Association study of folate-related enzymes (MTHFR, MTR, MTRR)
                    genetic variants with non-obstructive male infertility in a Polish
                    population

Kurzawski, Mateusz; Wajda, Anna; Malinowski, Damian; Kazienko, Anna; Kurzawa, Rafal; Drozdzik, Marek

doi:10.1590/S1415-475738120140179

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Genetics and Molecular Biology

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Human and Medical Genetics • Genet. Mol. Biol. 38 (01) • Jan-Mar 2015 • https://doi.org/10.1590/S1415-475738120140179 copy

Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population

Authorship SCIMAGO INSTITUTIONS RANKINGS

Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population.

MTHFR; MTR; MTRR; polymorphism; infertility

	Fertile n = 352		Infertile n = 284		p^* * Calculated by means of Fisher’s exact test.	OR (95%CI)

		n	%	n	%
MTR rs1805087 (2756A > G, Asp919Gly)
Genotype
AA	218	61.9%	178	62.7%	-
AG	125	35.5%	93	32.7%	0.610	0.91 (0.78–1.46)
GG	9	2.6%	13	4.6%	0.271	1.77 (0.74–4.24)
(AG+GG) vs. AA	134	38.1%	106	37.3%	0.869	0.97 (0.70–1.34)
(AA+AG) vs. GG	343	97.4%	271	95.4%	0.193	0.55(0.23–1.29)
Allele
A	561	79.7%	449	79.0%
G	143	20.3%	119	21.0%	0.780
MTRR rs1801394 (66A > G, Ile22Met)
Genotype
AA	70	19.9%	51	18.0%	-
AG	171	48.6%	139	48.9%	0.666	1.12 (0.73–1.71)
GG	111	31.5%	94	33.1%	0.564	1.16 (0.74–1.83)
(AG+GG) vs. AA	282	80.1%	233	82.0%	0.608	1.13 (0.76–1.69)
(AA+AG) vs. GG	241	68.5%	190	66.9%	0.733	0.93 (0.77–1.50)
Allele
A	311	44.2%	241	42.4%
G	393	55.8%	327	57.6%	0.569
MTHFR rs1801133 (677C > T, Ala222Val)
Genotype
CC	166	47.2%	143	50.4%	-
CT	150	42.6%	113	39.8%	0.448	0.87 (0.63–1.21)
TT	36	10.2%	28	9.9%	0.783	0.90 (0.52–1.55)
(CT+TT) vs. CC	186	52.8%	141	49.6%	0.426	0.880 (0.64–1.20)
(CC+CT) vs. TT	316	89.8%	256	90.1%	0.895	1.04 (0.62–4.75)
Allele
C	482	68.5%	399	70.2%
T	222	31.5%	169	29.8%	0.502
MTHFR rs1801131 (1298A > C, Glu429Ala)
Genotype
AA	156	44.3%	128	45.1%	-
AC	156	44.3%	130	45.8%	0.933	1.02 (0.73–1.41)
CC	40	11.4%	26	9.2%	0.413	0.79 (0.46–1.37)
(AC+CC) vs. AA	196	55.7%	156	54.9%	0.873	0.97 (0.71–1.32)
(AA+AC) vs. CC	312	88.6%	258	90.8%	0.433	1.27 (0.76–2.14)
Allele
A	468	66.5%	386	68.0%
C	236	33.5%	182	32.0%	0.589

