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Choline is an essential nutrient involved in one-carbon metabolism, but its role in mechanisms underlying meiotic non-disjunction is poorly known. The relationship between

folate-homocysteine metabolic pathway gene polymorphism and Down syndrome (DS) risk has been widely analyzed, but there are limited reports on its correlation with choline metabolism. In the

present case–control association study, we investigated the relationship of three single-nucleotide polymorphisms (SNPs) (phosphatidylethanolamine N-methyltransferase (PEMT) rs12325817,

choline dehydrogenase (CHDH) rs12676 and homocysteine methyltransferase (BHMT) rs3733890) of choline metabolism with risk for DS.

Genotyping of 228 mothers of a down syndrome child (DSM) and 200 control mothers (CMs) for all SNPs was performed by PCR coupled with restriction fragment length polymorphism method.

A significantly increased risk for BHMT +742AA genotype with an odds ratio of 4.96 (95% confidence interval (CI): 1.66–14.88, P=0.0036) was observed. For PEMT rs12325817 and CHDH rs12676, no

significant difference in allelic and genotypic frequencies was observed. In genotypic combination analysis considering PEMT −744GG/CHDH +432GG/BHMT +742GG as the reference combination,

PEMT −744GC/CHDH +432GG/BHMT +742GG genotypic combination was significantly higher in DSM compared with that in CMs with an odds ratio of 2.061 (95% CI: 1.10–3.86, P=0.0342). We also

observed an epistatic interaction between methylenetetrahydrofolate reductase (MTHFR) rs1801133 and choline metabolic pathway gene variants.

Our findings indicate impaired choline metabolism showing a greater risk for DS, especially in a population associated with homocysteine-folate impairment. Further studies are required to

confirm our findings.

We thank Down syndrome mothers and control mothers for participation in the study. We record words of gratitude to our teacher Professor Rajiva Raman for critical analysis and comments. We

are thankful to Professor SK Singh, Institute of Medical Sciences, for permitting us to conduct chemiluminescence assay of vitamin B12 and folic acid in their lab. We also thank

UGC-sponsored Centre for Advanced Study, Department of Zoology and Interdisciplinary School of Life Sciences, BHU, Varanasi for HPLC analysis of homocysteine, and Centre for Genetic

Disorders, BHU for chromosomal analysis. We also acknowledge Ms Radha Raghuraman, Graduate Student, Synaptic Plasticity and Memory Lab, Department of Physiology and Yong Loo Lin, School of

Medicine, National University of Singapore for proofreading the final version of the manuscript. This work forms part of the contribution of the Disease biology thrust area under

DBT-sponsored Interdisciplinary School of Life Sciences, BHU. ICMR, New Delhi, is duly acknowledged for fellowship to SKJ.

Conceived and designed the experiments: SKJ, KKS and AKR; performed the experiments: SKJ and AC; analyzed the data: KKS, SKJ and AKR; wrote the manuscript: KKS, SKJ and AKR; grant for the

study: AKR; clinical samples provided by AK and ARL; collected the samples: SKJ; gave critical comments on the manuscript: AK and ARL.

Centre for Genetic Disorders, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Department of Zoology, Cytogenetics Laboratory, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Department of Botany, Applied Microbiology, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Department of Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

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