Association between Maternal FUT2 204A>G (rs492602) Genetic Polymorphism and Congenital Heart Disease in the Indian Population: A Study in Maternal-fetal Dyads

Sunitha Tella, Sowmya Gayatri Chukkayapalli, Jyothy Akka, Satyanarayana Uppala


Background: FUT2 secretor genetic variants are strongly associated with absorption and circulatory levels of vitamin B12, thereby affecting folate metabolism pathway. The aim of this study was to evaluate the association between maternal FUT2 204A>G (rs492602) genetic polymorphism and CHD in the Indian population.

Materials and method: One hundred and ten pregnant women who were vitamin B12 deficient with fetuses diagnosed with CHD were included in the case group and an equal number of healthy pregnant women with normal fetuses were selected as the control group. DNA was extracted from blood and umbilical cord tissue samples, and genotyped for FUT2 rs492602 polymorphism using allele-specific polymerase chain reaction. Hardy–Weinberg equilibrium test was used to calculate allele and genotype frequencies.

Results: Significant increase in the frequency of AG (odds ratio=2.25; 95% CI: 1.25–4.05; p=0.009) and GG (odds ratio=3.51; 95% CI: 1.47-8.43; p=0.006) genotypes as well as G allele of FUT2 rs492602 were observed in the maternal case group. Furthermore, in the fetus case group, there was a significantly higher incidence of GG genotype (odds ratio=2.87; 95% CI: 1.26–6.57; p=0.018) and G allele (odds ratio=1.70; 95% CI: 1.15–2.53; p=0.009).

Conclusion: FUT2 rs492602 are associated with CHD in the Indian population. Maternal genetic polymorphism that regulates vitamin B12 metabolic pathway might influence fetal cardiac development, thus serving as a predictor for CHD.

Keywords: congenital heart disease, FUT2, single nucleotide polymorphism (SNP), vitamin B12

Full Text:



Liu Y, Chen S, Zühlke L, Black GC, Choy MK, Li N, et al. Global birth prevalence of congenital heart defects 1970-2017: Updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019; 48(2): 455-63, CrossRef.

Dixit R, Rai SK, Yadav AK, Lakhotia S, Agrawal D, Kumar A, et al. Epidemiology of congenital heart disease in India. Congenit Heart Dis. 2015; 10(5): 437-46, CrossRef.

Vecoli C, Pulignani S, Foffa I, Andreassi MG. Congenital heart disease: The crossroads of genetics, epigenetics and environment. Curr Genomics. 2014; 15(5): 390-9, CrossRef.

Shi H, Yang S, Liu Y, Huang P, Lin N, Sun X, et al. Study on environmental causes and SNPs of MTHFR, MS and CBS genes related to congenital heart disease. PLoS One. 2015; 10(6): e0128646, CrossRef.

Botto LD, Mulinare J, Erickson JD. Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps. Am J Med Genet A. 2003; 121A(2): 95-101, CrossRef.

Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr. 2005; 81(5): 1213S-7S, CrossRef.

Hobbs CA, Cleves MA, Melnyk S, Zhao W, James SJ. Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism. Am J Clin Nutr. 2005; 81(1): 147-53, CrossRef.

Hobbs CA, Cleves MA, Zhao W, Melnyk S, James SJ. Congenital heart defects and maternal biomarkers of oxidative stress. Am J Clin Nutr. 2005; 82(3): 598-604, CrossRef.

Hobbs CA, James SJ, Jernigan S, Melnyk S, Lu Y, Malik S, et al. Congenital heart defects, maternal homocysteine, smoking, and the 677 C>T polymorphism in the methylenetetrahydrofolate reductase gene: Evaluating gene-environment interactions. Am J Obstet Gynecol. 2006; 194(1): 218-24, CrossRef.

Kapusta L, Haagmans ML, Steegers EA, Cuypers MH, Blom HJ, Eskes TK. Congenital heart defects and maternal derangement of homocysteine metabolism. J Pediatr. 1999; 135(6): 773-4, CrossRef.

van Driel LM, de Jonge R, Helbing WA, van Zelst BD, Ottenkamp J, Steegers EA, et al. Maternal global methylation status and risk of congenital heart diseases. Obstet Gynecol. 2008; 112(2 Pt 1): 277-83, CrossRef.

Wenstrom KD, Johanning GL, Johnston KE, DuBard M. Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol. 2001; 184(5): 806-17, CrossRef.

