Genetic variations in the 3′-untranslated region of SLC 18A2 are associated with serum FSH concentration in polycystic ovary syndrome patients and regulate gene expression in vitro
Genetic variations in the 3′-untranslated region of SLC 18A2 are associated with serum FSH concentration in polycystic ovary syndrome patients and regulate gene expression in vitro
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DOI：
10.1093/humrep/dew162
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发表时间：
2016-09-01
影响因子：
6.1
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Li, Qiaoli;Yan, Zheng;Wang, Lei
研究问题：人类溶质载体家族18成员A2（SLC 18 A2）基因座的遗传变异是否与多囊卵巢综合征（PCOS）的病因和/或PCOS患者的促卵泡激素（FSH）水平和胰岛素分泌相关？简要答复：我们在SLC 18 A2的3 '-非翻译区发现了两种常见的遗传变异（rs363282和rs363238），它们与PCOS组的血清FSH浓度相关。已知：SLC 18 A2是一种囊泡单胺转运蛋白，在多巴胺调节中至关重要。多巴胺可以通过D2受体负性调节FSH和胰岛素分泌。研究设计、规模、持续时间：本研究是一项在中国PCOS患者（n = 319）和对照组（n = 220）中进行的横断面研究。PCOS患者根据雄激素过量协会的标准进行诊断，包括高雄激素血症加上少经闭或多囊卵巢的临床和/或生化体征。对照组月经周期正常，无高雄激素血症或其他与PCOS相关的内分泌紊乱。根据48例PCOS患者的基因重测序数据和连锁不平衡分析，选择标记单核苷酸多态性（SNP）。在PCOS病例和对照组中检查了变异体（rs363282和rs363238）的等位基因频率沿着与数量性状的关系。将样本进一步分为两个亚组进行关联分析：AA + AG组和GG组（rs363282），CC + AC组和AA组（rs363238）。通过荧光素酶测定测量SLC 18 A2变体的功能效果。SLC 18 A2的基因表达与NCBI的Gene Expression Omnibus datasets.Main结果和机会的作用：在3 '-非翻译区的两个常见的遗传变异（rs363282和rs363238）与PCOS组的血清FSH相关（分别为P = 0.005和P = 0.001），而在对照组中没有发现相关性。功能研究表明，两个变体的次要等位基因（rs363282-G和rs363238-A）具有比rs363282-A（P = 0.009）和rs363238-C（P = 0.009）显著更低的荧光素酶活性。由于条件限制，未纳入更具体的参数，包括卵泡计数和抗苗勒管激素，无法评价SLC 18 A2与这些参数之间的关系。 研究结果的更广泛意义：我们发现了PCOS患者SLC 18 A2的两种遗传变异与FSH水平之间的新关联。这些发现可能提示PCOS卵泡发育和成熟的一种新的调控机制。 研究经费/竞争兴趣：本研究得到了国家自然科学基金（资助号：81571501和81270747）、国家基础研究计划（资助号：2015 CB 943300）的资助。没有宣布竞争利益。
STUDY QUESTION: Are genetic variations at the human solute carrier family 18 member A2 (SLC18A2) locus associated with the etiology of polycystic ovary syndrome (PCOS) and/or with follicle stimulating hormone (FSH) levels and insulin secretion in PCOS?SUMMARY ANSWER: We found two common genetic variants in the 3'-untranslated region of SLC18A2 (rs363282 and rs363238) that are associated with serum FSH concentration in the PCOS group.WHAT IS KNOWN ALREADY: SLC18A2 is a vesicular monoamine transporter that is essential in dopamine regulation. Dopamine can negatively regulate FSH and insulin secretion through the D2 receptor.STUDY DESIGN, SIZE, DURATION: This study was a cross-sectional examination in women with PCOS (n = 319) and controls (n = 220) from China.PARTICIPANTS/MATERIALS, SETTING, METHODS: The PCOS patients were diagnosed based on the criteria of the Androgen Excess Society, including clinical and/or biochemical signs of hyperandrogenemia plus oligoamenorrhea or polycystic ovaries. Controls had regular menstrual cycles and no hyperandrogenism or other endocrine disorders related to PCOS. Tag single nucleotide polymorphisms (SNPs) were selected based on resequencing data in 48 PCOS patients and linkage disequilibrium analysis. Allele frequencies for variants (rs363282 and rs363238) were examined in PCOS cases and controls along with their relationship to quantitative traits. The samples were further divided into two subgroups for association analysis: AA + AG group and GG group (rs363282), CC + AC group and AA group (rs363238). The functional effects of SLC18A2 variants were measured by luciferase assay. The gene expression of SLC18A2 was compared with the NCBI's Gene Expression Omnibus datasets.MAIN RESULTS AND THE ROLE OF CHANCE: Two common genetic variants in the 3'-untranslated region (rs363282 and rs363238) are associated with serum FSH in the PCOS group (P = 0.005 and P = 0.001, respectively), while no associations were found in controls. Functional studies showed that minor alleles of the two variants (rs363282-G and rs363238-A) had significantly lower luciferase activities than rs363282-A (P = 0.009) and rs363238-C (P = 0.009).LIMITATIONS, REASONS FOR CAUTION: Results were not validated in another independent cohort, though we provided functional evidence of the two SNPs. Because of limited condition, more specific parameters, including ovarian follicle count and anti-Mullerian hormone were not included and relationship between SLC18A2 and these parameters cannot be evaluated. WIDER IMPLICATIONS OF THE FINDINGS: We found a novel association between two genetic variants in SLC18A2 and FSH levels in PCOS patients. These findings might indicate a novel regulatory mechanism in follicular development and maturation in PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (grant numbers 81571501 and 81270747), National Basic Research Program of China (grant number 2015CB943300). No competing interests declared.