Medical

Communication

Biosci. Biotech. Res. Comm. 9(4): 718-724 (2016)

The rs4646903 gene transition and idiopathic male

infertility: A systematic literature review and

meta-analysis

Majid Nejati

and Mohammad Karimian

Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran

Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran

ABSTRACT

Cytochrome P450 (CYP) family enzymes have a crucial role in detoxi cation of environmental toxins which affected

on male reproductive function. In this study we investigate the association of 3801T>C transition (rs4646903) in

CYP1A1 gene with male infertility in an Iranian population which followed by a meta-analysis in Asian populations.

In the case-control study, we collected blood samples from 100 idiopathic infertile and 100 healthy controls. 3801T>C

genotyping was performed by PCR-RFLP method. In meta-analysis we selected eligible studies by searching in stand-

ard databases such as PubMed, Google Scholar, and etc. Our case-control study revealed that there is a signi cant

association of CC genotype (OR= 3.00, 95%CI= 1.20-7.48, P= 0.018) and C allele (OR= 1.93, 95%CI= 1.09-3.39, P=

0.023) with male infertility. Also, meta-analysis revealed that there are signi cant associations between rs4646903

and male infertility in all of  ve genetic models with a true heterogeneity (P

heterogeneity

< 0.01) within Asian popula-

tions. This study results indicated that, CYP1A1 3801T>C transition can be considered as a biomarker for risk of male

infertility within Asian populations.

KEY WORDS: MALE INFERTILITY; CYP1A1; GENETIC POLYMORPHISM; META-ANALYSIS

718

ARTICLE INFORMATION:

*Corresponding Author: mdkarimian@gmail.com (M. Karimian)

Received 29

Nov, 2016

Accepted after revision 27

Dec, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

INTRODUCTION

Idiopathic male infertility as a common health problem

involved about 10-15% of men worldwide (De Kretser,

1997). Some causes including environmental factors,

lifestyle and genetic factors may contribute in idiopathic

male infertility (Nikzad et al., 2015; Karimian and Cola-

gar 2016a). Despite the development of diagnostic tests

for male infertility, especially in the molecular genetics

 eld, many aspects are still unknown. Some evidences

suggested that xenobiotic damage to genome, may help

failure of spermatogenesis in about 30 percent of infer-

tility in men (Schuppe et al., 2000).

Majid Nejati and Mohammad Karimian

Cytochrome P450 (CYP) family enzymes are key

regulatory enzymes which catalyze the step 1 oxidation

reactions of endogenous agents and xenobiotics (Gon-

zalez, 1992). CYP enzymes belonging to families 1–3

(among 14 families) in human are most essential for

metabolic activation of numerous lipophilic compounds

called as environmental or industrial pollutants (Nebert

et al., 1996). The CYP1A1 (P4501A1) enzyme is con-

sidered in extra hepatic metabolism of agents including

polycyclic aromatic hydrocarbons (PAHs) (Guengerich,

1992). Given to environmental compounds such as PAHs

and their possible reproductive poisonousness through

metabolic activation, polymorphisms in CYP1A1 gene

may contribute in male infertility susceptibility (Crofts

et al., 1994; Schuppe et al., 2000).

The CYP1A1 gene is located on chromosome 15

(15q24.1) and containing 7 exons. This gene is known

as a polymorphic gene with several single nucleotide

polymorphisms (SNPs) (Nebert et al., 1996). Among its

polymorphisms, the 3801T>C (also known as, 2A, m1

or rs4646903) is the most common. This polymorphism

results in T to C substitution at 3’ untranslated region

(3’UTR) of the gene, and may change the expression of

CYP1A1 (Luo et al., 2014). The association of CYP1A1

3801T>C polymorphism with male infertility has been

studied only once (Salehi et al., 2012). Also, the results

of genetic association studies in Asian populations are

inconclusive. Therefor the aim of this study was to inves-

tigate the association of CYP1A1 3801T>C polymor-

phism with male infertility within an Iranian population

which followed by a meta-analysis in Asian population.

MATERIALS AND METHODS

SUBJECTS AND SNP GENOTYPING

Subjects of this study were selected randomly from an

Iranian population and included 100 idiopathic infertile

and 100 aged-match healthy fertile men from individu-

als refer to IVF center (Kashan, Iran). The causes of male

infertility of the subjects were remained unknown. The

inclusion and exclusion criteria of fertile and infertile

subjects were described in our previous study (Jamali

et al., 2016). According to WHO 1999 criteria all of infer-

tile subjects were classi ed as oligozospermia with less

than 20 millionspermperml in ejaculated semen. After

obtaining informed consent form from all subjects, we

collected 2ml blood samples on EDTA from all of them.

