AIMS/HYPOTHESIS Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. METHODS Participants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study-Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10-11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. RESULTS Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10-89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10-3). CONCLUSIONS/INTERPRETATION Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.

中文翻译：

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循环 galectin-1 在 2 型糖尿病和慢性肾病中的作用：来自横断面、纵向和孟德尔随机分析的证据。

目的/假设 Galectin-1 调节炎症和血管生成，横断面研究表明，galectin-1 可能是肥胖、2 型糖尿病和肾功能之间的联合因素。我们检查了循环 galectin-1 是否可以预测中年人群慢性肾脏病 (CKD) 和 2 型糖尿病的发病率，以及孟德尔随机化 (MR) 是否可以为影响的因果方向提供证据。方法 对 1991 年至 1994 年间（平均年龄 57.6 岁）参加的马尔默饮食和癌症研究 - 心血管队列的参与者（n = 4022；58.6% 女性）进行了检查。在基线和平均随访 16.6 ± 1.5 年后计算 eGFR。糖尿病状态通过登记联系确定（平均随访时间为 18.4 ± 6.1 年）。使用 Cox 回归评估基线 galectin-1 与 CKD 和 2 型糖尿病的关联，并调整已确定的风险因素。此外，利用从慢性肾脏病遗传学 (CKDGen) 联盟（41,395 例和 439,303 例对照）和糖尿病组获得的遗传关联，对半乳糖凝集素-1 进行了全基因组关联研究，以确定用于两样本 MR 分析的遗传工具遗传学复制和荟萃分析 (DIAGRAM) 联盟（74,124 例病例和 824,006 例对照）。鉴定了 galectin-1 基因区域中的一个全基因组显着位点（前哨 SNP rs7285699；p = 2.4 × 10-11）。还在斯堪尼亚全新糖尿病患者 (ANDIS) 队列中新诊断的糖尿病患者中检查了 galectin-1 和 eGFR 之间的关联。结果 Galectin-1 与基线时较低的 eGFR 密切相关（p = 2.3 × 10-89），但与 CKD 事件无关。然而，galectin-1 与 2 型糖尿病风险增加相关（每 SD 增加，HR 1.12；95% CI 1.02, 1.24）。在一般人群中，两样本 MR 分析无法确定 galectin-1 对 CKD（OR 0.92；95% CI 0.82, 1.02）或 2 型糖尿病（OR 1.05；95% CI 0.98, 1.14）的因果影响。然而，在属于严重胰岛素抵抗糖尿病亚组且糖尿病肾病高风险的 ANDIS 2 型糖尿病患者中，基因升高的半乳糖凝集素 1 与较高的 eGFR 显着相关（p = 5.7 × 10-3）。结论/解释在横断面分析中，Galectin-1 与肾功能降低密切相关，和两样本 MR 分析表明，对糖尿病肾病高风险 2 型糖尿病患者的肾功能具有因果保护作用。未来的研究需要探索 galectin-1 影响肾功能的机制，以及它是否可以成为 2 型糖尿病患者肾脏改善的有用靶点。