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Abstract：
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.
摘要：
糖尿病是非创伤性下肢截肢（LEA）的主要危险因素。遗传多态性在糖尿病患者易感伤口愈合受损导致LEA中的作用尚未得到充分探索。我们研究了慢性肾功能不全队列中属于血管生成/伤口修复途径的一组基因与LEA之间的关联，一项针对慢性肾病（CKD）成人的研究，其中包括糖尿病亚组。这项研究是对3,772名慢性肾功能不全队列参与者进行的，这些参与者在ITMAT-Broad-CARE阵列芯片上进行了基因分型。研究了22个属于血管生成/will修复途径的基因中的1,017个单核苷酸多态性（SNP）。根据患者自我报告确定LEA。在根据种族/民族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了遗传变异与LEA状态之间的关联。未调整的分析以及根据年龄调整的分析，性别,估计肾小球滤过率，身体质量指数,外周血管疾病,血红蛋白A1c，并进行了人群分层。在非西班牙裔白人糖尿病患者中，rs11938826和rs1960669，都是碱性成纤维细胞生长因子-2（FGF2）基因中的内含子SNP，在协变量校正分析中与LEA显著相关(OR:2.83(95%CI:1.73,4.62);p值:0.000034;Bonferroni校正p值:0.0006)和(OR:2.61(95%CI:1.48,4.61);p值:0.00095;Bonferroni校正p值:0.02).在同一个子群中，rs10883688，功能效应未知的FGF8SNP，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)。在其他种族中没有发现统计学上显着的关联。总之,FGF2和FGF8中的变异可能会使患有CKD的糖尿病患者易患LEA。FGF2基因的失调代表了进一步了解的机会，可能会干预，糖尿病CKD患者伤口愈合的机制。