Genomic DNA was extracted from blood samples

by salting out procedure. CYP1A1 3801T>C SNP geno-

typing was performed by polymerase chain reaction-

restriction fragment length polymorphism (PCR-RFLP).

The protocol of SNP genotyping was described pre-

viously (Islam et al., 2013). Brie y, the CYP1A1 gene

containing 3801T>C polymorphism was ampli ed by

PCR method with the following speci c primers: F:

5-CAGTGAAGAGGTGTAGCCGCT-3 and R: 5-TAG-

GAGTCTTGTCTCATGCCT-3. The 340-bp ampli ed frag-

ments were treated by MspI restriction enzyme. After

digestion procedure and separation by 1% agarose gel

electrophoresis, the samples with 340-bp fragment were

normal homozygote while the samples with 200-bp and

140-bp fragments were mutant homozygote. Moreover,

the samples with 340-bp, 200-bp, and 140-bp fragments

were heterozygote.

META-ANALYSIS

We employed standard databases including PubMed,

Google Scholar, and ScienceDirect, EMBase, and Med-

line till October 2016 for publication investigating the

association CYP1A1 3801T>C polymorphism with male

infertility. The keywords that used to search were as fol-

low: male infertility, CYP1A1, 3801T>C, rs4646903, SNP,

and polymorphism. The studies must met the following

criteria: 1- case-control plan, 2- evaluating the associa-

tion of CYP1A1 3801T>C transition with risk of male

infertility, and 3- containing suf cient data to estimate

odd ratios (ORs) with 95% con dence interval(95%CI)

for all alleles and genotypes. The following data were

excluded from eligible studies: country, author’s last

name, year of publication, and genotypes frequency.

STATISTICAL ANALYSIS

In case-control study, the Hardy-Weinberg equilibrium

(HWE) for genotypes frequencies was calculated by a

Chi-square test. For evaluation of association of CYP1A1

3801T>C transition with male infertility, odd ratios and

95%CI were calculated by binary regression logistic. A

P-value less than 0.05 was considered as statistically

signi cant. These calculations were performed by SPSS

ver.19 software.

In meta-analysis, the pooled OR was calculated in the

 ve following genetic models: allelic (C vs. T), homozy-

gous (CC vs. TT), and heterozygous (TC vs. TT), dominant

(CC+TC vs. TT), and recessive (CC vs. TC+TT). Heteroge-

neity was measured by the chi square based Q test and

2

score, and a p-value less than 0.1 was considered as

statistically signi cant. If there was a signi cant het-

erogeneity, ORs and 95%CI was calculated based on a

random-effect model. Otherwise, a  xed-effects model

was used. Egger’s test and Begg’s funnel plots were

employed to calculate possible publication bias. The

sensitivity analysis, relative effect of individual study on

the pooled OR, was calculated by eliminating one study

at a time. Statistical Meta-analyzes were performed by

Comprehensive Meta Analysis software.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE RS4646903 AND MALE INFERTILITY RISK 719

Majid Nejati and Mohammad Karimian

RESULTS

DISTRIBUTION OF CYP1A1 3801T>C IN CASE-

CONTROL STUDY

The data from Hardy-Weinberg test revealed that the

distribution of genotypes in case group was deviated

from HWE (

= 6.39, P= 0.011), whereas this distribu-

tion in control group met HWE (

= 3.39, P= 0.066). The

results of genetic association in case-control study are

given in table 1. For example: CC genotype is associated

with male infertility (OR= 3.00, 95%CI= 1.20-7.48, P=

0.018). Also, carriers of C allele were at a high risk for

male infertility (OR= 1.93, 95%CI= 1.09-3.39, P= 0.023).

In addition, C allele is signi cantly associated with male

infertility (OR= 1.91, 95%CI= 1.23-2.97, P= 0.004).

META-ANALYSIS

The initial search of database and screening of relevant

articles, 5 eligible studies were included in meta-anal-

ysis (Lu et al. 2008; Vani et al. 2009; Chen et al. 2010;

Salehi et al. 2011; Peng et al. 2012). Moreover, the data

from current study was added to the meta-analysis. The

characteristics of included studies in meta-analysis are

detailed in table 2. These studies included:3, 2, and 1

papers involved Chinese, Iranian, and Indian popula-

tions, respectively. This meta-analysis involved a total

of 957 cases and 1098 controls. The results of genetic

association in meta-analysis revealed that there is a sig-

ni cant associations between CYP1A1 3801T>C poly-

morphism and male infertility in all  ve genetic models

(C vs. T: OR= 1.53, 95%CI= 1.16-2.02, P= 0.003; CC vs.

