To examine the joint associations of multiple modifiable lifestyle factors with the risk of symptomatic peripheral artery disease (PAD) referred to secondary care in the healthy, community based ...population.
A prospective cohort study was conducted including 37 633 men from the Cohort of Swedish Men and 31 816 women from the Swedish Mammography Cohort who were free of clinically diagnosed PAD and 45 – 83 years of age at baseline. Healthy lifestyle factors were defined as avoidance of excessive alcohol consumption (≤ 2 drinks/day), high adherence to a healthy diet (modified Mediterranean diet score ≥ 4), moderate to high level of physical activity (≥ 30 minutes/day), and never smoking. PAD cases were ascertained by linkage with the Swedish National Patient Registry. Cox proportional hazards regression was used to analyse the data.
During a mean of 18.1 years of follow up (from 1 January 1998 to 31 December 2019), 2 795 incident symptomatic PAD cases were ascertained. All healthy lifestyle factors were associated with a reduced PAD risk. Individuals who adhered to all four healthy lifestyle factors had a 45% (95% confidence interval CI 38 – 51) lower risk of PAD compared with the remainder of the population (0 – 3 healthy lifestyle factors) and a 71% (95% CI 61 – 79) lower risk of PAD compared with the group without any healthy lifestyle factor. Adherence to the combination of four healthy lifestyle factors was estimated to prevent 40% (95% CI 34 – 47) of PAD cases.
Healthy lifestyle factors were associated with a reduced risk of PAD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. ...Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by ...conventional paradigms for assessing clinical cardiovascular risk remains unclear.
This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.
A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.
Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.
Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic ...health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.
We created a genetic risk score ...(GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.
Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 95% CI 0.80-0.87, p = 6.0 x 10-21; AAA OR 0.76 95% CI 0.68-0.86, p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 95% CI 0.71-0.97, p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 95% CI 0.78-0.93, p = 5.0 x 10-04).
Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Rates of major lower extremity amputation in patients with peripheral artery disease are higher in rural communities with markers of low socioeconomic status, but most Americans live in ...metropolitan areas. Whether amputation rates vary within US metropolitan areas is unclear, as are characteristics of high amputation rate urban communities. Methods and Results We estimated rates of major lower extremity amputation per 100 000 Medicare beneficiaries between 2010 and 2018 at the ZIP code level among ZIP codes with ≥100 beneficiaries. We described demographic characteristics of high and low amputation ZIP codes, and the association between major amputation rate and 3 ZIP code-level markers of socioeconomic status-the proportion of patients with dual eligibility for Medicaid, median household income, and Distressed Communities Index score-for metropolitan, micropolitan, and rural ZIP code cohorts. Between 2010 and 2018, 188 995 Medicare fee-for-service patients living in 31 391 ZIP codes with ≥100 beneficiaries had a major lower extremity amputation. The median (interquartile range) ZIP code-level number of amputations per 100 000 beneficiaries was 262 (75-469). Though nonmetropolitan ZIP codes had higher rates of major amputation than metropolitan areas, 78.2% of patients undergoing major amputation lived in metropolitan areas. Compared with ZIP codes with lower amputation rates, top quartile amputation rate ZIP codes had a greater proportion of Black residents (4.4% versus 17.5%,
<0.001). In metropolitan areas, after adjusting for clinical comorbidities and demographics, every $10 000 lower median household income was associated with a 4.4% (95% CI, 3.9-4.8) higher amputation rate, and a 10-point higher Distressed Communities Index score was associated with a 3.8% (95% CI, 3.4%-4.2%) higher amputation rate; there was no association between the proportion of patients eligible for Medicaid and amputation rate. These findings were comparable to the associations identified across all ZIP codes. Conclusions In metropolitan areas, where most individuals undergoing lower extremity amputation live, markers of lower socioeconomic status and Black race were associated with higher rates of major lower extremity amputation. Development of community-based tools for peripheral artery disease diagnosis and management targeted to communities with high amputation rates in urban areas may help reduce inequities in peripheral artery disease outcomes.
Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 ...genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy
. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM23
. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tobacco smoking is an important risk factor for peripheral artery disease (PAD), but it remains unknown whether smokeless tobacco, such as Swedish snuff (snus), is also associated with this disease. ...We used data from the Cohort of Swedish Men including 24,085 men. Individuals were grouped into never, past, and current snus dippers as well as never, past quitting ≥ 10 years, past, quitting < 10 years, and current smokers. Incident PAD cases were defined by linkage of the cohort with the Swedish National Patient Register. Cox proportional hazards regression was used to analyze the data. Over a mean follow-up period of 9.1 years (from July 1, 2009 to December 31, 2019), 655 incident PAD cases were ascertained. Cigarette smoking but not Swedish snus dipping was associated with an increased risk of PAD. Compared with never snus dippers, the hazard ratio of PAD was 0.95 (95% confidence interval CI 0.73-1.24) for past snus dippers and 0.88 (95% CI 0.66-1.17) for current snus dippers. Compared to never smokers, the hazard ratio of PAD was 1.38 (95% CI 1.14-1.68) for past smoker who stopped smoking for ≥ 10 years, 2.61 (95% CI 1.89-3.61) for past smoker who stopped smoking for < 10 years, and 4.01 (95% CI 3.17, 5.08) for current smoker. In conclusion, cigarette smoking but not Swedish snus dipping increases the risk of PAD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking ...is not fully understood.
Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.
The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% -23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI -20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.
Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background We conducted a 2-sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent ...single-nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25-hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome-wide significance level were used as instrumental variables. Summary-level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1-SD increase in the exposure were 1.34 (95% CI, 1.25-1.43) for height, 1.39 (95% CI, 1.27-1.52) for body mass index, 1.12 (95% CI, 1.04-1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16-1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62-0.92) per 1-SD increase in calcium levels and 0.97 (95% CI, 0.95-0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.
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