Primary Aldosteronism and ARMC5 Variants

Abstract

Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia.

Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects.

Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods.

Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023).

Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.

Trial registration: ClinicalTrials.gov NCT00005927.

Figures

Figure 1.

SST. Aldosterone was checked at baseline and hourly. Data are expressed as mean ± SEM. P = .49 from repeated measures analysis. Although patients with damaging ARMC5 variants started with higher aldosterone values, the difference was not significant.

Figure 2.

Liddle's test. A, 24-hour UFC, corrected by BSA (P = .81 from repeated measures analysis). B, 24-hour urinary 17OHS, corrected by gram creatinine (P = .62 from repeated measures analysis). C, Percentage change of 24-hour UFC, corrected for BSA (d 6 of Liddle's test) (P = .78). D, Percentage change of 17OHS, corrected by gram creatinine (P = .83).

Figure 3.

ARMC5 expression in adrenocortical nodules. A, Immunohistochemistry of adrenocortical nodules stained for ARMC5. A-I, Nonhyperplastic adrenal tissue, surrounding aldosterone-producing adenoma (no ARMC5 mutations). A-II and A-III, ADT110.01 (with a benign ARMC5 variant) is a 51-year-old male with a 5-year history of hypertension who underwent left adrenalectomy, which revealed a dominant left adrenal nodule 1.1 × 1.0 × 0.7 cm and surrounding hyperplasia. A-IV and A-V, ADT105.2 (with a predicted damaging ARMC5 variant) is a 63-year-old male with a 35-year history of hypertension who underwent left adrenalectomy, revealing a dominant nodule 1.3 × 0.8 × 0.8 cm, surrounded by macro- and micronodular adrenal hyperplasia. A-VI and A-VII, ADT130.01 is 44-year-old male (with a predicted damaging ARMC5 variant) with a 12-year history of hypertension. Computed tomography revealed bilateral adrenal hyperplasia; left adrenalectomy revealed a 1.4-cm dominant nodule with surrounding hyperplasia. B, Western blot analysis of ARMC5 protein in normal adrenal (N) and aldosterone-producing adrenal adenoma from a patient without ARMC5 mutations (ADT201.02) and from a patient with a predicted damaging ARMC5 variant (ADT130.01).