Genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus.

X chromosome inactivation can balance the effects of the two X chromosomes in females, and emerging evidence indicates that numerous genes on the inactivated X chromosome have the potential to evade inactivation. The mechanisms of escape include modification of DNA, RNA, histone, epitope, and various regulatory proteins, as well as the spatial structure of chromatin. The study of X chromosome inactivation escape has paved the way for investigating sex dimorphism in human diseases, particularly autoimmune diseases. It has been demonstrated that the presence of TLR7, CD40L, IRAK-1, CXCR3, and CXorf21 significantly contributes to the prevalence of SLE (systemic lupus erythematosus) in females. This article mainly reviews the molecular mechanisms underlying these genes that escape from X-chromosome inactivation and sexual dimorphism of systemic lupus erythematosus. Therefore, elucidating the molecular mechanisms underlying sexual dimorphism in SLE is not only crucial for diagnosing and treating the disease, but also holds theoretical significance in comprehensively understanding the development and regulatory mechanisms of the human immune system.

[Lycium barbarum polysaccharide reduces testicular spermatogenic injury in Immp2l－/－mice through GPX4 and AIF pathways].

OBJECTIVE: To investigate the protective effect of Lycium barbarum polysaccharide (LBP) against testicular spermatogenic injury in mice with oxidative stress (OS) and its mechanism. METHODS: A unique OS model was made in 1.5-month-old mice with mitochondrial inner membrane-like peptide-2 mutation (Immp2l－/－), which were fed with water (the negative control group) or LBP in water at the concentration of 20 mg/kg (the LBP intervention group), and wild-type Immp2l＋/＋ mice used as normal controls and fed with water only. Then all the mice were sacrificed at 13 months old and the testis tissue harvested for observation of pathological changes by HE staining, measurement of routine semen parameters, and detection of the apoptosis of spermatogenic cells by TUNEL and the expression levels of glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor (AIF) by immunohistochemistry and Western blot. RESULTS: Thinned testicular cortex was observed in the negative controls, with evident vacuolar degeneration and reduced numbers of germ cells and elongated spermatids in the lumen of the seminiferous tubules, but all these pathological changes were improved and the germ cells at different levels orderly arranged in the LBP intervention group. Compared with the normal controls, the mice in the negative control group showed dramatically reduced sperm count (ï¼»72.89 ± 8.28ï¼½ vs ï¼»20.78 ± 1.45ï¼½ ×106, P<0.01) and the percentages of progressively motile sperm (PMS) (ï¼»58.62 ± 6.15ï¼½% vs ï¼»18.37 ± 2.67ï¼½%, P<0.01) and morphologically normal sperm (MNS) (ï¼»65.81 ± 7.69ï¼½% vs ï¼»20.33 ± 3.17ï¼½%, P<0.01) and increased apoptosis of spermatogenic cells (ï¼»1.45 ± 0.43ï¼½% vs ï¼»7.14 ± 0.78ï¼½%, P<0.01). LBP intervention, however, significantly increased the sperm count (ï¼»45.25 ± 3.39ï¼½ ×106, P<0.05), PMS (ï¼»36.34 ± 4.56ï¼½%, P<0.05) and MNS (ï¼»38.72 ± 3.63ï¼½%, P<0.05) and decreased the apoptosis of spermatogenic cells (ï¼»2.28 ± 0.07ï¼½%, P<0.01). The mice in the LBP intervention group, in comparison with the negative controls, exhibited remarkably up-regulated expression of GPX4 (2.75 ± 0.48 vs 1.43 ± 0.17, P<0.05) and down-regulated expression of AIF (2.43 ± 0.15 vs 1.35 ± 0.51, P<0.05). CONCLUSIONS: Lycium barbarum polysaccharide at 20 mg/kg can reduce testicular spermatogenic injury in Immp2l－/－ mice with oxidative stress through GPX4 and AIF pathways.

[Hand dermatoglyphic traits and azoospermia in the Chinese Han males in Ningxia area].

