The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients
The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients
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DOI：
10.1046/j.1365-2265.2003.01798.x
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发表时间：
2003-07-01
影响因子：
3.2
通讯作者：
Lamberts, SWJ
中科院分区：
文献类型：
--
作者：
Di Blasio, AM;van Rossum, EFC;Lamberts, SWJ
目的我们最近报道，在荷兰健康老年人中，糖皮质激素受体（GR）基因的N363 S多态性与对低剂量地塞米松（0.25 mg）的更高敏感性相关，评价为皮质醇抑制和胰岛素反应，并与体重指数（BMI）增加相关。在本研究中，我们调查了N363 S多态性和Bcl I限制性位点多态性在一组意大利严重肥胖患者中的作用。设计：采用PCR-限制性片段长度多态性分析和Taqman序列检测系统对279例患者（平均BMI 45.9 +/- 0.9 kg/m2）进行基因分型。同时还测定了几个代谢和测量参数，以将它们与基因型相关联。（8名女性，5名男性）为N363 S变异杂合子（等位基因频率2.3%），并且当与野生型纯合子相比时，具有显著更高的BMI（P < 0.04）、静息能量消耗（P < 0.03）和食物摄入（P < 0.01）。当根据性别分析数据时，N363 S等位基因的女性杂合子比野生型363 GR基因的肥胖女性具有显著更高的BMI（P = 0.04）、静息能量消耗（P = 0.03）和食物摄入（P = 0.008）。这种变异的男性携带者在这些变量上也有更高的值，尽管差异没有达到统计学意义。对年龄、性别和BMI匹配的纯合子野生型肥胖受试者进行的病例对照研究显示，静息能量消耗和食物摄入没有差异。Bcl I变异的等位基因频率为27%（269例受试者中有89例女性和41例男性）。在该肥胖人群中，该变异型GR杂合子或纯合子受试者的人体测量和代谢参数无差异。然而，当我们研究同一个体中Bcl I多态性和N363 S变异体存在的影响时，我们发现携带这两种多态性的受试者倾向于更高的收缩压和舒张压以及显著更高的总胆固醇和LDL胆固醇水平（分别为P = 0.005和P = 0.05）.讨论利用本研究的结果和在荷兰人群中获得的结果，我们推测发展肥胖的N363 S变体的杂合携带者可能变得更加肥胖，这可能是因为它们具有超敏的胰岛素反应，因此通过激活脂肪生成，更有效地储存脂肪。此外，这些数据表明，携带Bcl I多态性的N363 S携带者往往具有略微不利的心血管特征。
OBJECTIVE We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low-dose dexamethasone (0.25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a Bcl I restriction site polymorphism in a group of Italian patients with severe obesity.DESIGN Two hundred and seventy-nine patients (mean BMI 45.9 +/- 0.9 kg/m(2) ) were genotyped using both PCR-restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype.RESULTS In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2.3%) and had significantly higher BMI (P < 0.04), resting energy expenditure (P < 0.03) and food intake (P < 0.01) when compared to wild-type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0.04), resting energy expenditure (P = 0.03) and food intake (P = 0.008) than obese women with the wild-type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case-control study with homozygous wild-type obese subjects which were age-, sex- and BMI-matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the Bcl I variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the Bcl I polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL-cholesterol levels (P = 0.005 and P = 0.05, respectively).DISCUSSION Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the Bcl I polymorphism as well, tend to have a slightly unfavourable cardiovascular profile.