持续肥胖、人类瘦素及瘦素受体基因多态性与不同分子亚型乳腺癌的关系研究

Study of the association between polymorphism of persistent obesity, human leptin gene/leptin receptor gene and molecular subtypes of breast cancer

目的 探讨持续肥胖、人类瘦素基因（LEP）及瘦素受体基因（LEPR）多态性与不同分子亚型乳腺癌的相关性.方法 2014年4月至2015年5月收集四川省肿瘤医院和华西医院经组织病理学诊断的原发性乳腺癌新发病例,排除转移性乳腺癌与有精神疾病的患者,共纳入703例乳腺癌患者作为病例组;选取同期在四川省人民医院体检中心的健康体检女性和成都双流妇幼保健院参加乡镇乳腺癌筛查的健康体检女性人群,排除有恶性肿瘤、乳腺相关疾病和精神疾病患者,共805名研究对象作为对照组.采用统一问卷调查收集研究对象基本信息,并对其10年间的肥胖状况进行判定.采用飞行时间质谱生物芯片技术检测LEP rs7799039、LEPR rs1137100、LEPR rs1137101基因型;采用无序多分类logistic回归模型分析不同分子亚型乳腺癌相关危险因素的风险,用二分类logistic回归模型分析持续肥胖、LEP/LEPR基因多态性对不同分子亚型乳腺癌的交互作用.结果 805名对照组的年龄为（48.98±8.83）岁,病例组三阴性（TNBC）、Luminal A、Luminal B、HER-2过表达型（HER-2＋型）乳腺癌患者分别有77、79、412、135例,年龄分别为（51.43±11.33）、（49.94±10.10）、（49.73±9.38）、（50.50±9.04）岁.对照组中LEP rs7799039 A、LEPR rs1137100 G和LEPR rs1137101 G基因型的出现频率分别为74.8%（1157/1546）、83.6%（1339/1602）和88.4%（1416/1602）,病例组分别为77.6%（1074/1384）、82.4%（1155/1402）和87.9%（1232/1402）.与非持续肥胖者比较,持续肥胖者TNBC型、Luminal A型与Luminal B型乳腺癌的发病风险均升高,OR（95%CI）值分别为3.58（1.90~6.72）、2.65（1.35~5.21）和1.90（1.26~2.89）;携带LEP rs7799039-AA基因型与Luminal B型乳腺癌的患病风险升高相关（OR=1.30,95%CI：1.00~1.69）,持续肥胖且携带LEPR rs1137101-GG基因型与患Luminal B型乳腺癌的风险相关（β=3.34,95%CI：1.00~11.12）.结论 持续肥胖可增加TNBC型、Luminal A型与Luminal B型乳腺癌的发生风险.持续肥胖且携带LEPR rs1137101-GG基因型的女性是Luminal B型乳腺癌的高危人群.

Objectives To explore the association between the polymorphism of persistent obesity and genetic variations in the LEP （human leptin gene, LEP） and LEPR （leptin receptor gene, LEPR） genes and different molecular subtypes of breast cancer. Methods All 703 female patients of breast cancer diagnosed by histopathology in the Sichuan Cancer Hospital or the West China Hospital, excluding patients with metastatic breast cancer or mental disease, were selected as cases from April 2014 to May 2015. At the same time, 805 healthy women received physical examination in medical examination center of Sichuan People Hospital or Shuangliu maternal and child health care hospital, excluding those with therioma, breast disease, and mental disease, were enrolled in control group. A uniform questionnaire was used to collect general information including demographic characteristic, reproductive history height, weight, and so on. And the obesity status in recent 10 years was judged. Time of Flight Mass Spectrometer was used to determine the genotypes of LEP rs7799039, LEPR rs1137100 and LEPR rs1137101, while the multinomial logistic regression analysis was conducted to estimate the effect of risk factors related to breast cancer in different molecular subtypes; and then, the association between polymorphism of persistent obesity, the LEP, LEPR genes and breast cancer of different molecular subtypes was analyzed by binary logistic regression models. Results The average age of controls was （48.98＆#177;8.83） years old, while the age of cases of TNBC, Luminal A, Luminal B, and HER-2＋ were （51.43＆#177;11.33）, （49.94＆#177;10.10）, （49.73＆#177;9.38）, （50.50＆#177;9.04） years old, respectively. The frequency of genotype LEP rs7799039, LEPR rs1137100 and LEPR rs1137101 in control group was separately 74.8%（1157/1546）, 83.6%（1339/1602） and 88.4%（1416/1602）; while 77.6%（1074/1384）, 82.4% （1155/1402） and 87.9% （1232/1402） respectively in case group. Compared with non-persistent obesity subjects, the persistent obesity ones showed an increased risk in TNBC （OR=3.58, 95%CI： 1.90-6.72）, Luminal A （OR=2.65, 95%CI： 1.35-5.21） and Luminal B （OR=1.90, 95%CI： 1.26-2.89） breast cancer. LEP rs7799039-AA was relevant with the upward risk of Luminal B independently （OR=1.30, 95%CI： 1.00-1.69）. Besides, persistent obesity was found to have a combined effect on Luminal B （β=3.34, 95% CI： 1.00- 11.12） with LEPR rs1137101-GG. Conclusion Persistent obesity could increase the potential risk of TNBC, Luminal A and Luminal B breast cancer. Women who were suffered from persistent obesity with a genotype of LEPR rs1137101-GG were more susceptible to Luminal B breast cancer.