Biomedical subjects

Alexis C Wood

Publications and source records attributed to Alexis C Wood.

7 recordsLinked to original sources

PubMed2026

Longitudinal Repeated Protein Measurements in a Multiethnic Cohort Identify Novel Diabetes Biomarkers That Reveal Unique Disease Pathways.

There is up to a fourfold increase in diabetes biomarkers identified with longitudinal repeated versus single time point proteomic measurements. The increase in biomarkers identified with longitudinal repeated measurements is supported by a similar proportion being nominated as causal for type 2 diabetes with Mendelian randomization. Proteins unique to the longitudinal repeated analyses highlighted biological pathways (e.g., posttranslational protein modification and cellular structure and cycle regulation) that were distinct from pathways enriched among the shared proteins (e.g., small-molecule metabolic and catabolic processes). Longitudinal protein measurements identify additional novel disease biomarkers and disparate biological pathways compared with single measurement analyses.

Journal Article↗

PubMed2026

Multi-omic signatures of genetic mechanisms inform on type 2 diabetes biology and patient heterogeneity.

Type 2 diabetes (T2D) is a heterogeneous disease shaped by genetic pathways related to insulin resistance and β-cell dysfunction, but how this heterogeneity is reflected molecularly remains unclear. We integrated partitioned polygenic scores (pPS) with proteomic and metabolomic profiling to define molecular signatures of T2D and their clinical relevance. We analyzed UK Biobank participants with genomic, proteomic, and metabolomic data. In a disease-free training subset, we used LASSO regression to identify multi-omic signatures associated with each pPS by jointly modeling proteins and metabolites. In an independent testing set, we constructed multi-omic scores and examined their associations with clinical traits and diabetes-related outcomes. Mediation analyses were used to investigate putative causal pathways. Key findings were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA). We identified distinct multi-omic signatures that capture the molecular architecture of T2D genetic risk across physiological subtypes. Compared with genetic scores alone, multi-omic pPS showed larger effect sizes and better disease discrimination. These scores recapitulated subtype-specific physiology and were associated with T2D risk. The Beta-Cell 2 multi-omic score showed marked stratification for insulin use, which was replicated in MESA, where it also predicted future insulin use. Mediation analyses implicated lipoprotein remodeling and fatty acid metabolism in the Lipodystrophy 1 cluster, accounting for 30-45% of the total effect of pPS on T2D risk. Integrating process-specific genetic risk with circulating multi-omic profiles reveals biologically distinct endotypes of T2D and supports a framework for improved patient stratification and risk assessment.

Journal Article↗

PubMed2025

Insulinemic and inflammatory dietary patterns and colorectal cancer risk: a dietary data harmonization study of one million participants in the Consortium of Metabolomics Studies (COMETS).

BACKGROUND: Inflammatory and insulinemic dietary patterns have been associated with colorectal cancer (CRC) risk, but generalizability across diverse populations with heterogeneous food supplies and dietary behaviors has not been established. OBJECTIVES: We harmonized disparate dietary and covariate data on a large scale to compute the reverse Empirical Dietary Index for Hyperinsulinemia (rEDIH), reverse Empirical Dietary Inflammatory Pattern (rEDIP), and Healthy Eating Index (HEI)-2015 scores, and tested their associations with CRC risk. METHODS: We leveraged data among 501,892 women and 407,390 men from 6 cohorts across the United States (NIH-AARP, Multi-Ethnic Study of Atherosclerosis, Prostate, Lung, Colorectal, and Ovarian, SCCS) and Europe (EPIC, ATBC) with varying sociodemographic characteristics, participating in the Consortium of Metabolomics Studies. We harmonized nomenclature and nutritional information of >800 unique food items across cohorts. We used multivariable-adjusted Cox regression, adjusting for demographic, clinical, and lifestyle factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between the dietary indices and CRC risk per cohort, then meta-analyzed the estimates. RESULTS: During a median follow-up of 14.9 y, 16,525 incident CRC cases were diagnosed. Participants in the highest quintile of rEDIH (low-insulinemic diet) had an 18% reduced risk of CRC (HR: 0.82; 95% CI: 0.78, 0.86) compared with those in the lowest quintile. For the same comparison, similar risk reductions were observed for rEDIP (anti-inflammatory diet) (HR: 0.84; 95% CI: 0.80, 0.89) and HEI-2015 (overall dietary quality) (HR: 0.80; 95% CI: 0.76, 0.85). Heterogeneity between cohorts in the meta-analyzed estimates was low for rEDIH (I2 = 22.3%) compared with rEDIP (I2 = 62.5%) and HEI-2015 (I2=83.9%). CONCLUSIONS: Using carefully harmonized data from nearly 1 million individuals in the United States and Europe, we observed significant CRC risk reduction with habitual intake of low-insulinemic and anti-inflammatory dietary patterns, comparable with higher overall dietary quality. Study findings underscore the utility of these dietary patterns for global cancer prevention efforts.

