Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Laaksonen, Jaakko; Mishra, Pashupati P.; Seppälä, Ilkka; Lyytikäinen, Leo-Pekka; Raitoharju, Emma; Mononen, Nina; Lepistö, Maija; Almusa, Henrikki; Ellonen, Pekka; Hutri‐Kähönen, Nina; Juonala, Markus; Raitakari, Olli T.; Kähönen, Mika; Salonen, Jukka T.; Lehtimäki, Terho

doi:10.1038/s41598-020-79931-6

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…To assess BP, a physician measured the systolic and diastolic BP of each participant using a mercury column sphygmomanometer, as described previously [20]. The first and the fifth Korotkoff sounds were taken as indicative of systolic and diastolic BPs, respectively.…”

Section: Methodsmentioning

confidence: 99%

The Mitochondrial tRNAAsp T7561C, tRNAHis C12153T, and A12172G Mutations May Be Associated with Essential Hypertension in a Han Chinese Pedigree

Sun

2022

Hum Hered

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Objectives: Mutations in mitochondrial tRNA (mt-tRNA) are the important causes for maternally inherited hypertension, however, the pathophysiology of mt-tRNA mutations in clinical expression of hypertension remains poorly understood. Material and Methods: In this study, we report the molecular features of a Han Chinese pedigree with maternally transmitted essential hypertension. The entire mitochondrial genomes are PCR amplified and sequenced, Moreover, phylogenetic analysis, haplogroup analysis, as well as pathogenicity scoring system are used to assess the potential roles for mtDNA mutations. Results: Strikingly, among ten matrilineal relatives, three of them suffer from variable degree of hypertension at different age at onset. Sequence analysis of the complete mitochondrial genomes suggests the presence of three possible pathogenic mtDNA mutations: tRNAAsp T7561C, tRNAHis C12153T and A12172G, together with a set of variants belonging to East Asian mitochondrial haplogroup M7a. Interestingly, the T7561C mutation occurs at position 44 in the variable region of tRNAAsp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNAHis gene, respectively, which are critical for tRNA steady-state level and function. Conclusions: Mitochondrial T7561C, C12153T and A12172G mutations may lead to the failure in tRNAs metabolism, and cause mitochondrial dysfunction that is responsible for hypertension. However, the homoplasmy form of mt-tRNA mutations, incomplete penetrance of hypertension suggest that T7561C, C12153T and A12172G mutations are insufficient to produce the clinical phenotype, hence, other risk factors such as environmental factors, nuclear genes and epigenetic modifications may contribute to the phenotypic manifestation of maternally inherited hypertension in this Chinese pedigree.

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Section: Methodsmentioning

confidence: 99%

The Mitochondrial tRNAAsp T7561C, tRNAHis C12153T, and A12172G Mutations May Be Associated with Essential Hypertension in a Han Chinese Pedigree

Sun

2022

Hum Hered

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“…In the YFS, mtSNPs were determined by next-generation sequencing. The pipeline has been described in detail earlier ( 46 ). In brief, mtDNA was amplified from genomic DNA samples ( n = 1807) and was sequenced with the Illumina HiSeq system.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci

Laaksonen

Mishra

Seppälä

et al. 2021

Human Molecular Genetics

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Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10−9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.

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“…152 However, a cross-sectional study in 4200 individuals failed to identify any sex-specific genetic associations between mitochondrial DNA and BP. 153 Better-powered studies may be needed to clarify the role of mitochondrial DNA in cardiovascular sex differences in the future.…”

Section: Mitochondrial Dnamentioning

confidence: 99%

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits

Vaura

Palmu

Aittokallio

et al. 2022

Circulation Research

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Despite the well-known sex dimorphism in cardiovascular disease traits, the exact genetic, molecular, and cellular underpinnings of these differences are not well understood. A growing body of evidence currently points at the links between cardiovascular disease traits and the genome, epigenome, transcriptome, and metabolome. However, the sex-specific differences in these links remain largely unstudied due to challenges in bioinformatic methods, inadequate statistical power, analytic costs, and paucity of valid experimental models. This review article provides an overview of the literature on sex differences in genetic architecture, heritability, epigenetic changes, transcriptomic signatures, and metabolomic profiles in relation to cardiovascular disease traits. We also review the literature on the associations between sex hormones and cardiovascular disease traits and discuss the potential mechanisms underlying these associations, focusing on human studies.

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Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Cited by 8 publications

References 52 publications

The Mitochondrial tRNA<sup>Asp</sup> T7561C, tRNA<sup>His</sup> C12153T, and A12172G Mutations May Be Associated with Essential Hypertension in a Han Chinese Pedigree

The Mitochondrial tRNA<sup>Asp</sup> T7561C, tRNA<sup>His</sup> C12153T, and A12172G Mutations May Be Associated with Essential Hypertension in a Han Chinese Pedigree

Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits

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