Sahin-Uysal N, Gulumser C, Kocaman E, Varan B, Bayraktar N, Yanık F. Maternal and cord blood homocysteine, vitamin B12, folate, and B-type natriuretic peptide levels at term for predicting congenital heart disease of the neonate: A case-control study. J Matern Fetal Neonatal Med. 2020; 33(15): 2649-56, CrossRef.

Johnston J, Bollekens J, Allen RH, Berliner N. Structure of the cDNA encoding transcobalamin I, a neutrophil granule protein. J Biol Chem. 1989; 264(27): 15754-7, CrossRef.

Ferrer-Admetlla A, Sikora M, Laayouni H, Esteve A, Roubinet F, Blancher A, et al. A natural history of FUT2 polymorphism in humans. Mol Biol Evol. 2009; 26(9): 1993-2003, CrossRef.

Tella S, Chukkayapalli SG, Jharna P, Uppala S. Maternal gene polymorphisms of vitamin B12 metabolic pathway and their association with congenital heart disease. Int J Adv Res. 2021; 9: 863-8, CrossRef.

Ye S, Humphries S, Green F. Allele specific amplification by tetra-primer PCR. Nucleic Acids Res. 1992; 20(5): 1152, CrossRef.

Puspasari A, Enis RN, Herlambang. Genetic variant of vascular endothelial growth factor (VEGF)-A rs699947 is associated with preeclampsia. Mol Cell Biomed Sci. 2022; 6(2): 70-6, CrossRef.

Anggriani RAH, Soeroso NN, Tarigan SP, Eyanoer PC, Hidayat. Association of CYP2A6 genetic polymorphism and lung cancer in female never smokers. Mol Cell Biomed Sci. 2022; 6(2): 63-9, CrossRef.

Ramadhani N, Soeroso NN, Tarigan SP, Eyanoer PC, Hidayat. Correlation between genetic polymorphism of CYP2A13 genotype and lung cancer in female passive smokers. Mol Cell Biomed Sci. 2022; 6(2): 89-95, CrossRef.

Dickey W, Collins JS, Watson RG, Sloan JM, Porter KG. Secretor status and Helicobacter pylori infection are independent risk factors for gastroduodenal disease. Gut. 1993; 34(3): 351-3, CrossRef.

Zinck JW, de Groh M, MacFarlane AJ. Genetic modifiers of folate, vitamin B-12, and homocysteine status in a cross-sectional study of the Canadian population. Am J Clin Nutr. 2015; 101(6): 1295-304, CrossRef.

Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras MG, Usala G, et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009; 84(4): 477-82, CrossRef.

Surendran S, Adaikalakoteswari A, Saravanan P, Shatwaan IA, Lovegrove JA, Vimaleswaran KS. An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr. 2018; 13: 2, CrossRef.

Andersen CB, Madsen M, Storm T, Moestrup SK, Andersen GR. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. Nature. 2010; 464(7287): 445-8, CrossRef.

Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB. Sequence and expression of a candidate for the human Secretor blood group alpha(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem. 1995; 270(9): 4640-9, CrossRef.

Carmel R, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and food-cobalamin malabsorption. Dig Dis Sci. 1994; 39(2): 309-14, CrossRef.

Hazra A, Kraft P, Selhub J, Giovannucci EL, Thomas G, Hoover RN, et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet. 2008; 40(10): 1160-2, CrossRef.

Lin X, Lu D, Gao Y, Tao S, Yang X, Feng J, et al. Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Hum Mol Genet. 2012; 21(11): 2610-7, CrossRef.

Gill HH, Majmudar P, Shankaran K, Desai HG. Age-related prevalence of Helicobacter pylori antibodies in Indian subjects. Indian J Gastroenterol. 1994; 13(3): 92-4, article.

Graham DY, Adam E, Reddy GT, Agarwal JP, Agarwal R, Evans DJ Jr, et al. Seroepidemiology of Helicobacter pylori infection in India. Comparison of developing and developed countries. Dig Dis Sci. 1991; 36(8): 1084-8, CrossRef.

Wang J, Zhao JY, Wang F, Peng QQ, Hou J, Sun SN, et al. A genetic variant in vitamin B12 metabolic genes that reduces the risk of congenital heart disease in Han Chinese populations. PLoS One. 2014; 9(2): e88332, CrossRef.

Brink LR, Bender TM, Davies R, Luo H, Miketinas D, Shah N, et al. Optimizing maternal nutrition: The importance of a tailored approach. Curr Dev Nutr. 2022; 6(9): nzac118, CrossRef.


Copyright (c) 2023 Cell and BioPharmaceutical Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Indexed by:



Cell and BioPharmaceutical Institute