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- Zhan, Y., et al.
(author)
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Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease : A Network Mendelian Randomization Study
- 2017
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In: Circulation Research. - : Lippincott Williams and Wilkins. - 0009-7330 .- 1524-4571. ; 121:3, s. 214-219
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Journal article (peer-reviewed)abstract
- Rationale: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.Objective: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design.Methods and Results: Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis - an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality - was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04).Conclusions: Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.
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- Jiang, M., et al.
(author)
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Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort
- 2017
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In: Aging. - : Impact Journals LLC. - 1945-4589. ; 9:12, s. 2629-2646
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Journal article (peer-reviewed)abstract
- Frailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. However, younger individuals (under 65 years) are less-studied in this respect. Also, the relationship between frailty and cause-specific mortality in community settings is understudied. We used a 42-item Rockwood-based frailty index (FI) in the Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks. The FI was independently associated with increased risk for all-cause mortality in younger (< 65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older (≥65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13). In conclusion, the FI is a strong mortality predictor especially among younger individuals and its associations with cause-specific mortality are sex-specific.
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- Karlsson, Ida K.
(author)
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Dementia and its comorbidities : genetic and epigenetic influences
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Dementia is a multifactorial disorder of late life, characterized by memory deficits, personality changes, and impaired reasoning abilities. There is considerable co-morbidity between dementia, cardiovascular disease (CVD), and late-life depression, but the nature of the associations remains elusive. We therefore seek to investigate how genetic and epigenetic factors act, independently and in concert, to contribute to dementia as well as to its association with CVD and depression. The first two studies focused on what role specific genes play in the association between dementia, depression, and CVD. In study I, we investigated how apolipoprotein E (APOE) genotype affects the association between depression and dementia, and whether the timing of depression onset is of importance. Utilizing a nested case-control design with 804 dementia cases and 1,600 matched controls, we found that depression within ten years of dementia onset was associated with disease regardless of APOE genotype, while depression more distal to dementia was a risk factor only in carriers of the ε4 risk allele. Study II focused on the shared genetic architecture between dementia and CVD, and entailed two parts. In the first part we used data from 13,231 Swedish twins, and found that genetically predisposed CVD was a stronger risk factor for dementia compared to CVD with a lower genetic risk. In the second part of the study we utilized summary statistics from previously published genome-wide association studies to investigate the genetic overlap between Alzheimer´s disease (AD), the most common form of dementia, and coronary artery disease. We found no evidence of genetic overlap between the disorders, but that both diseases have a significant number of genes in common with lipid levels. The last two studies focused on epigenetic factors and investigated how gene specific methylation is associated with dementia. Study III focused on the APOE gene, and how methylation levels in leukocytes relate to the risk of dementia, AD, and CVD. Using data from 447 Swedish twins, we demonstrated that hypermethylation in the promoter region of the gene was associated with dementia and AD, but not with CVD. Results were similar within discordant twin pairs, and did not differ as a function of APOE genotype. In study IV, we focused on five other AD related genes that are differentially methylated in post-mortem brain samples from AD patients compared to controls. The aim was to investigate whether these differences could also be detected in blood samples collected pre-mortem. There was a significant difference in methylation of SORL1 in leukocytes from dementia patients and of BIN1 in leukocytes from AD patients. Findings were stronger in discordant twin pairs, indicating that the association cannot be attributed to genetic factors. In conclusion, the studies included in this thesis highlight the complexity of late-life comorbidities, and the importance of taking both genetic factors and the timing of disease into account when studying these associations. Furthermore, methylation of genes related to AD is of importance for dementia, and has the potential to serve both as a biomarker and identify mechanisms of disease development.
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- Karlsson, Ida K., et al.
(author)
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Genetic susceptibility to cardiovascular disease and risk of dementia
- 2017
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In: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 7:5
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Journal article (peer-reviewed)abstract
- Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer´s disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98-1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05-2.41) in the first GRS quartile to 1.91 (95% CI: 1.28-2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors.
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