at 5 years. We performed LC-MS untargeted metabolomic and lipidomic analysis with targeted integration of known signals. Individual linear and ordinal logistic regression models were adjusted for age, sex, BMI, diet, exercise, alcohol, smoking and family history of DM followed by elastic net regression to identify metabolites most contributory to the outcome. There were 258 metabolites with detectable signal in >98% of samples. Fifty-nine metabolites were associated with prevalent DM, 32 with fasting glucose and 45 with HbA1c at follow-up [FDR < 0.05]. An elastic net model identified a subset of important metabolites (Table 1). Predominant metabolites associated with glycemic measures in South Asians were sphingomyelins, tri- and di-acylglycerols and carnitines. Future work will externally validate our findings and determine the effects of modifiable risk factors for DM. Disclosure: M.D. Gadgil: None. C. Sands: None. M.R. Lewis: None. A.M. Kanaya: None. N.R. Kandula: None. D.M. Herrington: None. Funding: National Institutes of Health (1K23DK119404-01A1)

Background

South Asians are at higher risk for diabetes (DM) than many other racial/ethnic groups. Circulating metabolites are measurable products of metabolic processes that may explain the aetiology of elevated risk. We characterized metabolites associated with prevalent DM and glycaemic measures in South Asians.

Methods

We included 717 participants from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, aged 40-84 years. We used baseline fasting serum for metabolomics and demographic, behavioural, glycaemic data from baseline and at 5 years. We performed LC-MS untargeted metabolomic and lipidomic analysis with targeted integration of known signals. Individual linear and ordinal logistic regression models were adjusted for age, sex, BMI, diet, exercise, alcohol, smoking and family history of DM followed by elastic net regression to identify metabolites most associated with the outcome.

Results

There were 258 metabolites with detectable signal in >98% of samples. Thirty-four metabolites were associated with prevalent DM in an elastic net model. Predominant metabolites associated with DM were sphingomyelins, proline (OR 15.86; 95% CI 4.72, 53.31) and betaine (OR 0.03; 0.004, 0.14). Baseline tri- and di-acylglycerols [DG (18:0/16:0) (18.36; 11.79, 24.92)] were positively associated with fasting glucose and long-chain acylcarnitines [CAR 26:1 (-0.40; -0.54, -0.27)] were inversely associated with prevalent DM and HbA_1c at follow-up.

Discussion

A metabolomic signature in South Asians may help determine the unique aetiology of diabetes in this high-risk ethnic group. Future work will externally validate our findings and determine the effects of modifiable risk factors for DM.

Background

There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD.

Objective

The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research.

Methods

A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways.

Results

Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation.

Conclusion

PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. © 2017 International Parkinson and Movement Disorder Society.

Background

White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites.

Methods

We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (P_FDR)<0.05 were considered significant.

Results

In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (P_FDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (P_FDR.full.adj=1.40×10^-7) and in both the pooled sample (P_FDR.full.adj=1.66×10^-4) and statin-untreated (P_FDR.full.adj=1.65×10^-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (P_FDR=0.047).

Conclusions

Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY_207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF_9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK_361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.