Choline metabolic pathway gene polymorphisms and risk for Down syndrome: An association study in a population with folate-homocysteine metabolic impairment.
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.
Centre for Genetic Disorders, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
S K
SK
Jaiswal
Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
K K
KK
Sukla
Applied Microbiology, Department of Botany, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
A
A
Chauhan
Department of Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
A R
AR
Lakhotia
Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
A
A
Kumar
Centre for Genetic Disorders, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
A K
AK
Rai
D000328:Adult; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002794:Choline / Q000378:metabolism*; D050545:Choline Dehydrogenase / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009035:Mothers; D016017:Odds Ratio; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006710:Homocysteine; D005492:Folic Acid; D050545:Choline Dehydrogenase; C494489:PEMT protein, human; D050918:Phosphatidylethanolamine N-Methyltransferase; C494548:BHMT protein, human; D050940:Betaine-Homocysteine S-Methyltransferase; D002794:Choline
Hum Genet. 2012 May;131(5):739-46
22116453
Biomed Environ Sci. 2011 Apr;24(2):89-93
21565678
Genet Epidemiol. 2009 Apr;33(3):247-55
19048631
Mol Genet Metab. 2008 Jul;94(3):326-35
18457970
Hum Reprod. 2015 Aug;30(8):1982-93
26040482
Annu Rev Nutr. 1994;14:269-96
7946521
Genet Test Mol Biomarkers. 2012 Jun;16(6):628-31
22339736
J Nutr. 1999 Apr;129(4):779-82
10203550
FASEB J. 2006 Jul;20(9):1336-44
16816108
Atherosclerosis. 2003 Apr;167(2):205-14
12818402
Nucleic Acids Res. 1988 Feb 11;16(3):1215
3344216
Am J Med Genet A. 2005 Jun 15;135(3):274-7
15887275
Clin Biochem. 2011 Jun;44(8-9):596-600
21349258
Mol Biol Rep. 2012 May;39(5):5553-60
22183302
Mol Biol Rep. 2012 Mar;39(3):3123-30
21688148
J Med Genet. 2008 Nov;45(11):721-30
18635682
J Nutr. 2003 Dec;133(12):4135-8
14652361
BMC Med Genet. 2009 Jun 03;10:49
19493349
Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):67-72
21429654
Mol Biol Rep. 2013 Aug;40(8):4685-9
23645037
Mol Genet Metab. 2000 Nov;71(3):511-9
11073719
J Hum Genet. 2006;51(4):278-83
16489479
J Med Genet. 2010 Dec;47(12):809-15
19737740
Environ Health Perspect. 2006 Oct;114(10):1547-52
17035141
Carcinogenesis. 2007 Jul;28(7):1510-9
17389618
J Nutrigenet Nutrigenomics. 2011;4(4):203-9
21876361
Arch Biochem Biophys. 1998 Aug 1;356(1):93-8
9681996
J Hum Genet. 2005;50(12 ):655-63
16244782
Eur J Clin Nutr. 2012 Jan;66(1):111-8
21878957
Am J Clin Nutr. 1999 Oct;70(4):495-501
10500018
Am J Med Genet A. 2003 Jun 1;119A(2):172-6
12749058
J Med Screen. 2002;9(1):2-6
11943789
Nat Genet. 1996 Dec;14(4):400-5
8944019
FASEB J. 2008 Jun;22(6):2045-52
18230680
Birth Defects Res A Clin Mol Teratol. 2015 Apr;103(4):299-305
25656965
Arch Biochem Biophys. 1997 Sep 1;345(1):171-4
9281325
Dis Markers. 2012;32(2):73-81
22377700