一种一氧化氮合酶3基因多态性决定1型糖尿病或肥胖儿童内皮细胞对叶酸的反应。

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

作者信息

Wiltshire Esko J, Peña Alexia S, MacKenzie Karen, Bose-Sundernathan Tulika, Gent Roger, Couper Jennifer J

机构信息

Department of Pediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand; Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia.

Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia; Diabetes and Endocrinology Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.

出版信息

J Pediatr. 2015 Feb;166(2):319-25.e1. doi: 10.1016/j.jpeds.2014.10.050. Epub 2014 Dec 2.

DOI:10.1016/j.jpeds.2014.10.050

PMID:25477161

Abstract

OBJECTIVE

To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity.

STUDY DESIGN

A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies.

RESULTS

Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001).

CONCLUSIONS

A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies.

摘要

目的

确定一氧化氮合酶3（NOS3）和叶酸代谢途径酶基因多态性对糖尿病或肥胖儿童血管功能、叶酸状态以及内皮细胞对叶酸反应的影响。

研究设计

采用聚合酶链反应/限制性片段长度多态性方法，对总共244名受试者（年龄13.8±2.8岁，男性125名）进行NOS3和/或叶酸代谢途径基因多态性研究，其中包括基线时：139例1型糖尿病患者；58例肥胖患者；47例对照。在干预试验期间，对85例糖尿病患者和28例肥胖患者进行活性治疗，评估NOS3基因型对内皮细胞对叶酸（5毫克）反应的影响。在叶酸干预研究中，于基线和8周时评估血管功能（血流介导的血管舒张[FMD]和硝酸甘油介导的血管舒张）、临床和生化指标。

结果

叶酸代谢途径酶和NOS3基因多态性对基线血管功能无显著影响。内皮型一氧化氮合酶第4内含子的多态性显著改变了内皮细胞对叶酸的反应：糖尿病患者中，FMD在插入型携带者中改善了6.4±5%，而在缺失型携带者中仅改善了2.3±6.6%，P = 0.01；肥胖患者中，FMD在插入型携带者中改善了1.8±5.4%，而在缺失型携带者中恶化了-3.2±7.2%，P = 0.05。补充叶酸后，更多携带插入型的受试者FMD恢复正常（插入型64%，缺失型28%，χ(2)=10.14，P = 0.001）。