16 March 2021: Clinical Research
Associations Between Cytochrome P450 (CYP) Gene Single-Nucleotide Polymorphisms and Second-to-Fourth Digit Ratio in Chinese University Students
Jing Zhang12ABCDEF, Mengyi Yang1B, Pengfei Luan1B, Wei Jia1B, Qiujun Liu1B, Zhanbing Ma1A, Jie Dang1A, Hong Lu1A, Qian Ma1B, Yanfeng Wang1B, Chunlan Mu1B, Zhenghao Huo13AG*DOI: 10.12659/MSM.930591
Med Sci Monit 2021; 27:e930591
Abstract
BACKGROUND: Cytochrome P450 (CYP) genes are necessary for the production or metabolism of fetal sex hormones during pregnancy. The second-to-fourth digit ratio (2D: 4D) is formed in the early stage of human fetal development and considered an indicator reflecting prenatal sex steroids levels. We explored the association between 2D: 4D and single-nucleotide polymorphisms (SNPs) of CYP.
MATERIAL AND METHODS: Correlation analysis between 2D: 4D and 8 SNPs, rs2687133 (CPY3A7), rs7173655 (CYP11A1), rs1004467, rs17115149, and rs2486758 (CYP17A1), and rs4646, rs2255192, rs4275794 (CYP19A1), was performed using data from 426 female and 412 male Chinese university students. SNP genotyping was conducted using PCR. Digit lengths were photographed and measured by image processing software.
RESULTS: rs2486758 (CYP17A1) correlated with left hand 2D: 4D in men (P=0.026), and rs1004467 (CYP17A1) correlated with right hand 2D: 4D in men (P=0.008) and the whole population (P=0.032). In men, allele G rs1004467 decreased right hand 2D: 4D, while allele C of rs2486758 increased left hand 2D: 4D. In women, left hand 2D: 4D was higher in genotypes with allele A of SNP rs4646 (CYP19A1) under the dominant genetic model; female DR-L was higher in genotypes with allele T of rs17115149 (CYP11A1). SNPs rs2687133 (CYP3A7) and rs1004467 (CYP17A1) were significantly correlated with right hand 2D: 4D (P=0.0107).
CONCLUSIONS: SNPs rs1004467 and rs2486758 of CYP17A1 are significant in the relationship between 2D: 4D and CYP gene polymorphisms under different conditions. SNP interactions between CYP genes probably impact 2D: 4D. The correlation between 2D: 4D and some sex hormone-related diseases may be due to the effect of CYP variants on the 2 phenotypes.
Keywords: Fetal Development, Genetics, Gonadal Steroid Hormones, Polymorphism, Single Nucleotide, Alleles, aromatase, Asians, Case-Control Studies, Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Fingers, Gene Frequency, Genetic Association Studies, Genotype, Nucleotides, Steroid 17-alpha-Hydroxylase, Students, Universities, young adult
Background
The ratio of the second-to-fourth digit length (2D: 4D) in human hands is a sex dimorphism trait that tends to be higher in females than in males and is believed to reflect prenatal sex steroid levels [1]. This ratio is possibly determined by the balance of prenatal testosterone and estrogen levels in a narrow window during the fetal period and remains stable after birth [2]. Thus, 2D: 4D is commonly used as a noninvasive retrospective index of prenatal exposure to sex steroids, especially androgen and estrogen. Studies have shown that 2D: 4D is strongly associated with health conditions and diseases of sex dimorphisms or those affected by sex hormones. Therefore, 2D: 4D might be an indicator of human conditions such as body composition [3], personality traits [4], and physical performance [5], and of disease susceptibilities, including cancer [6], congenital adrenal hyperplasia [7], infertility [8], and mental disorders [9].
