Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study
Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study
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DOI：
10.1016/s2213-8587(13)70200-6
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发表时间：
2014-04-01
影响因子：
44.5
通讯作者：
Nordestgaard, Borge G.
中科院分区：
文献类型：
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作者：
Afzal, Shoaib;Brondum-Jacobsen, Peter;Nordestgaard, Borge G.
低血浆25-羟基维生素D （25[OH]D）浓度和高BMI与糖尿病风险增加相关。我们验证了与低浓度25(OH)D相关的遗传变异与糖尿病相关的假设，以及与高BMI相关的遗传变异对糖尿病的影响部分是通过降低血浆25(OH)D浓度介导的。方法在这项孟德尔随机化研究中，我们对来自3项研究的96423名年龄在20-100岁的丹麦白人进行了基因分型。其中5037人患有2型糖尿病。从1977年到2011年，所有人都接受了糖尿病调查。31,040名参与者测量了他们的血浆25(OH)D浓度，90169名参与者测量了他们的BMI。我们评估了DHCR7（与内源性生成相关）和CYP2R1（与肝脏转化相关）基因变异对血浆25(OH)D浓度的影响，以及FTO、MCR4和TMEM18基因变异对BMI的影响。然后，我们评估了这些基因的遗传变异对2型糖尿病风险的影响，以及测量的血浆25(OH)D浓度和BMI与2型糖尿病风险的关系。我们进行了一项中介分析，以评估BMI基因型对糖尿病风险的影响有多少是通过血浆25(OH)D浓度介导的。DHCR7和CYP2R1的2型糖尿病的优势比分别为1.51 （95% CI 0.98-2.33）和1.02(0.75-1.37)，遗传决定血浆25(OH)D浓度降低20 nmol/L。DHCR7等位基因评分与2型糖尿病风险增加显著相关（p = 0.04），而CYP2R1等位基因评分与此无关。对于血浆25(OH)D浓度降低20 nmol/L的参与者，2型糖尿病的调整优势比为1.16（1.08-1.25）。对于由遗传决定的BMI增加10 kg/m(2)的参与者，2型糖尿病的优势比为19.4 (6.4-59.1)；这与11.1 nmol/L（2.6-19.6）的血浆25(OH)D浓度降低有关。测量的BMI每增加10 kg/m(2)， 2型糖尿病的校正优势比为4.33 (3.70-5.07)；这与血浆25(OH)D浓度降低9.1 nmol/L（8.4-9.7）有关。中介分析显示，BMI对2型糖尿病风险影响的3%（1-5）是通过降低血浆25(OH)D浓度介导的。与低血浆25(OH)D浓度相关的遗传变异与2型糖尿病有关，低血浆25(OH)D浓度可能是肥胖和糖尿病风险增加之间的适度中介。与内源性25(OH)D产生相关的遗传变异可能部分解释了这种增加的风险；然而，由于DHCR7的发现没有统计学意义，我们的结果需要独立证实。
Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration and high BMI have been associated with increased risk of diabetes' We tested the hypotheses that genetic variants associated with low concentrations of 25(OH)D are associated with diabetes, and that the effect on diabetes of genetic variants associated with high BMI is partly mediated through reduced plasma 25(OH)D concentration.Methods In this mendelian randomisation study, we genotyped 96 423 white Danes aged 20-100 years from three studies. 5037 of these participants had type 2 diabetes. All individuals were surveyed for diabetes from 1977 to 2011. 31 040 participants had their plasma 25(OH)D concentration measured and 90 169 had their BMI measured. We assessed the effects of genetic variation in DHCR7 (related to endogenous production) and CYP2R1 (related to liver conversion) on plasma 25(OH)D concentration, and the effects of variation in FTO, MCR4, and TMEM18 on BMI. We then assessed the effect of genetic variation in these genes on risk of type 2 diabetes, and the association of measured plasma 25(OH)D concentration and BMI with risk of type 2 diabetes. We did a mediation analysis to assess how much of the effect of BMI genotype on risk of diabetes was mediated through plasma 25(OH)D concentration.Findings The odds ratios for type 2 diabetes for participants who had a 20 nmol/L reduction in plasma 25(OH)D concentration as determined by genetics were 1.51 (95% CI 0.98-2.33) for DHCR7 and 1.02 (0.75-1.37) for CYP2R1. The DHCR7 allele score was significantly associated with increased risk of type 2 diabetes (p for trend = 0.04), whereas the allele score for CYP2R1 was not. For participants who had a measured 20 nmol/L reduction in plasma 25(OH)D concentration, the adjusted odds ratio for type 2 diabetes was 1.16 (1.08-1.25). For participants who had a 10 kg/m(2) increase in BMI as determined by genetics, the odds ratio for type 2 diabetes was 19.4 (6.4-59.1); this was associated with an 11.1 nmol/L (2.6-19.6) lower plasma 25(OH)D concentration. For a 10 kg/m(2) increase in measured BMI, the adjusted odds ratio for type 2 diabetes was 4.33 (3.70-5.07); this was associated with a 9.1 nmol/L (8.4-9.7) lower plasma 25(OH)D concentration. Mediation analysis showed that 3% (1-5) of the effect of BMI on risk of type 2 diabetes was mediated through lowered plasma 25(OH)D concentrations.Interpretation Genetic variants associated with low plasma 25(OH)D concentrations are associated with type 2 diabetes and low plasma 25(OH)D concentrations might be a modest mediator between obesity and increased risk of diabetes. Genetic variants associated with endogenous production of 25(OH)D might partially explain this increased risk; however, as findings for DHCR7 were not statistically significant, our results require independent confirmation.