Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach
Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach
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DOI：
10.1093/ndt/gfq402
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发表时间：
2011-01-01
影响因子：
6.1
通讯作者：
Dekker, Friedo W.
中科院分区：
文献类型：
--
作者：
Verduijn, Marion;Prein, Robert A.;Dekker, Friedo W.
背景低水平的循环胎球蛋白A与透析患者死亡率增加相关。本研究的目的是通过调查α 2-Heremans-Schmid糖蛋白（AHSG）基因的功能多态性是否与死亡率相关，以及通过使用孟德尔随机设计估计胎球蛋白A水平对死亡率的因果作用，来研究胎球蛋白A对死亡率的潜在因果作用。对1043例透析患者进行Thr 256 Ser多态性（rs 4918）基因分型，并随访5年;对549例患者进行血清胎球蛋白A水平测定。丝氨酸等位基因的携带者表现出较低的胎球蛋白-A水平（每个等位基因-0.07 g/L，P < 0.001）。与Thr/Thr基因型相比，Thr/Ser和Ser/Ser基因型的死亡风险略有增加（HR分别为1.03，95% CI 0.83-1.28和HR 1.10，95% CI 0.78-1.55）。使用AHSG基因型作为工具变量，胎球蛋白A水平对死亡率的致病HR估计为每0.1 g/L增加1.01。炎症和糖尿病部分改变了胎球蛋白A水平与预后的关系。Thr 256 Ser多态性与死亡率弱相关，未观察到胎球蛋白A水平对该结果的影响。其他危险因素，包括炎症和糖尿病，可能导致胎球蛋白-A水平降低，和/或改变低胎球蛋白-A对终末期肾病患者死亡率的影响。
Background. Low levels of circulating fetuin-A are associated with increased mortality in dialysis patients. This study aimed to examine a potential causative role for fetuin-A on mortality by investigating whether a functional polymorphism in the alpha2-Heremans-Schmid glycoprotein (AHSG) gene associates with mortality, and by estimating the causative effect of fetuin-A levels on mortality using a Mendelian randomization design.Methods. One thousand and forty-three incident dialysis patients were genotyped for the Thr256Ser polymorphism (rs4918) and followed up for 5 years; in 549 patients, serum fetuin-A levels were measured.Results. Carriers of a serine allele displayed lower fetuin-A levels (-0.07 g/L per allele, P < 0.001). A small increased mortality risk was observed for the Thr/Ser and Ser/Ser genotype compared with the Thr/Thr genotype (HR 1.03, 95% CI 0.83-1.28 and HR 1.10, 95% CI 0.78-1.55, respectively). Using the AHSG genotype as an instrumental variable, the causative HR of fetuin-A levels on mortality was estimated as 1.01 per 0.1-g/L increase. Inflammation and diabetes partially modified the association of fetuin-A levels with outcome.Conclusions. The Thr256Ser polymorphism was weakly associated with mortality, and no causative effect of fetuin-A levels on this outcome was observed. Other risk factors, including inflammation and diabetes, might lead to lower fetuin-A levels, and/or modify the effect of low fetuin-A on mortality in end-stage renal disease patients.