Liu Jixia, Zhao Ran, Ye Zhan, Frey Alexander J, Schriver Emily R, Snyder Nathaniel W, Hebbring Scott J
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
J Steroid Biochem Mol Biol. 2017 Nov;174:169-175. doi: 10.1016/j.jsbmb.2017.08.017. Epub 2017 Sep 1.
Human cytosolic sulfotransferase 1A1 (SULT1A1) is considered to be one of the most important SULT isoforms for metabolism, detoxification, and carcinogenesis. This theory is driven by observations that SULT1A1 is widely expressed in multiple tissues and acts on a wide range of phenolic substrates. SULT1A1 is subject to functional common copy number variation (CNV) including deletions or duplications. However, it is less clear how SULT1A1 CNV impacts health and disease. To better understand the biological role of SULT1A1 in human health, we genotyped CNV in 14,275 Marshfield Clinic patients linked to an extensive electronic health record. Since SULT1A1 is linked to steroid metabolism, select serum steroid hormones were measured in 100 individuals with a wide spectrum of SULT1A1 CNV genotypes. Furthermore, comprehensive phenome-wide association studies (PheWAS) were conducted using diagnostic codes and clinical text data. For the first time, individuals homozygous null for SULT1A1 were identified in a human population. Thirty-six percent of the population carried >2 copies of SULT1A1 whereas 4% had ≤1 copy. Results indicate SULT1A1 CNV was negatively correlated with estrone-sulfate to estrone ratio predominantly in males (E1S/E1; p=0.03, r=-0.21) and may be associated with increased risk for common allergies. The effect of SULT1A1 CNV on circulating estrogen metabolites was opposite to the predicted CNV-metabolite trend based on enzymatic function. This finding, and the potential association with common allergies reported herein, warrants future studies.
人胞质磺基转移酶1A1（SULT1A1）被认为是参与代谢、解毒和致癌过程的最重要的磺基转移酶同工型之一。这一理论是基于以下观察结果得出的：SULT1A1在多种组织中广泛表达，并作用于多种酚类底物。SULT1A1存在功能性常见拷贝数变异（CNV），包括缺失或重复。然而，SULT1A1的CNV如何影响健康和疾病尚不清楚。为了更好地理解SULT1A1在人类健康中的生物学作用，我们对14275名与广泛电子健康记录相关的马什菲尔德诊所患者的CNV进行了基因分型。由于SULT1A1与类固醇代谢有关，我们在100名具有广泛SULT1A1 CNV基因型的个体中测量了选定的血清类固醇激素。此外，还使用诊断代码和临床文本数据进行了全面的全表型关联研究（PheWAS）。首次在人群中鉴定出SULT1A1纯合缺失个体。36%的人群携带>2个拷贝的SULT1A1，而4%的人群携带≤1个拷贝。结果表明，SULT1A1的CNV主要在男性中与硫酸雌酮与雌酮的比值呈负相关（E1S/E1；p=0.03，r=-0.21），并且可能与常见过敏风险增加有关。SULT1A1 CNV对循环雌激素代谢物的影响与基于酶功能预测的CNV-代谢物趋势相反。这一发现以及本文报道的与常见过敏的潜在关联值得未来进一步研究。