Genetic polymorphism studied	Association reported	Study population	Reference
MTHFR 677C > T	MTHFR 677C > T (TT homozygotes) with infertility	255 infertile men and 200 controls, ethnicity not given, Germany	*Bezold et al., 2001*Bezold G, Lange M and Peter RU (2001) Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med 344:1172–1173.
MTHFR 677C > T	no association with infertility	93 infertile and 105 controls, Italian Caucasians	*Stuppia et al., 2003*Stuppia L, Gatta V, Scarciolla O, Colosimo A, Guanciali-Franchi P, Calabrese G and Palka G. (2003) The methylenetethrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility in Italy. J Endocrinol Invest 26:620–622.
MTHFR 677C > T	no association with subfertility	113 fertile and 77 subfertile males, Dutch Caucasians	*Ebisch et al., 2003*Ebisch IMW, Van Heerde WL, Thomas CMG, Van der Put N, Wong WY and Steegers-Theunissen RPM (2003) C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril 80:1190–1194.
20 SNPs in 12 genes related to folate, homocysteine and B12 metabolism	no association of folate-related gene polymorphisms with infertility; PEMT (phosphatidylethanolamine N-methyltransferase) rs7946 and CD320 (transcobalamin receptor) rs173665 with infertility	153 infertile men and 184 controls, ethnicity not given, Sweden	*Murphy et al., 2011*Murphy LE, Mills JL, Molloy AM, Qian C, Carter TC, Strevens H, Wide-Swensson D, Giwercman A and Levine RJ (2011) Folate and vitamin B12 in idiopathic male infertility. Asian J Androl 13:856–861.
MTHFR 677C > T	no association with infertility or sperm counts	107 infertile men and 25 controls, ethnicity not given, Spain	*Camprubi et al., 2013*Camprubí C, Pladevall M, Grossmann M, Garrido N, Pons MC and Blanco JJ (2013) Lack of association of MTHFR rs1801133 polymorphism and CTCFL mutations with sperm methylation errors in infertile patients. J Assist Reprod Genet 30:1125–1131.
MTHFR 677C > T, 1298A > C; MTR 2756A > G; MTRR 66A>G; SHMT1 1420C > T; MTHFD1 1958G > A; CBS 844ins68	MTHFD1 1958G>Aand MTR 2756A > G with infertility (without correction for multiple testing only); MTHFR 677C > T with azoospermia;	275 infertile men and 349 controls, Russian Caucasians	*Weiner et al., 2014*Weiner AS, Boyarskikh UA, Voronina EN, Tupikin AE, Korolkova OV, Morozov IV and Filipenko ML (2014) Polymorphisms in folate-metabolizing genes and risk of idiopathic male infertility: a study on a Russian population and a meta-analysis. Fertil Steril 101:87–94.
MTHFR 677C > T, 1298A > C, 215GA; MTRR 66A > G, 524C > T; CBS 919G > A	no association with reduced sperm counts	70 azoospermia and 182 oligozoospermia cases, 114 normospermic controls, “French ethnic origin” stated	*Ravel et al., 2009*Ravel C, Chantot-Bastaraud S, Chalmey C, Barreiro L, Aknin-Seifer I, Pfeffer J, Berthaut I, Mathieu EE, Mandelbaum J, Siffroi JP, et al. (2009) Lack of association between genetic polymorphisms in enzymes associated with folate metabolism and unexplained reduced sperm counts. PLoS One 4:e6540.
MTHFR 677C > T, 1298A > C	MTHFR 677C > T with infertility	373 infertile men + 396 controls, Korean Asians	*Park et al., 2005*Park JH, Lee HC, Jeong YM, Chung TG, Kim HJ, Kim NK, Lee SH and Lee S (2005) MTHFR C677T polymorphism associates with unexplained infertile male factors. J Assist Reprod Genet 22:361–368.
MTHFR 677C > T, 1298A > C; MTR 2756A > G; MTRR 66A>G	MTHFR 677C > T and MTRR 66A>G with infertility; MTHFR 677C > T and MTR 2756A > G with azoospermia	360 infertile men and 325 controls, Korean Asians	*Lee et al., 2006*Lee HC, Jeong YM, Lee SH, Cha KY, Song SH, Kim NK, Lee KW and Lee S (2006) Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod 21:3162–3170.
MTHFR 677C > T	MTHFR 677C > T with infertility	355 infertile and 252 fertile Chinese Asians	A et al., 2007
MTHFR 677C > T, 1298A > C, 215GA; MTRR 66A>G,524C>T	MTHFR 677C > T with hyperhomocysteinemia; no association with sperm counts	522 men, mixed ethnic origin, France	*Montjean et al.* 2011**Montjean D, Benkhalifa M, Dessolle L, Cohen-Bacrie P, Belloc S, Siffroi JP, Ravel C, Bashamboo A and McElreavey K (2011) Polymorphisms in MTHFR and MTRR genes associated with blood plasma homocysteine concentration and sperm counts. Fertil Steril 95:635–640.
MTHFR 677C > T, 1298A > C	MTHFR 677C > T with non-obstructive azoospermia and severe oligozoospermia	156 infertile men and 233 controls, mixed ethnic origin, Brazil	*Gava et al., 2011*Gava MM, Chagas Ede O, Bianco B, Christofolini DM, Pompeo AC, Glina and Barbosa CP (2011) Methylenetetrahydrofolate reductase polymorphisms are related to male infertility in Brazilian men. Genet Test Mol Biomarkers 15:153–157.
MTHFR 677C > T, 1298A > C; DNMT3B 46359C > T	no association with infertility	179 infertile and 200 fertile men, India	Dhillon et al., 2007Dhillon VS, Shahid M and Husain SA (2007) Associations of MTHFR DNMT3b 4977 bp deletion in mtDNA and GSTM1 deletion, and aberrant CpG island hypermethylation of GSTM1 in non-obstructive infertility in Indian men. Mol Hum Reprod 13:213–222.
MTHFR 677C > T	MTHFR 677C > T with infertility, also confirmed by meta-analysis of data from available studies	522 infertile and 315 controls, India	*Gupta et al., 2011*Gupta N, Gupta S, Dama M, David A, Khanna G, Khanna A and Rajender S (2011) Strong association of 677C>T substitution in the MTHFR gene with male infertility - A study on an Indian population and a meta-analysis. PLoS One 6:e22277.
MTHFR 677C > T, 1298A > C; MTRR 66A>G	MTHFR 677C > T with infertility	150 infertile and 150 controls, Arab Jordanian population	*Mfady et al., 2014*Mfady DS, Sadiq MF, Khabour OF, Fararjeh AS, Abu-Awad A and Khader Y (2014) Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population. Gene 536:40–44.
MTHFR 677C > T	MTHFR 677C > T with infertility in Asians, but not I Caucasians	metaanalysis of previously published data	*Wu et al, 2012*Wu W, Shen O, Qin Y, Lu J, Niu X, Zhou Z, Lu C, Xia Y, Wang S and Wang X (2012) Methylenetetrahydrofolate reductase C677T polymorphism and the risk of male infertility: A meta-analysis. Int JAndrol 35:18–24.
MTHFR 1298A > C	MTHFR 1298A > C with infertility and azoospermia (metaanalysis included only one Caucasian study)	metaanalysis of previously published data	*Shen et al., 2012*Shen O, Liu R, Wu W, Yu L and Wang X (2012) Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with male infertility: A meta-analysis. Ann Hum Genet 76:25–32.
MTHFR 677C > T, 1298A > C; MTR 2756A > G; MTRR 66A>G	no association with infertility	284 infertile and 352 fertile Polish Caucasians	present study

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[1] Send correspondence to Mateusz Kurzawski. Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstanców Wlkp. 72, 70-111 Szczecin, Poland. E-mail: mateusz.kurzawski@pum.edu.pl.