一项双向孟德尔随机化研究评估了南亚人和欧洲人血液维生素 D 水平降低与 2 型糖尿病风险之间的因果关系。
A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.
机构信息
Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, OK, 73104, OK City, USA.
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
出版信息
Nutr J. 2021 Jul 27;20(1):71. doi: 10.1186/s12937-021-00725-1.
CONTEXT
Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent.
OBJECTIVES AND METHODS
To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration.
RESULTS
Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument.
CONCLUSION
Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.
背景
多项观察性研究报告称，25-羟维生素 D 浓度（25（OH）D）与 2 型糖尿病（T2D）呈负相关。然而，关于 25（OH）D 与 T2D 风险之间关系的短期和长期干预试验结果并不一致。
目的和方法
为了评估血液 25（OH）D 减少在 T2D 中的因果作用，我们使用来自欧洲和印度血统的 59890 个人（5862 例 T2D 病例和 54028 例对照）进行了双向孟德尔随机化研究。我们使用了六个已知的 SNP，包括三个 T2D SNP 和三个维生素 D 途径 SNP，作为遗传工具来评估 T2D 和循环 25（OH）D 浓度之间关联的因果关系和方向。
结果
参加的八项研究的综合荟萃分析结果表明，三种 T2D SNP 的综合评分会显著增加 T2D 风险，比值比（OR）为 1.24，p=1.82×10-5；Z 分数 11.86，然而，这与 25（OH）D 状态没有显著关联（Beta-0.02nmol/L±SE0.01nmol/L；p=0.83；Z 分数-0.21）。同样，降低 25（OH）D 浓度的遗传工具合成评分的复合评分（-2.1nmol/L±SE0.1nmol/L，p=7.92×10-5；Z 分数-18.68）显著降低了 25（OH）D 浓度，但与 T2D 风险增加无关（OR1.00，p=0.12；Z 分数 1.54）。然而，使用 25（OH）D 合成 SNP（DHCR7；rs12785878）作为个体遗传工具，每等位基因降低 25（OH）D 浓度（-4.2nmol/L±SE0.3nmol/L）可预测 T2D 风险增加 5%，p=0.004；Z 分数 2.84。然而，当用作个体工具时，其他 25（OH）D SNP（GCrs2282679、CYP2R1rs12794714）并未出现这种情况。
结论
我们在这项双向孟德尔随机化研究中的新数据表明，遗传工具化的 T2D 风险不会导致 25（OH）D 水平发生变化。然而，由于维生素 D 合成基因（DHCR7）导致的遗传调节的 25（OH）D 缺乏可能会影响 T2D 的风险。
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