TT: OR= 2.43, 95%CI= 1.33-4.42, P= 0.004; TC vs. TT:

OR= 1.36, 95%CI: 1.13-1.64, P= 0.001; CC+TC vs. TT:

OR= 1.57, 95%CI= 1.17-2.11, P= 0.003; CC vs. TC+TT:

OR= 2.02, 95%CI= 1.21-3.37, P= 0.007) (Table 3 and

Figure 1). The heterogeneity analysis revealed that there

are true heterogeneities for association of 3801T>C with

male infertility risk in C vs. T (P

heterogeneity

< 0.001, I

= 77%),

CC vs. TT (P

heterogeneity

= 0.003, I

= 73%), CC+TC vs. TT (P

het-

erogeneity

= 0.021, I

= 62%), CC vs. TC+TT (P

heterogeneity

= 0.010,

= 67%) models within Asian populations (Table 3). The

data from publication bias test revealed that there are

publication biases in CC vs. TT (P

Egger

= 0.018) and CC vs.

TC+TT (P

Egger

= 0.017) genetic models (Figure 2).

DISCUSSION

In this study we investigated the association of CYP1A1

3801T>C polymorphism with male infertility in an Ira-

nian population and a meta-analysis in Asian popu-

lations. Our case-control study indicated a signi cant

association between 3801CC genotype and 3801C allele

and male infertility in study population. Moreover,

results of meta-analysis revealed that there are signi -

cant association between CYP1A1 3801T>C and male

Table 1: Genotype and allele frequencies of CYP1A1 3801T>C in cases and controls.

Genotype/Allele Control (%) (n= 100) Cases (%) (n= 100) OR (95% CI)

-value

TT 64 (64%) 48 (48%) - -

TC 28 (28%) 34 (34%) 1.62 (0.87-3.02) 0.131

CC 8 (8%) 18 (18%) 3.00 (1.20-7.48) 0.018

TC+CC 36 (36%) 52 (52%) 1.93 (1.09-3.39) 0.023

T 156 (78%) 130 (65%) - -

C 44 (22%) 70 (35%) 1.91 (1.23-2.97) 0.004

OR, Odds Ratio; CI, Con dence Interval. The signi cant differences are bolded

Table 2: Characteristics of included studies in meta-analysis

Country Genotype frequencies Allele frequencies Reference

Control Case Control Case

TTTCCCTTTCCCTCTC

China 95 104 27 69 96 27 294 158 234 150 Lu et al. 2008

India 146 80 4 108 80 18 372 88 296 116 Vani et al. 2009

China 88 45 7 35 47 23 221 59 117 93 Chen et al. 2010

Iran 85 91 24 58 72 20 261 139 188 112 Salehi et al. 2012

China 78 94 30 72 93 39 250 154 237 171 Peng et al. 2012

Iran 64 28 8 48 34 18 156 44 130 70 Current study

720 THE RS4646903 AND MALE INFERTILITY RISK BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Majid Nejati and Mohammad Karimian

FIGURE 1. Forest plot for the association of CYP1A1 3801T>C polymorphism

and male infertility. Findings of quantitative data synthesis under TC vs. TT

model (A) and CC+TC vs. TT model (B).

Table 3: Results of meta-analysis for association of 3801T>C with male infertility risk

Genetic model Analysis model OR (95%CI)

-value tau

Q(df=5)

hI2

C vs. T (Allelic model) Random effect 1.53 (1.16-2.02) 0.003 0.092 21.56 < 0.001 77% 0.057

CC vs. TT (Homozygous model) Random effect 2.43 (1.33-4.42) 0.004 0.40 18.35 0.003 73% 0.018

TC vs. TT (Heterozygous model) Fixed effect 1.36 (1.13-1.64) 0.001 - 7.24 0.203 31% 0.141

CC+TC vs. TT (Dominant model) Random effect 1.57 (1.17-2.11) 0.003 0.083 13.25 0.021 62% 0.118

CC vs. TC+TT (Recessive model) Random effect 2.02 (1.21-3.37) 0.007 0.263 15.06 0.010 67% 0.017

OR, odds ratio; CI, con dence interval; Ph, P-values for heterogeneity from Q test; Pe: PEgger (p< 0.05) was considered as a signi cant difference.

infertility in all of  ve genetic models. But, heterogene-

ity analysis demonstrated a true heterogeneity in four

genetic models. The different results from various stud-

ies may be due to differences in environmental condi-

tions and ethnicities. Also, a publication bias was found

in TC vs. TT and CC vs. TC+TT genetic models. This pub-

lication bias may arise from small sample sizes and more

chance of positive outputs for publications.