OBJECTIVE: To investigate the relationship between hand dermatoglyphic traits and azoospermia in the Chinese Han males in Ningxia area. METHODS: Using the inkpad prints, we obtained dermatoglyphics of both hands from 212 Han males in Ningxia area, including 106 azoospermia patients and 106 fathers as normal controls. We analyzed the photographs of the prints with the Image-Pro Plus 6.0 software and compared the finger print patterns, finger ridge counts, atd angles (the angle between the index finger triradius ï¼»aï¼½ and the little finger triradius ï¼»dï¼½ to the axial triradius ï¼»tï¼½) and a-b ridge counts between the two groups of subjects. RESULTS: The prevalence rate of radial loops in both hands was markedly higher in the azoospermia patients than in the normal controls (3.77% vs 1.70%, P < 0.01) while that of arches showed no statistically significant difference between the two groups (1.89% vs 1.51%, P > 0.05). The prevalence rates of whorls and ulnar loops, the finger ridge counts, and the a-b ridge counts were all lower in the azoospermia patients than in the fertile controls though none with statistically significant difference between the two groups (P > 0.05). The atd angles in both hands were significantly lower in the former than in the latter group (right hand: ï¼»40.52 ± 4.61ï¼½° vs ï¼»42.99 ± 4.65ï¼½°, P < 0.05; left hand: ï¼»40.04 ± 4.21ï¼½° vs ï¼»42.18 ± 4.87ï¼½°, P < 0.05). CONCLUSIONS: There are some abnormal variations in the hand dermatoglyphic traits, especially the prevalence of radial loops and the atd angle in the Chinese Han male patients with azoospermia in Ningxia area.

[Correlation of the second to fourth digit ratio with the body mass index of infertile men].

OBJECTIVE: To investigate the relationship between the second to the fourth digit ratio (2D:4D) and body mass index (BMI) in infertile men of the Han ethnic group in Ningxia. METHODS: Using anthropometry, we calculated the mean ratio of 2D:4D and BMI of 197 infertile men and 148 normal healthy male controls, followed by analysis of their relationship. RESULTS: The BMI was correlated positively with the 2D:4D ratio of the left hand in the infertile men (P < 0.05) and in the patients with a higher 2D:4D ratio of the left hand (P < 0.05), but negatively with the 2D:4D ratio of the righ/left (Dr-1) (left: P < 0.01; Dr-l: P < 0.05). The mean 2D: 4D ratio and BMI were both lower in the normal control than in the infertile men, with statistically significant differences in BMI (P < 0.05) and the 2D:4D ratio of the left hand (P < 0.05). CONCLUSION: There is a correlation between the 2D:4D ratio and BMI in infertile men.

Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss.

MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3'UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.

8q24 rs4242382 polymorphism is a risk factor for prostate cancer among multi-ethnic populations: evidence from clinical detection in China and a meta-analysis.

BACKGROUND: Evidence supporting an association between the 8q24 rs4242382-A polymorphism and prostate cancer (PCa) risk has been reported in North American and Europe populations, though data from Asian populations remain limited. We therefore investigated this association by clinical detection in China, and meta-analysis in Asian, Caucasian and African-American populations. MATERIALS AND METHODS: Blood samples and clinical information were collected from ethnically Chinese men from Northern China with histologically- confirmed PCa (n=335) and from age-matched normal controls (n=347). The 8q24 (rs4242382) gene polymorphism was genotyped by polymerase chain reaction-high-resolution melting analysis. We initially analyzed the associations between the risk allele and PCa and clinical covariates. A meta-analysis was then performed using genotyping data from a total of 1,793 PCa cases and 1,864 controls from our study and previously published studies in American and European populations, to determine the association between PCa and risk genotype. RESULTS: The incidence of the risk allele was higher in PCa cases than controls (0.222 vs 0.140, P=7.3?10-5), suggesting that the 8q24 rs4242382-A polymorphism was associated with PCa risk in Chinese men. The genotypes in subjects were in accordance with a dominant genetic model (ORadj=2.03, 95%CI: 1.42-2.91, Padj=1.1?10-4). Presence of the risk allele rs4242382-A at 8q24 was also associated with clinical covariates including age at diagnosis ≥65 years, prostate specific antigen >10 ng/ml, Gleason score <8, tumor stage and aggressive PCa, compared with the non-risk genotype (P=4.6?10-5-3.0?10-2). Meta-analysis confirmed the association between 8q24 rs4242382-A polymorphism and PCa risk (OR=1.62, 95%CI: 1.39-1.88, P=1.0?10-5) across Asian, Caucasian and African American populations. CONCLUSIONS: The replicated data suggest that the 8q24 rs4242382-A variation might be associated with increased PCa susceptibility in Asian, Caucasian and African American populations. These results imply that this polymorphism may be a useful risk biomarker for PCa in multi-ethnic populations.

