Genetically Predicted Blood Pressure Across the Lifespan

Georgakis, Marios K.; Malik, Rainer; Protogerou, Athanase D.; Webb, Alastair; Dichgans, Martin

doi:10.1161/hypertensionaha.120.15136

Cited by 24 publications

(21 citation statements)

References 52 publications

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“…However, our Mendelian randomization analyses are inherently limited in not taking such effects into account. Novel methods in addressing the time-varying effects 47 of these phenotypes on stroke subtypes should be examined in the future using datasets with available data. Finally, our analyses were primarily based on datasets involving individuals of European ancestry and might thus not be applicable to other ethnicities.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease

et al. 2021

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Objective:We employed Mendelian randomization (MR) to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.Methods:We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n=421,923), fasting glucose levels (n=133,010), insulin resistance (n=108,557), and β-cell dysfunction (n=16,378) based on published genome-wide association studies. Applying two-sample MR, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).Results:Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower grey matter volume, and total brain volume.Conclusions:This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for anti-diabetic treatments targeting these mechanisms.Classification of Evidence:This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease

et al. 2021

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“…PP is a well-known risk factor for cardiovascular disease and the clinical manifestation of increased vascular stiffness. 22 Surprisingly, PP was higher in BAV patients with a non-dilated aorta, which may seem counterintuitive since AR is associated with both increased PP and aortic dilatation. However, it may be speculated that the higher PP seen in these patients may rely on structural changes due to an increased hemodynamic burden associated with a BAV.…”

Section: Discussionmentioning

confidence: 89%

Clinical Classifiers to Identify Ascending Aortic Dilatation in Patients With Bicuspid Versus Tricuspid Aortic Valves

Gaye

Vignac

Gådin

et al. 2021

Preprint

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Objective: We aimed to develop clinical classifiers to identify prevalent ascending aortic dilatation in patients with BAV and tricuspid aortic valve (TAV). Methods: This study included BAV (n=543) and TAV (n=491) patients with aortic valve disease and/or ascending aortic dilatation but devoid of coronary artery disease undergoing cardiothoracic surgery. We applied machine learning algorithms and classic logistic regression models, using multiple variable selection methodologies to identify predictors of high risk of ascending aortic dilatation (ascending aorta with a diameter above 40 mm). Analyses included comprehensive multidimensional data (i.e., valve morphology, clinical data, family history of cardiovascular diseases, prevalent diseases, demographic, lifestyle and medication). Results: BAV patients were younger (60.4±12.4 years) than TAV patients (70.4±9.1 years), and had a higher frequency of aortic dilatation (45.3% vs. 28.9% for BAV and TAV, respectively. P<0.001). The aneurysm prediction models showed mean AUC values above 0.8 for TAV patients, with the absence of aortic stenosis being the main predictor, followed by diabetes and high sensitivity C-Reactive Protein. Using the same clinical measures in BAV patients our prediction model resulted in AUC values between 0.5-0.55, not useful for prediction of aortic dilatation. The classification results were consistent for all machine learning algorithms and classic logistic regression models. Conclusions: Cardiovascular risk profiles appear to be more predictive of aortopathy in TAV patients than in patients with BAV. This adds evidence to the fact that BAV- and TAV-associated aortopathy involve different pathways to aneurysm formation and highlights the need for specific aneurysm preventions in these patients. Further, our results highlight that machine learning approaches do not outperform classical prediction methods in addressing complex interactions and non-linear relations between variables.

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“…In Japanese and other populations, hypertension increases risk of death from CHD [25], cerebrovascular accident (stroke) [25,26], and dementia [27], each of which has genetic components [28][29][30][31]. Other GHR SNPs -rs6182, rs6180, rs6184 (minor allele frequencies 0.137, 0.387, 0.077) that are non-synonymous (amino acid changes Cys440Phe, Leu544Ile and Pro579Thr, respectively)have been found to be associated with hypertension and elevated blood pressure in Japanese men [32].…”

Section: Discussionmentioning

confidence: 99%

Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension

Donlon

Chen

Willcox

et al. 2021

Aging

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The single nucleotide polymorphism (SNP) rs4130113 of the growth hormone receptor gene (GHR) is associated with longevity. Here we explored whether longevity-associated genotypes protect against mortality in all individuals, or only in individuals with aging-related diseases. Rs4130113 genotypes were tested for association with mortality in 3,557 elderly American men of Japanese ancestry. At baseline (1991-1993), 1,000 had diabetes, 730 had coronary heart disease (CHD), 1,901 had hypertension, 485 had cancer, and 919 lacked these diseases. The men were followed from baseline until Dec 31, 2019 or death (mean 10.8 ± 6.5 SD years, range 0.01-28.8 years; 99.0% deceased by that date). In a heterozygote disadvantage model, longevity-associated genotypes were associated with significantly lower mortality risk in individuals having hypertension (covariateadjusted hazard ratio [HR] 0.83 [95% CI: 0.76-0.93, p = 4. 3 x10 -4 ]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension (p = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men (p = 0.11). We found that SNP rs4130113 potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter GHR expression. We propose that in individuals with hypertension, longevity-associated genetic variation in GHR enhances cell resilience mechanisms to help protect against cellular stress caused by hypertension. As a result, hypertension-affected men who possess the longevityassociated genetic variant of GHR live as long as normotensive men.

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Genetically Predicted Blood Pressure Across the Lifespan

Cited by 24 publications

References 52 publications

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease

Clinical Classifiers to Identify Ascending Aortic Dilatation in Patients With Bicuspid Versus Tricuspid Aortic Valves

Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension

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