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Mol Genet Metab Rep. 2017 Jan 27;10:84-91. doi: 10.1016/j.ymgmr.2017.01.005. eCollection 2017 Mar.

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.

Author information

1
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.

Abstract

CONTEXT:

Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10- 20).

OBJECTIVE:

To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.

DESIGN:

Retrospective cohort study.

SETTING:

Academic research.

PATIENTS:

Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.

MAIN OUTCOME MEASURES:

DHEA, DHEA-S, and DHEA-S/DHEA ratio.

RESULTS:

Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10- 13 ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03).

CONCLUSIONS:

Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

KEYWORDS:

DHEA; DHEA-S; SLC13A1; Serum sulfate; Sulfation

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