Gupta Jayanta, Mitra Nandita, Townsend Raymond R, Fischer Michael, Schelling Jeffrey R, Margolis David J
Division of Biostatistics and Epidemiology, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas.
Center for Clinical Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Wound Repair Regen. 2016 Jul;24(4):705-11. doi: 10.1111/wrr.12447. Epub 2016 Jun 20.
Diabetes is the major risk factor for nontraumatic lower extremity amputation (LEA). The role of genetic polymorphisms in predisposing diabetics to impaired wound healing leading to LEA has not been sufficiently explored. We investigated the association between a set of genes belonging to the angiogenesis/wound repair pathway with LEA in the Chronic Renal Insufficiency Cohort, a study of adults with chronic kidney disease (CKD) that includes a subgroup with diabetes. This study was performed on 3,772 Chronic Renal Insufficiency Cohort participants who were genotyped on the ITMAT-Broad-CARe array chip. A total of 1,017 single-nucleotide polymorphisms (SNPs) in 22 genes belonging to the angiogenesis/would repair pathway were investigated. LEA was determined from patient self-report. The association between genetic variants and LEA status was examined using logistic regression and additive genetic models after stratifying the cohort by race/ethnicity and diabetic status. Unadjusted analyses as well as analyses adjusted for age, sex, estimated glomerular filtration rate, body mass index, peripheral vascular disease, hemoglobin A1c, and population stratification were performed. In non-Hispanic white participants with diabetes, rs11938826 and rs1960669, both intronic SNPs in the gene basic fibroblast growth factor-2 (FGF2), were significantly associated with LEA in covariate-adjusted analysis (OR: 2.83 (95% CI: 1.73, 4.62); p-value: 0.000034; Bonferroni adjusted p-value: 0.0006) and (OR: 2.61 (95% CI: 1.48, 4.61); p-value: 0.00095; Bonferroni adjusted p-value: 0.02). In the same subgroup, rs10883688, an FGF8 SNP of unknown functional effect, was also associated with LEA (OR: 1.72 (95% Confidence Interval: 1.14, 2.6); p-value: 0.00999; Bonferroni adjusted p-value: 0.04). No statistically significant associations were identified in the other ethnic groups. In conclusion, variant/s in FGF2 and FGF8 may predispose diabetics with CKD to LEA. Dysregulation of the FGF2 gene represents an opportunity to understand further, and possibly intervene upon, mechanisms of wound healing in diabetics with CKD.
糖尿病是下肢非创伤性截肢（LEA）的主要风险因素。基因多态性在使糖尿病患者易发生伤口愈合受损进而导致LEA方面的作用尚未得到充分研究。我们在慢性肾功能不全队列研究中调查了一组属于血管生成/伤口修复途径的基因与LEA之间的关联，该研究针对患有慢性肾脏病（CKD）的成年人，其中包括一个糖尿病亚组。本研究对3772名慢性肾功能不全队列参与者进行，他们在ITMAT - 布罗德 - 卡罗尔阵列芯片上进行了基因分型。共研究了属于血管生成/伤口修复途径的22个基因中的1017个单核苷酸多态性（SNP）。LEA通过患者自我报告确定。在按种族/族裔和糖尿病状态对队列进行分层后，使用逻辑回归和加性遗传模型检查基因变异与LEA状态之间的关联。进行了未调整分析以及针对年龄、性别、估计肾小球滤过率、体重指数、外周血管疾病、糖化血红蛋白A1c和群体分层进行调整的分析。在患有糖尿病的非西班牙裔白人参与者中，基因碱性成纤维细胞生长因子2（FGF2）中的两个内含子SNP，即rs11938826和rs1960669，在协变量调整分析中与LEA显著相关（OR：2.83（95%CI：1.73，4.62）；p值：0.000034；Bonferroni调整p值：0.0006）以及（OR：2.61（95%CI：1.48，4.61）；p值：0.00095；Bonferroni调整p值：0.02）。在同一亚组中，功能效应未知的FGF8 SNP rs10883688也与LEA相关（OR：1.72（95%置信区间：1.14，2.6）；p值：0.00999；Bonferroni调整p值：0.04）。在其他种族群体中未发现具有统计学意义的关联。总之，FGF2和FGF8中的变异可能使患有CKD的糖尿病患者易发生LEA。FGF2基因的失调为进一步了解并可能干预患有CKD的糖尿病患者的伤口愈合机制提供了契机。
