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炎症基因变异与美国人群白蛋白尿易感性:第三次国家健康和营养调查(NHANES III),1991-1994 年的分析。

Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994.

机构信息

Office of Public Health Genomics, Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA, USA.

出版信息

BMC Med Genet. 2010 Nov 5;11:155. doi: 10.1186/1471-2350-11-155.

Abstract

BACKGROUND

Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria.

METHODS

We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models.

RESULTS

Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group.

CONCLUSIONS

Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

摘要

背景

白蛋白尿是肾脏损害的常见标志物,也是肾脏疾病进展和心血管疾病发展的重要预测因素。虽然其潜在病因尚不清楚,但慢性、低度炎症是一个可疑的关键因素。因此,炎症过程中涉及的基因内的遗传变异可能导致白蛋白尿的发生。

方法

我们评估了来自美国第三次全国健康和营养检查调查(NHANES III)第二期(1991-1994 年)的 27 个炎症反应基因内的 60 个多态性,这是一项基于人群和全国代表性的调查。白蛋白尿的评估采用对数转换的白蛋白与肌酐比值(ACR),ACR≥30mg/g 以及 ACR 高于性别特异性阈值。在 5321 名年龄在 20 岁或以上的参与者中,进行多变量线性回归和单体型趋势分析以检测遗传关联。在加性和共显性遗传模型中,检测非西班牙裔白人、非西班牙裔黑人和墨西哥裔美国人中不同等位基因和基因型分布的差异。

结果

在至少一个种族/民族群体中,发现多个基因的变异与 log(ACR)呈边缘关联(未经校正的 P 值<0.05),但当校正假发现率(FDR)时,在未校正或完全校正的模型中,没有一个变异仍然具有统计学意义。在分析性别特异性白蛋白尿时,墨西哥裔美国人的 IL1B(rs1143623)与增加的比值比仍显著相关,而 IL1B(rs1143623)、CRP(rs1800947)和 NOS3(rs2070744)在该人群中与 ACR≥30mg/g 显著相关(加性模型,FDR-P<0.05)。相比之下,在对多次检验进行校正后,在非西班牙裔黑人中未发现与白蛋白尿相关的变异。在非西班牙裔白人中唯一与任何结果显著相关的变异是 TNF(rs1800750),该变异在该人群中未能通过 Hardy-Weinberg 比例检验。在至少一个种族/民族群体中,MBL2、CRP、ADRB2、IL4R、NOS3 和 VDR 内的单体型与 log(ACR)或白蛋白尿显著相关(FDR-P<0.05)。

结论

我们的研究结果表明,炎症相关基因内的遗传变异对白蛋白尿的易感性有一定的作用。需要进一步的研究来进一步评估这些炎症基因和未测试的炎症基因中的遗传变异是否改变了对肾脏损害的易感性。

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