Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Shoulder Unit, Princess Elizabeth Orthopaedic Centre, Royal Devon and Exeter Hospital, Exeter, UK.
Int J Epidemiol. 2024 Feb 1;53(1). doi: 10.1093/ije/dyad187.
BACKGROUND: Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. METHODS: In the UK Biobank's unrelated European cohort (N = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. RESULTS: Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20-1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01-1.35), trigger finger: OR = 1.30 (95% CI, 1.09-1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09-1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93-17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50-5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10-1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90-0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42-2.69) P = 3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36-1.95) P = 8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. CONCLUSIONS: Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications.
背景：糖尿病（无论类型）和肥胖与一系列肌肉骨骼疾病有关。对于许多上肢疾病，导致这些关联的因果机制尚不清楚。我们使用遗传技术来测试血糖、肥胖与肌肉骨骼状况之间的因果关系。
方法：在英国生物库的非相关欧洲队列（N=379708）中，我们进行了孟德尔随机化（MR）分析，以测试长期高血糖和肥胖对四种肌肉骨骼疾病（冻结肩、掌腱膜挛缩症、腕管综合征和扳机指）的因果作用。我们还使用 GCK 基因中的罕见变异进行了单基因 MR。
结果：使用 MR，我们发现长期高血糖在上肢疾病的发病机制中起因果作用。遗传预测的血红蛋白 A1C（HbA1c）每增加 10mmol/mol，与冻结肩相关：比值比（OR）=1.50 [95%置信区间（CI），1.20-1.88]，掌腱膜挛缩症：OR=1.17（95%CI，1.01-1.35），扳机指：OR=1.30（95%CI，1.09-1.55）和腕管综合征：OR=1.20（95%CI，1.09-1.33）。携带 GCK 突变的个体冻结肩的可能性增加：OR=7.16（95%CI，2.93-17.51）和腕管综合征：OR=2.86（95%CI，1.50-5.44），但不是掌腱膜挛缩症或扳机指。我们发现证据表明，遗传预测体重指数（BMI）增加 5kg/m2 与腕管综合征相关：OR=1.13（95%CI，1.10-1.16），与掌腱膜挛缩症呈负相关：OR=0.94（95%CI，0.90-0.98），但与冻结肩或扳机指无关联。我们发现，遗传预测体脂肪增加一个标准差与扳机指（OR 1.96（95%CI，1.42-2.69）P=3.6e-05）和腕管综合征[OR 1.63（95%CI，1.36-1.95）P=8.5e-08]呈正相关。
结论：我们的研究一致表明，长期高血糖在上肢肌肉骨骼疾病的发病机制中起因果作用。治疗糖尿病患者的临床医生应在临床上注意这些并发症，特别是那些管理 GCK 突变携带者护理的医生。上肢肌肉骨骼疾病应被视为糖尿病并发症。
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