Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.
Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.
复制标题
血清硫酸盐水平和 SLC13A1 无义变异对 DHEA 稳态的性别特异性影响。
DOI：
10.1016/j.ymgmr.2017.01.005
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发表时间：
2017
影响因子：
1.9
通讯作者：
Yerges-Armstrong,LauraM
中科院分区：
文献类型：
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作者：
Tise,ChristinaG;Anforth,LeslieE;Zhou,AlbertE;Perry,JamesA;McArdle,PatrickF;Streeten,ElizabethA;Shuldiner,AlanR;Yerges-Armstrong,LauraM
背景硫酸盐对于多种化合物通过硫酸化的生物转化至关重要。这些化合物包括神经递质、蛋白聚糖、异生素和脱氢表雄酮 (DHEA) 等激素。硫酸化反应被认为受到内源硫酸盐浓度的限制。 SLC13A1 基因编码钠-硫酸盐协同转运蛋白 NaS1，负责肠道和肾脏中的硫酸盐（再）吸收。我们之前报道了SLC13A1中两种罕见的、非连锁的、无意义的变异（R12X和W48X）与低硫酸盐血症相关（P= 9 × 10− 20）。目的探讨血清硫酸盐浓度和降低硫酸盐的基因型对DHEA稳态的影响。设计回顾性队列研究。设置学术研究。患者参与者的阿米什药物基因组学抗血小板干预 (PAPI) 研究和阿米什遗传和表型干预 (HAPI) 研究。主要结果测量 DHEA、DHEA-S 和 DHEA-S/DHEA 比率。结果在男性中，血清硫酸盐升高与 DHEA-S (P= 0.03) 和 DHEA-S/DHEA 比率 (P= 0.06) 降低相关，但在女性中则不然。与女性非携带者相比，女性 SLC13A1 无义变异携带者的血清硫酸盐含量较低 (P=9×10−13)，其 DHEA 水平低 14% (P=0.01)，DHEA-S/DHEA 比率高 7% (P=0.002)。与这一发现一致，与非携带者女性相比，女性 SLC13A1 无义变异携带者的总睾酮水平也较低 (P = 0.03)。结论我们的结果表明，男性血清硫酸盐与 DHEA-S 和 DHEA-S/DHEA 比率之间呈负相关，同时也表明硫酸盐降低变异体 SLC13A1R12X 和 W48X 降低 DHEA 和睾酮水平，并增加女性 DHEA-S/DHEA 比率。虽然矛盾，但这些结果说明了 DHEA 稳态机制的复杂性，并需要进行更多研究以更好地了解硫酸盐在激素生理学中的作用。
ContextSulfate 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).ObjectiveTo examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.DesignRetrospective cohort study.SettingAcademic research.PatientsParticipants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.Main outcome measuresDHEA, DHEA-S, and DHEA-S/DHEA ratio.ResultsIncreased 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).ConclusionsOur 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.