Genetic studies on 2D: 4D in twins have shown that 2D: 4D is highly heritable (about 80%) [10]. Gene polymorphisms and the 2D: 4D ratio are significant in studies on factors that can affect the upper limbs [11]. Therefore, 3 genome-wide association studies (GWAS) have been conducted to identify the single-nucleotide polymorphisms (SNPs) associated with 2D: 4D. In 2010, Medland et al studied a sample of 1382 twins and their siblings from Australia, and the SNP rs314277 of gene
In humans, cytochrome P450s (CYPs) constitute one of the most abundant and diverse enzyme superfamilies, whose members catalyze the oxidative transformation of many organic substrates [17]. The function of CYP genes is critical for many metabolic processes, particularly for sex steroid conversion [18]. The altered expression of CYP genes involved in steroid metabolism may affect sex hormone levels and further increase the risk of some sex-related diseases, such as breast cancer [19], prostate cancer [20], infertility [21], polycystic ovary syndrome [22], and congenital adrenal hyperplasia [23]. During pregnancy, fetal sex hormones affect embryo development in many ways. The expression of specific CYP genes in the fetal liver, gonad, and placenta is indispensable across the development to synthesize sex hormones including progesterone, estrogen, and androgen [24]. First, CYP11A1, an enzyme initiating the steroidogenesis to converse cholesterol to pregnenolone, is pivotal for fetal survival in the early phase of pregnancy. Also, about 30% of the estrogen produced during pregnancy is yielded from the pregnenolone conversion by placental CYP17A1. In humans, dehydroepiandrosterone (DHEA) and DHEA sulfate produced by the fetal adrenal glands mainly undergo 16-hydroxylation by CYP3A7 in the liver, and are then metabolized by the placental enzyme aromatase (CYP19A1) [25]. Additionally, CYP19A1 is a rate-limiting enzyme involved in catalyzing the conversion of androgen to estrogen [26]. There is growing evidence to support that the analysis of sex hormone balance in a developing fetus might be helpful for predicting adult diseases during the lifespan [27].
In particular, some SNPs of CYP genes may affect the sex steroids, leading to physiological or pathological changes in humans. The C allele of rs45446698 in
Herein, we conducted a study on 4 CYP genes involved in fetal or placental sex steroid synthesis and metabolism, namely
Material and Methods
STUDY SUBJECTS:
The participants were 426 women aged 19.6±1.3 years and 412 men aged 19.2±1.2 years. All participants were recruited from the Ningxia Medical University in Yinchuan city of the Ningxia Hui Autonomous Region in northwestern China. All participants were physically and mentally healthy. The study design was approved by the Ningxia Medical University Ethics Committee (No.2019-057). Informed written consent was obtained from each participant. All the study samples are stored securely. The DNA samples, research data, and any information that can be traced to individual participants will not be provided to any other party.
SNP GENOTYPING:
Four CYP genes were chosen based on the review of related literature, namely
Genomic DNA was extracted from peripheral blood samples using DNA extraction kits, according to the manufacturer’s instructions (DP304 TIANamp Genomic DNA Kit, TIANGEN Biotech Co. Ltd., Beijing, China). Genotyping of each variant was performed using the multiplex polymerase chain reaction (PCR) technique developed by Novogene Biotech Co., Ltd. (Beijing, China). The PCR program was performed in 2 rounds: round 1 consisted of 1 cycle at 95°C for 15 min; 4 cycles at 94°C for 30 s, 60°C for 10 min, and 72°C for 30 s; and 24 cycles at 94°C for 30s, 60°C for 1 min, and 72°C for 30 s; and round 2 consisted of 1 cycle at 95°C for 15 min; 5 cycles at 94°C for 30 s, 60°C for 4 min, and 72°C for 30 s; and 10 cycles at 94°C for 30 s, 65°C for 1 min, and 72°C for 30 s. After PCR, the amplified products were mixed in a centrifuge tube and shaken overnight. The PCR products were then purified using a CA2 absorption column. The purified PCR product was loaded and run on the Illumina X-10 sequencer. Illumina RTA software was used to perform quality control and raw data analysis.
DATA COLLECTION:
The participants put their 2 hands flat against the same white background with the palms facing up and fingers straight. A digital camera was used to collect the images of both hands. The photos were not used when the fine structures of each digit were not clearly visible. The Image-Pro Plus 6.0 (Media Cybernetics, Inc., USA) was used to measure the digit lengths of both hands (from the fingertip to the middle point of the most proximal crease to the palm). The measurement of each digit was performed 3 times by 3 different individuals who were well trained in the procedure, and the mean value was used for further analysis. The length ratios of both hands between the second and fourth digits were calculated.
STATISTICAL ANALYSES:
The Statistical Package for the Social Sciences (SPSS) 22.0 software (IBM, Armonk, NY, USA) was used to conduct the statistical analyses. The intra-class correlation coefficients (r1) were used for evaluating the digit length measurement credibility. The difference comparisons were performed using the
The Hardy-Weinberg equilibrium, minor allele frequency, and linkage disequilibrium were analyzed using Haploview software (Broad Institute of Harvard and MIT, MA, USA). The haplotype block was defined using the method of the Four Gamete Rule in Haploview.
