Tise Christina G, Anforth Leslie E, Zhou Albert E, Perry James A, McArdle Patrick F, Streeten Elizabeth A, Shuldiner Alan R, Yerges-Armstrong Laura M
Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.
Mol Genet Metab Rep. 2017 Jan 27;10:84-91. doi: 10.1016/j.ymgmr.2017.01.005. eCollection 2017 Mar.
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, , 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 (R12X and W48X) associated with hyposulfatemia ( = 9 × 10).
To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.
Retrospective cohort study.
Academic research.
Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.
DHEA, DHEA-S, and DHEA-S/DHEA ratio.
Increased serum sulfate was associated with decreased DHEA-S ( = 0.03) and DHEA-S/DHEA ratio ( = 0.06) in males but not females. Female nonsense variant carriers, who had lower serum sulfate ( = 9 × 10 ), exhibited 14% lower DHEA levels ( = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers ( = 0.002). Consistent with this finding, female nonsense variant carriers also had lower total testosterone levels compared to non-carrier females ( = 0.03).
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, 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.
硫酸盐在多种化合物通过硫酸化作用进行的生物转化过程中至关重要。这些化合物包括神经递质、蛋白聚糖、外源性物质以及诸如脱氢表雄酮（DHEA）等激素。硫酸化反应被认为受内源性硫酸盐浓度的限速。该基因编码钠 - 硫酸盐协同转运蛋白NaS1，负责肠道和肾脏中硫酸盐的（再）吸收。我们之前报道了该基因中的两个罕见、非连锁的无义变体（R12X和W48X）与低硫酸盐血症相关（P = 9×10⁻⁶）。
研究血清硫酸盐浓度和降低硫酸盐的基因型对脱氢表雄酮稳态的影响。
回顾性队列研究。
学术研究机构。
阿米什人抗血小板干预药物基因组学（PAPI）研究和阿米什人遗传与表型干预（HAPI）研究的参与者。
脱氢表雄酮（DHEA）、硫酸脱氢表雄酮（DHEA - S）以及DHEA - S/DHEA比值。
血清硫酸盐升高与男性DHEA - S降低（P = 0.03）和DHEA - S/DHEA比值降低（P = 0.06）相关，但与女性无关。女性该基因无义变体携带者血清硫酸盐水平较低（P = 9×10⁻⁶），与女性非携带者相比，其DHEA水平低14%（P = 0.01），DHEA - S/DHEA比值高7%（P = 0.002）。与这一发现一致，女性该基因无义变体携带者与非携带者女性相比，总睾酮水平也较低（P = 0.03）。
我们的结果表明男性血清硫酸盐与DHEA - S以及DHEA - S/DHEA比值之间呈负相关，同时也表明降低硫酸盐的变体R12X和W48X会降低女性的DHEA和睾酮水平，并增加DHEA - S/DHEA比值。尽管看似矛盾，但这些结果说明了脱氢表雄酮稳态所涉及机制的复杂性，需要进一步研究以更好地理解硫酸盐在激素生理学中的作用。
