Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

Nanba, Kazutaka; Omata, Kei; Gómez-Sánchez, Celso E.; Stratakis, Constantine A.; Demidowich, Andrew P.; Suzuki, Mari; Thompson, Lester D.�R.; Cohen, Debbie L.; Luther, James M.; Gellert, Lan L.; Vaidya, Anand; Barletta, Justine A.; Else, Tobias; Giordano, Thomas J.; Tomlins, Scott A.; Rainey, William E.

doi:10.1161/hypertensionaha.118.12070

Cited by 128 publications

(126 citation statements)

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“…Germline and somatic mutations associated with PA may account for some of the population variance. CYP11B2 variants in particular are more prevalent in black populations, while recent studies have shown that CACNA1D is the most frequently mutated aldosterone‐driver gene in black Americans . Some authors suggest that the higher prevalence of hypertension among blacks may be due to underdiagnosed PA, and that blacks are more likely to have BAH than unilateral disease .…”

Section: Introductionmentioning

confidence: 99%

Clinical presentation and surgical outcomes in primary aldosteronism differ by race

Gershuni

Ermer

Kelz

et al. 2019

Journal of Surgical Oncology

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Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension; early diagnosis and intervention correlate with outcomes. We hypothesized that race may influence clinical presentation and outcomes.Methods: We conducted a retrospective analysis of patients with PA (1997PA ( -2017 who underwent adrenal vein sampling (AVS). Patients were classified by self-reported race as black or non-black. Improvement was defined as postoperative decrease in mean arterial pressure (MAP), antihypertensive medications (AHM), or both.Results: Among patients undergoing AVS (n = 443), 287 underwent adrenalectomy. Black patients (28.2%) had higher body mass index (33.9 vs 31.8 kg/m 2 ; P = .01), longer median duration of hypertension (12 vs 10 years; P = .003), higher modified Elixhauser comorbidity index (2 vs 1; P = .004), and lower median income ($47 134 vs $78 280; P < .001). Black patients had similar aldosterone:renin ratios (150 vs 135.6 [ng/dL]/[ng·mL· −1 hr −1 ]; P = .23) compared to non-blacks. At long-term follow-up, black patients had a similar requirement for AHM (1 vs 0; P = .13) but higher MAP (100.6 vs 95.3 mm Hg; P = .004).Conclusion: Black patients present with longer duration of hypertension and more comorbidities. They are equally likely to lateralize on AVS, suggesting similar disease phenotype. However, black patients demonstrate less improvement with adrenalectomy; this may reflect a delay in diagnosis or concomitant essential hypertension.adrenal, aldosteronoma, disparities, hypertension, primary aldosteronism, race 1 | INTRODUCTION Primary aldosteronism (PA) is the most common etiology of secondary hypertension, affecting 3% to 20% of hypertensive patients 1-4 and 14%to 21% of patients with resistant hypertension. 5 Hyperaldosteronism is associated with end organ dysfunction and cardiovascular morbidity and mortality, independent of level of hypertension. 6-8 As compared to those with essential hypertension, patients with PA have increased risk of myocardial infarction, atrial fibrillation, and stroke, in excess of the projected risk related to degree of hypertension alone. 9 Effective control of blood pressure (BP) and aldosterone level lead to improved cardiovascular outcomes. 10 Therefore, early diagnosis and appropriate treatment of PA is essential to improve cardiovascular outcomes and minimize end organ dysfunction. Subtype differentiation of PA is an essential component of early diagnosis and treatment. Unilateral causes of PA include aldosteroneproducing adenoma and unilateral hyperplasia, which are potentially The authors have no disclosures.surgically curable, while bilateral adrenal hyperplasia (BAH) is managed medically with mineralocorticoid antagonists. 11 Shorter duration of disease has been associated with improved operative outcomes in multiple studies of subjects with unilateral PA. 12,13 An extensive literature exists on race and hypertension, particularly as it pertains to black patients. 14,15 Racial disparities in diagnosis, prevalence, treatment, and outcomes, a...

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Section: Introductionmentioning

confidence: 99%

Clinical presentation and surgical outcomes in primary aldosteronism differ by race

Gershuni

Ermer

Kelz

et al. 2019

Journal of Surgical Oncology

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“…Our findings with S652W (the loss-of-function mutation) emphasize that, in the case of CACNA1D, the amino acid position itself does not allow predictions about the disease risk of a variant, even if bioinformatics prediction tools provide high scores for protein damage. A high probability for pathogenicity can also be assumed if a variant identical to the germline mutation has also been found in at least two different individuals as a somatic mutation in an APA or an aldosterone-producing cellcluster [34,47,48]. Our report should raise awareness for the pathogenic potential of CACNA1D mutations, especially in patients without additional congenital endocrine symptoms as diagnostic features.…”

Section: Discussionmentioning

confidence: 76%

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

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Background: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 Ltype Ca 2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely diseasecausing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~13-17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca 2+-levels during action potential-like stimulations, characteristic for gain-offunction changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca 2+-channel blocker isradipine by 3-4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca 2+-channel blockers.

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“…Prevalence of CACNA1D mutations varies in different ethnic groups. Sequencing of DNA from aldosterone producing cell cluster found the higher percentage of CACNA1D mutation (>40%) in black population 59 . Unlike KCNJ5 mutants, CACNA1D mutants have been reported to be more prevalent in males, older, and smaller APAs.…”

Section: Cacna1dmentioning

confidence: 96%

Genetic and molecular alterations in aldosterone producing adenomas

Dutta

2020

Linköping University Medical Dissertations

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Aldosterone producing tumors (APA, also known as Conn tumors) are adrenal tumors that overproduce aldosterone, a hormone that regulates the sodium levels in blood and contributes to blood pressure (BP) regulation. Excessive production of aldosterone causes hypertension and approximately 5-15% of hypertensive patients have hyperaldosteronism, known as primary aldosteronism (PA). Major causes of PA are bilateral adrenal hyperplasia (BAH) or aldosterone producing adenoma (APA) and about 30% of PA patients have APAs. In most cases, the disease is unilateral, in rare case bilateral. Patients with APA are often detected when they have elevated blood pressure (BP>160/100mmHg) or when BP cannot be controlled with drugs. Surgery dramatically normalizes or lowers BP in patients with APA.

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Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

Cited by 128 publications

References 44 publications

Clinical presentation and surgical outcomes in primary aldosteronism differ by race

Clinical presentation and surgical outcomes in primary aldosteronism differ by race

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Genetic and molecular alterations in aldosterone producing adenomas

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