Snpstats (https://www.snpstats.net/start.htm) was used to analyze the differences in haplotype, genotype, and allele frequencies between sexes. The linear regression analysis in the Plink package (v.1.9) was used to verify the associations between 2D: 4D and CYP SNPs. We assessed the interactions among SNPs of CYP genes using the generalized multifactor dimensionality reduction (GMDR) method [33]. The box-shaped scatter composite figure plotted by R was used to visualize the 2D: 4D genotype association characteristics.
Results
DESCRIPTION AND DISTRIBUTION OF CYP SNPS IN OUR POPULATION:
A total of 8 SNPs separately located in CPY3A7, CYP11A1, CYP17A1, and CYP19A1 were selected. The information and locations of the associated SNPs are listed in Table 1. The genotype frequencies of all the SNPs met the requirement of Hardy-Weinberg equilibrium in our population (P>0.05). The results indicated that the genotype and allele frequencies of all SNPs were not significantly different between men and women. A good linkage disequilibrium was found in the 2 groups of the following SNPs: 3 SNPs (rs1004467, rs17115149, rs2486758) of CYP17A1 and 3 SNPs (rs4646, rs2255192, rs4275794) of CYP19A1 (Figure 1). The haplotypes in the blocks were established and analyzed for differences between sexes, but no statistically significant differences were observed.
2D: 4D CHARACTERIZATIONS IN OUR POPULATION:
Remeasurement reliability of all digit lengths were acceptable for both hands in the intra-class correlation coefficient test (digit length of left hand: F=44.620, P<0.001; digit length of right hand: F=44.484, P<0.001). The significant difference was observed between different sexes in the left hand (L)2D: 4D (t=−2.951, P=0.003) and the right hand (R)2D: 4D) (t=−2.353, P=0.019). The L2D: 4D and R2D: 4D were both higher in women than in men, which was consistent with previous reports. However, the R2D: 4D minus L2D: 4D (DR-L) was not different between men and women (Table 2).
CORRELATION OF SINGLE CYP SNPS TO 2D: 4D IN THE STUDY POPULATION:
The L2D: 4D, R2D: 4D, and DR-L of CYP SNP genotypes were analyzed to explore the relationship between the CYP gene polymorphisms and the prenatal sex hormones. From the analytical results, the R2D: 4D was found to be significantly different in the 3 genotypes of SNP rs1004467 (F=4.113, P=0.017) (Table 3). The existence of minor allele G decreased the R2D: 4D, suggesting an increased fetal androgen or decreased fetal estrogen level. However, no genotype difference was observed in L2D: 4D and DR-L.
The associations between CYP SNPs and 2D: 4D by sex were then assessed, and only SNPs of CYP17A1 showed a relationship (Figure 2). For men, the L2D: 4D showed a statistically significant difference among different genotypes of SNP rs2486758 (F=4.771, P=0.009) and the genotypes with minor allele C had a higher L2D: 4D. The R2D: 4D was significantly different among different genotypes of SNPs rs1004467 (F=5.997, P=0.003) and rs2486758 (F=4.973, P=0.007). The minor allele G of rs1004467 was associated with a decrease in the R2D: 4D, while the minor allele C of rs2486758 was associated with an increase in the R2D: 4D. For women, a statistically significant difference in the L2D: 4D was observed in SNP rs4646 (F=3.142, P=0.044), and the L2D: 4D was higher in genotypes with minor allele A. Also, the DR-L in women was higher in genotypes containing the minor allele T of rs17115149 (F=3.260, P=0.039).
Further, the linear regression model was used to verify the causal relationship between CYP SNPs and 2D: 4D. As shown in Table 4, rs2486758 was correlated with the L2D: 4D (P=0.026) in men, and rs1004467 was correlated with the R2D: 4D in men (P=0.008) and the whole population (P=0.032). However, no relationship was found between CYP SNPs and the 2D: 4D in women. Additionally, there was no correlation between CYP SNPs and DR-L for either men or women.
