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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 459-466. doi: 10.19723/j.issn.1671-167X.2019.03.013

• 论著 • 上一篇    下一篇

IgA肾病易感基因遗传多态性的种族差异分析

康玉琦1,2,张月苗1△(),侯平1,师素芳1,刘立军1,周绪杰1,吕继成1,张宏1   

  • 收稿日期:2019-03-18 出版日期:2019-06-18 发布日期:2019-06-26
  • 作者简介:张月苗,2017年毕业于北京大学,获得医学博士学位,为北京大学第一医院肾脏内科临床医师。现任全国幽门螺杆菌学组编委会编委、中国中药协会肾病中药发展研究专业委员会青年委员,被Autoimmune Disease、Clinical Science、Medicine、PLoS One等多个杂志邀请为审稿人。致力于IgA肾病遗传背景及发病机制、黏膜免疫异常与肾脏病发病以及幽门螺杆菌临床诊治研究。于2017年6—8月以访问学者身份赴香港大学学习。目前主持国家自然科学基金1项、北京市自然科学基金1项、北大医学青年科技创新培育基金1项,发表论文近20余篇,累计影响因子36.627。基于遗传学线索,发现IgA肾病的多个易感基因,及其通过调控Th17细胞和黏膜免疫参与IgA肾病发病的内在机制;基于临床随机对照研究,提出来自于黏膜的成浆细胞可能为CD20单抗美罗华(rituximab)治疗无效,而口服制剂nefecon通过在远端回肠和升结肠靶向释放糖皮质激素布地奈德显著降低IgA肾病患者尿蛋白水平的机制假说,并进行深入机制研究;检测发现IgA肾病患者中幽门螺杆菌的感染率约为55%,为黏膜免疫异常参与IgA肾病的发病和进展提供了线索,有望为IgA肾病黏膜免疫异常机制诊疗提供新的分子标志物,为靶向黏膜治疗提供新的证据和方向。
  • 基金资助:
    国家自然科学基金(81800636)、北京市自然科学基金(7184253)和北大医学青年科技创新培育基金(BMU2017PY007)-中央高校基本科研业务费

Trans-ethnic analysis of susceptibility variants in IgA nephropathy

Yu-qi KANG1,2,Yue-miao ZHANG1△(),Ping HOU1,Su-fang SHI1,Li-jun LIU1,Xu-jie ZHOU1,Ji-cheng LV1,Hong ZHANG1   

  • Received:2019-03-18 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China (81800636), Beijing Natural Science Foundation (7184253), and the Fundamental Research Funds for the Central Universities: Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (BMU2017PY007)

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摘要： 目的 在中国和欧洲人群中比较IgA肾病易感基因遗传多态性的种族差异。方法 检索欧洲人群中已报道的IgA肾病易感基因遗传位点,验证其在中国人群(1 194例患者和902例对照)中的关联性,比较两个人群中显著相关位点的危险等位基因型及其基因型频率、效应OR值、人群归因风险百分比之间的差异。利用所有相关位点计算遗传危险度评分,比较其在亚欧人群中的分布,分析其与临床表型的关联。结果 共有11个遗传座位上16个独立相关遗传位点与欧洲人群中IgA肾病的遗传易感性显著相关。93.75%(15/16)欧洲人相关遗传位点在中国人群中得到独立验证(P<0.05),且危险等位基因型在两个人群中一致。与欧洲人群相比,中国人群遗传位点拥有更高的危险等位基因型频率(P=3.09×10 -2)、OR值(P=1.94×10 -2)和人群归因风险百分比(P=3.03×10 -4)。中国人群IgA肾病患者与健康对照、东亚人群与欧洲人群相比遗传危险度评分更高(P值分别为3.60×10 -27和1.78×10 -163),东亚人群和欧洲人群各亚组之间差异无统计学意义。研究人群中IgA肾病遗传危险度评分与血浆IgA1水平、慢性肾脏病(chronic kidney disease,CKD)分期和Hass分级显著相关。 结论 IgA肾病相关易感基因在欧洲人群和中国人群相似,中国人群有更高遗传风险,提示亚洲人群中IgA肾病高患病率具有遗传基础。

关键词: IgA肾病, 多态性, 单核苷酸, 中国人群, 欧洲人群

Abstract: Objective: To compare the genetic architecture of susceptibility variants of IgA nephropathy (IgAN) in Chinese and Europeans.Methods: We selected the independent genome-wide significant variants of IgAN in European population as candidate variants. Their associations, risk alleles, risk allele frequencies, odds ratios and population attributable risk scores were derived and calculated, then compared with those in the current Chinese population, including 1 194 IgAN patients and 902 controls. Using the significant variants, genetic risk scores were calculated and compared between the East Asians and the Europeans. The correlation between the genetic risk scores and clinical manifestations was also evaluated. Results: There were 16 independent single nucleotide polymorphisms (SNPs) located in 11 loci showing significantly association with susceptibility to IgAN in the Europeans. 93.75% (15/16) of them also showed significant associations in the Chinese (P<0.05). The effects of all the associated SNPs were in the same direction, either risk or being protective for IgAN, between the Chinese and the Europeans. On the contrary, remarkable higher risk allelic odds ratio (P=1.94×10 -2), higher risk allele frequency (P=3.09×10 -2), and higher population attributable risk (P=3.03×10 -4) were observed for most of the associated SNPs in the Chinese than in the Europeans. Furthermore, genetic risk scores were significantly larger in the Asian populations compared with the Europeans (P=1.78×10 -163). While there was no significance among the subpopulations in both the East Asians and the Europeans. Compared with the healthy controls, the genetic risk score in the IgAN patients was significantly larger (P=3.60×10 -27). Clinical analysis showed the genetic risk score was positively associated with serum levels of IgA and IgA1, phases of chronic kidney disease and Haas grades. Conclusion: Our study provides further evidence in the shared genetic architecture between Chinese and Europeans, while diffe-rences with respect to the effect sizes and risk allele frequencies across ethnicities, contributing partially to the differences of disease prevalence.

Key words: IgA nephropathy, Polymorphism, single nucleotide, Chinese, Europeans

中图分类号: 

  • R692.31

表1

1 194例IgAN患者的基线临床资料"

Characteristic Median or percentage
Age/years, IQR 32 (25, 39)
Gender, male/female 651/543
Systolic blood pressure/mmHg, IQR 120 (110, 130)
Diastolic blood pressure/mmHg, IQR 80 (70, 88)
Hypertension/% 47.90
Urinary protein (g/24 h)/%
<1 33.93
1-2 27.52
2-3.5 15.60
≥3.5 20.95
eGFR/[mL/(min·1.73 m2)], IQR 85.63 (63.52, 106.63)
Haas classification/%
Ⅰ 38.19
Ⅱ 6.71
Ⅲ 38.43
Ⅳ 7.87
Ⅴ 8.80

表2

lgAN 易感基因遗传性位点在中国人群和欧洲人群中的分布比较"

图1

IgAN易感基因遗传性位点在中国人群和欧洲人群的疾病风险比较"

图2

IgAN患者和健康对照遗传危险度评分比较"

表3

lgAN 遗传风险评分与基线临床病理资料分析"

图3

东亚人群和欧洲人群IgAN遗传危险度评分比较"

图4

东亚人群之间IgAN遗传危险度评分比较"

图5

欧洲人群之间IgAN遗传危险度评分比较"

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ISSN 1671-167X
CN 11-4691/R
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