Systemic Evidence for Mitochondrial Dysfunction in Age-Related Macular Degeneration as Revealed by mtDNA Copy Number Measurements in Peripheral Blood.

Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach with plasmid normalization in elderly participants with and without AMD from the AugUR study (n = 2262). We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (OR = 1.76, 95% CI 1.19-2.60, p = 0.004), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.

Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number.

Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10-13) and GSDMA (rs56030650, p = 4.85 × 10-08) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.

Differential Effects of Very-Low-Volume Exercise Modalities on Telomere Length, Inflammation, and Cardiometabolic Health in Obese Metabolic Syndrome Patients: A Subanalysis from Two Randomized Controlled Trials.

Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.

Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations. METHODS: We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis. RESULTS: Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16-1.72, p < 0.001) higher risk for incident CAD. CONCLUSIONS: We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected.

Relative Telomere Length Is Associated With Age-Related Macular Degeneration in Women.

Purpose: Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals. Methods: We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale. Results: Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043). Conclusions: Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.