Numerous studies suggested a time-dependent reduc-

tion of quality of human sperm (Adamopoulos et al.,

1996; Van Waeleghem et al., 1996). The causes of proba-

ble alterations in quality of human semen and the cumu-

lative rate of male infertility were not fully understood.

Among the several suggestions in this  eld, the possible

roles of environmental exposures and their effects on

functions and development of male reproductive system

less regarded. (Sharpe and Skakkebaek, 1993). Speci -

cally chemical compounds disrupting the endocrine sys-

tem such as polychlorinated biphenyls (PCBs), pesticides,

and etc. have been debated as possible risks of fertility

(Sonnenschein and Soto, 1998). Since the xenobiotics

including chlorinated hydrocarbons are indissoluble,

they could accumulate in ecosystem and reproductive

system of males affected by them. (Wagner et al., 1990).

Therefore the protective procedures in human body

were ampli ed. In order to prevent the accumulation

of xenobiotic materials in human body, a wide range

of enzymes with variable catalytic activity are involved

in the process of detoxi cation (Nebert et al., 1996).

The cytochrome P450 (CYP) superfamily are important

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE RS4646903 AND MALE INFERTILITY RISK 721

Majid Nejati and Mohammad Karimian

enzymes in phase I oxidation/ reactions for metaboliz-

ing both endogenous substrates and xenobiotic agents

(Nelson et al., 1996). The CYP familiy enzymes are mem-

ber of 1-3 families (from 14 cytochrome families), that

are very important for catabolism of lipophilic chemicals

(Gonzalez, 1992). Among these, CYP1A1 enzyme metab-

olizes extra-hepatic catabolism of heterocyclic amines

and polycyclic aromatic hydrocarbons (PAHs) (Guenger-

ich, 1992). Given to the complex procedure of spermato-

genesis (Weinbauer & Wessels, 1999), xenobiotics accu-

mulation in different sections of the testicular tissues

may be damaging for the process. In addition, immune

activation of cells by reactive metabolites can lead to

testicular immunopathology. The capacity of testicular

tissue for metabolizing of xenobiotics was investigated

in experimental models. For instance Leydig cells in rats

are able to metabolize PAHs (Georgellis and RydstroÈm,

1987). Also, in certain strains of rats, the expression of

CYP enzymes in the testes altered at caloric restriction

(Seng et al., 1996).

Therefore CYP1A1 has a protective role in male

reproductive function any changes in the structure

and expression of CYP1A1 gene could alter the risk

of male infertility. SNPs could alter the functions and

expression of genes depending on their locations on

the genes (Karimian and Colagar 2016b; Karimian et

al., 2015). Therefore CYP1A1 3801T>C gene transition

which located at 3’UTR of CYP1A1 may alter the gene

expression. Our previous studies revealed that bioinfor-

matics tools are suitable for evaluation of the effects of

SNPs on several molecular aspects (Raygan et al., 2016;

Soleimani et al., 2016). Then we suggest that the further

studies were focused on effects of 3801T>C on molecular

aspects of CYP1A1 by in silico analysis.

Finally there are some limitation in this study that

should be declared. The gene-gene and gene-environ-

ment interactions were not considered in case-control

study, since these issue may moderate the effects of

3801T>C CYP1A1 on male infertility. Moreover, origi-

nal data of included studies in meta-analysis such as

biochemical characteristics and BMI were not available,

therefor we could not able to justify the role of 3801T>C

CYP1A1 in male infertility by mentioned parameters.

Moreover, the number of studies which included in

FIGURE 2. Funnel plot for the association of CYP1A1 3801T>C polymorphism

and male infertility. Possible publication bias under TC vs. TT model (A) and

CC+TC vs. TT model (B).

722 THE RS4646903 AND MALE INFERTILITY RISK BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Majid Nejati and Mohammad Karimian

meta-analysis was very low, therefore more studies with

larger sample size are needed to gain more precise data.

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