Abstract：Objective To study the association of maternal diabetes mellitus (DM), uncoupling protein 2 (UCP2) gene polymorphisms, and their interaction with the risk of congenital heart disease (CHD) in offspring. Methods A hospital-based case-control study was conducted. A total of 464 mothers of children with CHD alone who were diagnosed in Hunan Children's Hospital from March 2018 to August 2019 were enrolled as the case group. A total of 504 mothers of healthy children who were hospitalized during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect the information on exposure. Venous blood samples (5 mL) were collected from the mothers to detect UCP2 gene polymorphisms. A multivariate logistic regression analysis was used to investigate the association of maternal DM, UCP2 gene polymorphisms, and their interaction with CHD in offspring. Results After control for confounding factors, the multivariate logistic regression analysis showed that mothers with gestational DM (OR=2.96, 95%CI:1.57-5.59), a history of gestational DM (OR=3.16, 95%CI:1.59-6.28), and pregestational DM (OR=4.52, 95%CI:2.41-8.50) significantly increased the risk of CHD in offspring (P < 0.05). The polymorphisms of the UCP2 gene at rs659366 (T/C vs C/C:OR=1.49, 95%CI:1.02-2.16; T/T vs C/C:OR=2.77, 95%CI:1.67-4.62) and rs660339 (A/A vs G/G:OR=2.19, 95%CI:1.34-3.58) were significantly associated with risk of CHD in offspring (P < 0.05). The interaction analysis showed an interaction between the polymorphisms of the UCP2 gene at rs659366 and rs660339 and maternal DM in the development of CHD (P < 0.05). Conclusions Maternal DM, UCP2 gene polymorphisms, and their interaction are associated with the development of CHD in offspring.
LUO Liu,HUANG Peng,WANG Ting-Ting et al. Association of maternal diabetes mellitus and UCP2 gene polymorphisms with congenital heart disease in offspring: a case-control study[J]. CJCP, 2020, 22(10): 1092-1099.
Moore LL, Singer MR, Bradlee ML, et al. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus[J]. Epidemiology, 2000, 11(6):689-694.
[3]
Eidem I, Stene LC, Henriksen T, et al. Congenital anomalies in newborns of women with type 1 diabetes:nationwide population-based study in Norway, 1999-2004[J]. Acta Obstet Gynecol Scand, 2010, 89(11):1403-1411.
[4]
Liu S, Joseph KS, Lisonkova S, et al. Association between maternal chronic conditions and congenital heart defects:a population-based cohort study[J]. Circulation, 2013, 128(6):583-589.
[5]
Øyen N, Diaz LJ, Leirgul E, et al. Prepregnancy diabetes and offspring risk of congenital heart disease:a nationwide cohort study[J]. Circulation, 2016, 133(23):2243-2253.
Yamada K, Mito F, Matsuoka Y, et al. Fluorescence probes to detect lipid-derived radicals[J]. Nat Chem Biol, 2016, 12(8):608-613.
[8]
Moazzen H, Lu X, Ma NL, et al. N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes[J]. Cardiovasc Diabetol, 2014, 13:46.
[9]
Ruiz-Ramírez A, López-Acosta O, Barrios-Maya MA, et al. Cell death and heart failure in obesity:role of uncoupling proteins[J]. Oxid Med Cell Longev, 2016, 2016:9340654.
Sies H, Berndt C, Jones DP. Oxidative stress[J]. Annu Rev Biochem, 2017, 86:715-748.
[12]
Kayama Y, Raaz U, Jagger A, et al. Diabetic cardiovascular disease induced by oxidative stress[J]. Int J Mol Sci, 2015, 16(10):25234-25263.
[13]
de Souza BM, Michels M, Sortica DA, et al. Polymorphisms of the UCP2 gene are associated with glomerular filtration rate in type 2 diabetic patients and with decreased UCP2 gene expression in human kidney[J]. PLoS One, 2015, 10(7):e0132938.
[14]
Su M, Chen X, Chen Y, et al. UCP2 and UCP3 variants and gene-environment interaction associated with prediabetes and T2DM in a rural population:a case control study in China[J]. BMC Med Genet, 2018, 19(1):43.
[15]
Lupo PJ, Canfield MA, Chapa C, et al. Diabetes and obesity-related genes and the risk of neural tube defects in the National birth defects prevention study[J]. Am J Epidemiol, 2012, 176(12):1101-1109.
[16]
Chen L, Yang T, Chen L, et al. Risk of congenital heart defects in offspring exposed to maternal diabetes mellitus:an updated systematic review and meta-analysis[J]. Arch Gynecol Obstet, 2019, 300(6):1491-1506.
Gul A, Ateş Ö, Özer S, et al. Role of the polymorphisms of uncoupling protein genes in childhood obesity and their association with obesity-related disturbances[J]. Genet Test Mol Biomarkers, 2017, 21(9):531-538.
[19]
Gamboa R, Huesca-Gómez C, López-Pérez V, et al. The UCP2-866G/A, Ala55Val and UCP3-55C/T polymorphisms are associated with premature coronary artery disease and cardiovascular risk factors in Mexican population[J]. Genet Mol Biol, 2018, 41(2):371-378.
