Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Nephrol Dial Transplant. 2012 Apr;27(4):1511-5. doi: 10.1093/ndt/gfr442. Epub 2011 Aug 5.
We tested for associations between estimated glomerular filtration rate (eGFR) and retinol-binding protein 4 (RBP4) haplotypes found on human chromosome 10q23. This locus had been linked to eGFR in a previous linkage scan in patients with Type 2 diabetes mellitus.
We analysed 469 patients with Type 2 diabetes and 174 normoalbuminuric controls for associations between RBP4 haplotypes and eGFR. For comparison with controls, 295 cases with proteinuria/end-stage renal disease were tested for associations with advanced diabetic nephropathy. Genotyping was performed using high-resolution DNA melting assays. Data analysis was performed using the haplo.stats package.
Genetic variations in RBP4 were not associated with advanced diabetic nephropathy. Compared with the common A/G/G/C haplotype, C/A/A/C carriers among the normoalbuminuric controls had higher eGFR values among younger patients but lower eGFRs among the older patients (effect size=2.2, P=3.3×10(-7)). Furthermore, while eGFR values were fairly consistent over the range of systolic blood pressure (SBP) values for the common haplotype, eGFR in C/A/A/C carriers increased with SBP (effect size=3.6, P=1.5×10(-2)). There was a significant interaction between the C/A/A/C haplotype and HbA1c as they affect eGFR compared to the common haplotype (effect size=2.1, P=2.1×10(-3)). Power calculations demonstrated that our study had >90% power to detect the observed interactions even while performing multiple hypotheses testing. The interaction between SBP and the C/A/A/C haplotype remained significant (P=2.8×10(-2)) even when these three haplotype-environment interactions were simultaneously estimated.
RBP4 haplotypes may be important in genetically modulating renal function in response to environmental challenges among patients with Type 2 diabetes.
我们检测了位于人类 10q23 染色体上的估算肾小球滤过率 (eGFR) 和视黄醇结合蛋白 4 (RBP4) 单体型之间的关联。该基因座先前在 2 型糖尿病患者的连锁扫描中与 eGFR 相关。
我们分析了 469 例 2 型糖尿病患者和 174 例正常白蛋白尿对照组，以检测 RBP4 单体型与 eGFR 之间的关联。为了与对照组进行比较，我们对 295 例蛋白尿/终末期肾病患者进行了与晚期糖尿病肾病相关的关联检测。使用高分辨率 DNA 熔解分析进行基因分型。使用 haplo.stats 包进行数据分析。
RBP4 的遗传变异与晚期糖尿病肾病无关。与常见的 A/G/G/C 单体型相比，正常白蛋白尿对照组中的 C/A/A/C 携带者在年轻患者中具有更高的 eGFR 值，但在老年患者中具有更低的 eGFR 值（效应大小=2.2，P=3.3×10(-7)）。此外，虽然常见单体型的收缩压 (SBP) 值范围内 eGFR 值相当稳定，但 C/A/A/C 携带者的 eGFR 随 SBP 增加（效应大小=3.6，P=1.5×10(-2)）。C/A/A/C 单体型与 HbA1c 之间存在显著的相互作用，因为它们与常见单体型相比会影响 eGFR（效应大小=2.1，P=2.1×10(-3)）。即使在进行多次假设检验时，我们的研究也有超过 90%的能力检测到观察到的相互作用。即使同时估计这三种单体型-环境相互作用，SBP 与 C/A/A/C 单体型之间的相互作用仍然显著（P=2.8×10(-2)）。
RBP4 单体型可能在 2 型糖尿病患者对环境挑战的肾功能遗传调节中起重要作用。
