Norrina B Allen | Search PubMed

PubMed2025

Genetic Variants Associated With the Biochemical Response to Vitamin D3 in the Multi-Ethnic Study of Atherosclerosis.

CONTEXT: The response to treatment with vitamin D varies between patients. OBJECTIVE: To identify genetic variants associated with the biochemical response to vitamin D3 supplementation. DESIGN: Randomized placebo-controlled trial conducted between 2017 and 2019. SETTING: The trial was nested in an ongoing community-based cohort study, the Multi-Ethnic Study of Atherosclerosis. INTERVENTION: 2000 International Units of vitamin D3 or placebo daily for 16 weeks. PARTICIPANTS: The analytic sample included 427 participants assigned to vitamin D3 (mean age, 73 years; 54% females) and was 36% White, 33% Black, 18% Hispanic, and 14% Chinese. MAIN OUTCOME MEASURES: The biochemical response to vitamin D3 included changes in serum concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], PTH, and 25-hydroxyvitamin D3 [25(OH)D3]. RESULTS: In genome-wide analyses, single nucleotide polymorphisms in 8 regions of the genome had significant association (P < 5E-08) with 1 of the traits (2 with change in 1,25(OH)2D3, 1 with change in PTH, and 5 with change in 25(OH)D3). rs16867276 within an intergenic region on 2q31 was associated with change in serum 1,25(OH)2D3 (+8.37 pg/mL difference per effect allele; P = 4.93E-08) and was the only locus that achieved genome-wide significance in transethnic meta-analysis. rs114044709 adjacent to FAM20A, which encodes a protein required for biomineralization, was associated with change in PTH among Black participants (+20.32 pg/mL difference per effect allele; P = 1.34E-08). In candidate analyses, single nucleotide polymorphisms within SULT2A1 and CYP24A1 had significant association (P < .05÷36 = .0014) with the changes in 1,25(OH)2D3 and PTH, respectively. CONCLUSION: Our results reveal potential new pathways of vitamin D regulation that require replication in other vitamin D trials.

Humans↗

PubMed2025

Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study.

BACKGROUND: Pulmonary emphysema occurs frequently in older adults, often without airflow limitation. Its presence predicts symptoms, respiratory hospitalizations and deaths, and all-cause mortality. Proteomics may provide further insights into emphysema pathogenesis and inform therapeutic targets. OBJECTIVE: We performed a proteomic discovery analysis of percent emphysema on computed tomography (CT) in a population-based, multiethnic sample from the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Replication was performed in two chronic obstructive pulmonary disease (COPD)-based studies, the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) and the Genetic Epidemiology of COPD (COPDGene) Study. METHODS: MESA recruited participants from the general population in 2000-02. The MESA Lung Study performed full-lung CT scans in 2010-12. Percent emphysema was defined as the percentage of lung voxels < -950 Hounsfield units. Over 7,200 plasma aptamers were measured via SomaScan. Cross-sectional linear and least absolute shrinkage and selection operator (LASSO) regression models were adjusted for demographics, anthropometrics, smoking, renal function, and scanner parameters. Statistical significance was defined as a false discovery rate p-value < 0.05. Gene Ontology (GO)/Reactome enrichment analyses were performed. LASSO-selected proteins' predictive performance was evaluated. RESULTS: Among 2,504 participants in the MESA Lung Study, mean age was 69.4 years, 1,291 had ever smoked, and median percent emphysema-like lung was 1.4%. In total, 1,234 aptamers were significantly associated with percent emphysema in the MESA Lung Study, and 35 replicated in the SPIROMICS and COPDGene Studies. Novel associations included protein family with sequence similarity (FAM) 177A1, syntenin-2, ubiquitin carboxyl-terminal hydrolase 25, and uncharacterized protein C20orf173. Previously identified emphysema-associated proteins included soluble advanced glycosylation end product-specific receptor (sRAGE), protein S100-A12, high mobility group protein B1, and roundabout homolog 2. Enrichment analyses identified 40 GO biological processes, including chemokine production and regulation and cell-cell adhesion and regulation, and two Reactome pathways, including RAGE signaling. In tenfold cross-validation, novel proteins were largely retained by LASSO (R2 = 5.4%), improved overall model performance (R2 = 24.8%), and uniquely explained greater variance in percent emphysema. CONCLUSIONS: This analysis in a general population sample identified novel and previously characterized proteins whose functional roles were validated by GO/Reactome enriched pathways, offering new insights into emphysema pathophysiology and therapeutics.

Humans↗