Humans↗

PubMed2025

Sleep-disordered breathing subtypes and future diet quality in the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: Sleep-disordered breathing (SDB) and diet quality impact cardiometabolic disease, but few studies have examined if SDB influences diet quality. This study estimated the association between SDB subtypes (with and without sleepiness) and future diet quality in the Multi-Ethnic Study of Atherosclerosis. METHODS: Probable SDB was characterized by self-reported physician-diagnosed sleep apnea (PDSA) or habitual snoring and subtyped by presence or absence of sleepiness. A food frequency questionnaire measured diet 1.6 years before, and 7.8 years after SDB assessment. Diet quality was measured with the Alternate Healthy Eating Index-2010 (AHEI). Mean differences in AHEI at follow-up by SDB subtypes were estimated with multivariable linear regression adjusting for baseline AHEI, demographic, and lifestyle factors. RESULTS: Among 3294 participants (mean age 62 years, 51% women), 29.5% had SDB. When grouped by sleepiness, 20.6% had SDB without, and 8.9% had SDB with, sleepiness. Adjusting for baseline diet and potential confounders, those with SDB had lower follow-up AHEI scores compared with unaffected individuals (mean AHEI difference [95% CI]: -1.02 [-1.69, -0.35]). Upon stratifying by sleepiness, both groups had lower AHEI scores at follow-up compared with unaffected individuals, and the difference was greater for those with sleepiness (mean score difference [95% CI]: -0.8 [-1.56, -0.04], without sleepiness; -1.52 [-2.59, -0.45], with sleepiness). The difference between those with and without sleepiness was not statistically significant. CONCLUSIONS: In a multi-ethnic cohort, SDB was associated with lower diet quality after 7.8 years and this association was larger among participants with SDB with sleepiness.

Humans↗

PubMed2025

Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.

Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Humans↗

PubMed2024

Urinary Metal Levels, Cognitive Test Performance, and Dementia in the Multi-Ethnic Study of Atherosclerosis.

IMPORTANCE: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited. OBJECTIVE: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4). DESIGN, SETTING, AND PARTICIPANTS: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024. EXPOSURE: Urine samples were collected at baseline (2000-2002), and arsenic, cadmium, cobalt, copper, lead, manganese, tungsten, uranium, and zinc levels were measured in 2020-2022. MAIN OUTCOMES AND MEASURES: Digit Symbol Coding (DSC) (n = 3819) (possible score range, 0-133), Cognitive Abilities Screening Instrument (CASI) (n = 3918) (possible score range, 0-100), and Digit Span (DS) (n = 4176) (possible score range, 0-30) cognitive tests were administered in 2010-2012; higher scores of each test indicate increasing levels of positive response. RESULTS: A total of 6303 participants were followed up for dementia diagnosis through 2018. The median age at baseline was 60 (IQR, 53-70) years, and 3303 participants (52.4%) were female. The median cognitive scores were 51 (IQR, 38-64) for DSC, 90 (IQR, 84-95) for CASI, and 15 (IQR, 12-18) for DS. There were 559 cases of dementia through the follow-up period. Inverse associations with DSC were identified: mean differences in z scores per IQR increase in metal levels were -0.03 (95% CI, -0.07 to 0.00) for arsenic, -0.05 (95% CI, -0.09 to -0.004) for cobalt, -0.05 (95% CI, -0.07 to -0.02) for copper, -0.04 (95% CI, -0.08 to -0.001) for uranium, and -0.03 (95% CI, -0.06 to -0.01) for zinc. Among 1058 APOE4 carriers, manganese was also inversely associated with DSC. The joint mean difference of DSC comparing percentile 95th with the 25th of the 9-metal mixture was -0.30 (95% CI, -0.47 to -0.14) for APOE4 carriers and -0.10 (95% CI, -0.19 to -0.01) for noncarriers. Arsenic, cadmium, cobalt, copper, tungsten, uranium, and zinc were individually associated with dementia, with hazard ratios per IQR of metal ranging from 1.15 (95% CI, 1.03-1.29) for tungsten to 1.46 (95% CI, 1.06-2.02) for uranium. The joint hazard ratio of dementia comparing percentiles 95th with the 25th of the 9-metal mixture was 1.71 (95% CI, 1.24-3.89), with no significant difference by APOE4 status. CONCLUSIONS AND RELEVANCE: In this study, participants with higher concentrations of metals in their urine, compared with those with lower concentrations, had worse performance on cognitive tests and greater likelihood of developing dementia. The findings of this multicenter multiethnic cohort study might inform screening and potential interventions for prevention of dementia based on individuals' metal exposure levels and genetic profiles.

Humans↗

PubMed2024

Metagenomic Study of the MESA: Detection of Gemella Morbillorum and Association With Coronary Heart Disease.

BACKGROUND: Inflammation is a feature of coronary heart disease (CHD), but the role of proinflammatory microbial infection in CHD remains understudied. METHODS AND RESULTS: CHD was defined in the MESA (Multi-Ethnic Study of Atherosclerosis) as myocardial infarction (251 participants), resuscitated arrest (2 participants), and CHD death (80 participants). We analyzed sequencing reads from 4421 MESA participants in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program using the PathSeq workflow of the Genome Analysis Tool Kit and a 65-gigabase microbial reference. Paired reads aligning to 840 microbes were detected in >1% of participants. The association of the presence of microbe reads with incident CHD (follow-up, ~18 years) was examined. First, important variables were ascertained using a single regularized Cox proportional hazard model, examining change of risk as a function of presence of microbe with age, sex, education level, Life's Simple 7, and inflammation. For variables of importance, the hazard ratio (HR) was estimated in separate (unregularized) Cox proportional hazard models including the same covariates (significance threshold Bonferroni corrected P<6×10-5, 0.05/840). Reads from 2 microbes were significantly associated with CHD: Gemella morbillorum (HR, 3.14 [95% CI, 1.92-5.12]; P=4.86×10-6) and Pseudomonas species NFACC19-2 (HR, 3.22 [95% CI, 2.03-5.41]; P=1.58×10-6). CONCLUSIONS: Metagenomics of whole-genome sequence reads opens a possible frontier for detection of pathogens for chronic diseases. The association of G morbillorum and Pseudomonas species reads with CHD raises the possibilities that microbes may drive atherosclerotic inflammation and that treatments for specific pathogens may provide clinical utility for CHD reduction.

Humans↗