Sex-specific effects of serum sulfate level andSLC13A1nonsense variants on DHEA homeostasis.
BACKGROUND
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 inSLC13A1(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.


METHODS
Retrospective cohort study.


METHODS
Academic research.


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


METHODS
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. FemaleSLC13A1nonsense 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, femaleSLC13A1nonsense 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,SLC13A1R12X 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.
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Christina G
CG
Tise
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Leslie E
LE
Anforth
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Albert E
AE
Zhou
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
James A
JA
Perry
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Patrick F
PF
McArdle
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Elizabeth A
EA
Streeten
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Alan R
AR
Shuldiner
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Laura M
LM
Yerges-Armstrong
DHEA; DHEA-S; SLC13A1; Serum sulfate; Sulfation