Diet Quality Scores are Positively Associated with Whole Blood-derived Mitochondrial DNA Copy Number in the Framingham Heart Study

2021 ◽  
Author(s):  
Jiantao Ma ◽  
Xue Liu ◽  
Yuankai Zhang ◽  
Hanning Cheng ◽  
Wencheng Gao ◽  
...  

Abstract Background Association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. Objectives We aimed to study the relationship between diet quality and mtDNA-CN. Methods We analyzed data from 2,931 Framingham Heart Study (FHS) participants with mean age of 57 years and 55% females. Whole genome sequencing was used to calculate mtDNA-CN from whole blood samples. We examined the cross-sectional associations between three diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet-style score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. Results We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. One standard deviation (SD) increase in the DASH score was associated with a 0.042 SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, mtDNA-CN increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for one SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10–6),  lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10–5),  and there was no significant change in platelet, 0.1 thousands/μL (95% CI: –1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts, the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). Conclusions We observed that higher diet quality is associated with a greater whole blood derived mtDNA-CN in middle aged to older adults in FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

2020 ◽  
Author(s):  
Stephanie Y. Yang ◽  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Vamsee K. Pillalamarri ◽  
Brian O’Rourke ◽  
...  

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues.ResultsWe evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35).In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90).ConclusionsThe observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.


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