CORRELATION OF CYP SNPS WITH 2D: 4D UNDER DIFFERENT GENETIC MODELS AND HAPLOTYPES:
The digit ratios of dominant and recessive models of SNP genotypes were compared. For the whole population, L2D: 4D was significantly lower in C/C than in A/C and A/A genotypes under the dominant model of rs4646 (
Next, 2D: 4D in different haplotypes of CYP17A1 and CYP19A1 were analyzed. As shown by the data summarized in Table 5, only rs17115149-rs1004467-rs2486758 in CYP17A1 showed significant differences in male R2D: 4D values (F=4.382, P=0.005). Multiple comparisons were performed, and the results indicated that R2D: 4D was significantly lower in the haplotype G-G-T.
IMPLICATIONS OF SNP-SNP INTERACTIONS WITHIN CYP GENES IN 2D: 4D:
Next, we used GMDR analysis to detect the potential high-dimension interactions among the CYP SNPs, with the interaction confirmed by cross-validation consistency. Key variables were defined as L2D: 4D, R2D: 4D, and DR-L for each participant, with SNP variables ranging from 0 to 2, indicating the number of minor alleles in an individual participant (0=0 minor allele, 1=1 minor allele, 2=2 minor alleles). Considering the effect on the R2D: 4D, CYP17A1 SNP rs1004667 had the highest testing balanced accuracy and CV consistency among the 8 SNPs, but without statistical significance. On testing, SNPs rs2687133 (CYP3A7) and rs1004467 (CYP17A1) had the highest accuracy in a 2-way interaction (P=0.0107) (Table 6, Figure 3).
Discussion
The current study was designed to help us understand the genetic polymorphisms of CYP genes and the association of these polymorphisms with the prenatal sex hormone balance in a northwestern Chinese population. Our results support the hypothesis that polymorphisms in CYP genes are correlated with the 2D: 4D; that is, variants of CYP genes might affect the synthesizing and metabolizing of sex hormones in utero and further result in the difference of digit ratio formation during early embryo development.
Genetic polymorphisms in CYP genes might lead to changes in CYP gene expression and thereby affect steroid synthetization and endocrine regulation [18]. Studies have found that the allele frequencies of many CYP SNPs vary between different ethnic groups [34] and diseases [35], but differences due to sex have been rarely investigated. For example, the
Research in the last decades has shown that unbalanced exposure to prenatal testosterone (PT) or prenatal estrogen (PE) may cause differences in 2D: 4D. High PT or low PE might lead to a low 2D: 4D, while low PT or low PE might result in a high 2D: 4D [37]. Many studies have demonstrated that women have a higher 2D: 4D than men, which is consistent with our findings. In addition, the DR-L or DL-R of 2D: 4D can reveal 2D: 4D asymmetry between the left and right hands [38]. Several reports have suggested that PT influences R2D: 4D and DR-L more than it influences L2D: 4D, and the DR-L of 2D: 4D is negatively correlated with prenatal exposure and sensitivity to testosterone [39]. However, in our present study, we did not observe marked differences in the range of DL-R between the sexes. Also, a study found that the number of TA(n) repeats in the promoter region of the
Three SNPs, namely rs1004467, rs17115149, and rs2486758 of
The product of the
Heredity and GWAS studies have demonstrated that digit ratio is a polygenic genetic trait; that is, a single gene seldomly contributes to its development. The formation of 2D: 4D is influenced by multiple genes and environmental factors. Hence, the combined function and interaction among CYP genes involved in the synthesizing and metabolizing of sex steroids were studied to elucidate the relationship between CYP SNPs and 2D: 4D. The haplotype of rs17115149-rs1004467-rs2486758 in
Our study has the following limitations: 1) the SNPs of CYP genes selected in our research were not numerous enough to cover all potential function locations, and therefore more SNPs, as well as their interactions, might be required in future studies; 2) the source of all participants was limited to the Ningxia Medical University, and the small sample size of this study probably resulted in weak statistical significance; 3) the factor of a limited ethnic group might affect the results of SNP distributions and digit ratios; and 4) the study lacks functional validation. Therefore, an association study with more CYP SNP loci, a larger sample size, more ethic groups with different genetic backgrounds, and molecular function validation might be conducted in future.
Conclusions
Our research demonstrated that the SNPs rs1004467 and rs2486758 of the
Figures



Tables
Table 1. Specific information on candidate SNPs of CYP genes.





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