Napoli Nicola, Rini Giovam Battista, Serber Daniel, Giri Tusar, Yarramaneni Jayasree, Bucchieri Salvatore, Camarda Lawrence, Di Fede Gaetana, Camarda Marcello Rosolino, Jain Sudahansu, Mumm Steven, Armamento-Villareal Reina
Division of Bone and Mineral Diseases, Washington University School of Medicine Campus, St. Louis, MO 63110, USA.
Bone. 2009 Mar;44(3):442-8. doi: 10.1016/j.bone.2008.09.018. Epub 2008 Oct 15.
Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age=63.5+/-0.53 years) and 248 from Palermo, Italy (mean age=72.9+/-0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23+/-0.04, 1.35+/-0.02, and 1.34+/-0.03; p=0.03), and significantly lower BMD (gm/cm(2)) in the lumbar spine (1.009+/-0.02, 0.955+/-0.01 and 0.931+/-0.02; p=0.03) and the femoral neck (0.748+/-0.02, 0.717+/-0.01 and 0.693+/-001, p=0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.
编码代谢雌激素的酶的细胞色素P450（CYP450）基因多态性与激素相关癌症有关。我们调查了先前报道的与激素相关疾病相关的CYP1B1基因的两种多态性对来自不同种族背景女性的雌激素代谢和骨矿物质密度（BMD）（另一种激素依赖性状况）的影响。468名绝经后白种女性参与了研究，其中220名来自美国密苏里州圣路易斯市（平均年龄=63.5±0.53岁），248名来自意大利巴勒莫市（平均年龄=72.9±0.44岁）。仅在美国女性中通过酶联免疫吸附测定法测量尿雌激素代谢物，通过超灵敏放射免疫测定法测量血清雌二醇，通过免疫放射分析测定血清性激素结合球蛋白，而通过双能X线吸收法测量BMD并通过焦磷酸测序法进行基因分型，美国和意大利女性均进行此项检测。通过协方差分析对代谢物水平、游离雌二醇指数和BMD的差异进行分析。对美国参与者中缬氨酸432亮氨酸多态性的分析表明，与具有Val/Val基因型的女性相比，具有Leu等位基因（Val/Leu和Leu/Leu）的女性总尿雌激素代谢物（ng/mg-肌酐）水平的对数转换值显著更高（分别为1.23±0.04、1.35±0.02和1.34±0.03；p=0.03），并且腰椎（分别为1.009±0.02、0.955±0.01和0.931±0.02；p=0.03）和股骨颈（分别为0.748±0.02、0.717±0.01和0.693±0.01，p=0.03）的BMD（gm/cm²）显著更低，Val/Val、Val/Leu和Leu/Leu基因型的BMD依次降低。美国女性中丙氨酸119丝氨酸多态性的不同基因型在尿代谢物和BMD方面无显著差异。同时，对意大利女性的单独分析显示，所研究的两种多态性的不同基因型之间的BMD无显著差异。总之，与具有Val/Val基因型的女性相比，具有CYP1B1 Val432多态性Leu等位基因的女性尿雌激素代谢物水平更高，表明其雌激素分解代谢增加。这可能导致这些女性相对雌激素缺乏以及腰椎和股骨颈BMD降低。我们的数据表明，通过其对雌激素分解代谢速率的影响，CYP1B1基因的Val432Leu多态性可能是美国女性骨质疏松症的一个潜在遗传危险因素。