Correlations between digit ratio and infertility in Chinese men.

BACKGROUND: Digit ratio, especially second to fourth digit ratio (2D:4D) is lower in men than in women. The ratios of digit may be established in utero and is negatively correlated with sperm counts and testosterone in men and positively correlated with estrogen in men and women. AIM: To study whether the digit ratio (especially 2D:4D) are associated with the a+b ratio of sperm number in Chinese populations. METHODS: Photocopies of the two hands of 268 men (controls: 72; patients: 196) and seminal parameters of masturbatory semen samples were collected. RESULTS: The mean values of digit ratio of the controls and the patients all presented a trend as 2D:3D<2D:4D<3D:4D<2D:5D<4D:5D<3D:5D; the patients have higher mean values than controls; significant variances of 2D:3D, 3D:4D (left: P<0.05; right: P ≤ 0.05) and 2D:4D (left: P<0.001; right: P<0.01) were found between two groups; there was a higher percentage of 2D>4D in the patients; the relationship between 2D:4D and a+b ratio of sperm number in the patients was significant (P<0.001). CONCLUSION: Digit ratio, especially 2D:4D in the left hand maybe one of the important markers of infertility in men for early diagnosis.

Association of six susceptibility Loci with prostate cancer in northern chinese men.

BACKGROUND/AIM: Six prostate cancer (PCa) susceptibility loci were identified in a genome-wide association study (GWAS) in populations of European decent. However, the associations of these 6 single-nucleotide polymorphisms (SNPs) with PCa has remained tobe clarified in men in Northern China. This study aimed to explore the loci associated with PCa risk in a Northern Chinese population. METHODS: Blood samples and clinical information of 289 PCa patients and 288 controls from Beijing and Tianjin were collected. All risk SNPs were genotyped using polymerase chain reaction (PCR)-high resolution melting curve technology and gene sequencing. Associations between PCa and clinical covariates (age at diagnosis, prostate-specific antigen [PSA], Gleason score, tumor stage, and level of aggressiveness) and frequencies of alleles and genotypes of these SNPs were analyzed using genetic statistics. RESULTS: Among the candidate SNPs, 11p15 (rs7127900, A) was associated with PCa risk (P = 0.02, odds ratio [OR] = 1.64, 95% confidence interval [CI] = 1.09-2.46). Genotypes showed differences between cases and controls on 11p15 (rs7127900, A), 11q13 (rs7931342, T), and HNF1B (rs4430796, A) (P = 0.03, P = 0.01, and P = 0.04, respectively). The genotype TG on 11q13 (rs7931342, T) was positively associated with an increased Gleason score (P = 0.04, OR = 2.15, 95% CI = 1.02-4.55). Patients carrying TG on 17q24 (rs1859962, G) were negatively associated with an increased body mass index (BMI) (P = 0.03, OR = 0.44, 95% CI = 0.21-0.92) while those with AG on HNF1B (rs4430796, A) were more likely to have PSA increase (P = 0.002). CONCLUSION: Our study suggests that 11p15 (rs7127900, A) could be a susceptibility locus associated with PCa in Northern Chinese. Genotype TG on 11q13 (rs7931342, T) could be related to an increased Gleason score, AG on HNF1B (rs4430796, A) could be associated with PSA increase, and TG on 17q24 (rs1859962, G) could be negatively associated with an increased BMI in Chinese men with PCa.

[Association of the polymorphisms in the promoter region of tumor necrosis factor alpha and interleukin 6 genes with schizophrenia].

OBJECTIVE: To investigate the relationship between the -308G/A, -857C/T and -1031T/C of tumor necrosis factor alpha gene (TNF- alpha), -174G/C and -572C/G of interleukin-6 gene (IL-6) polymorphisms and schizophrenia. METHODS: Genomic DNA was isolated from the venous blood leukocytes of 346 unrelated patients with schizophrenia and 323 healthy unrelated individuals (control group). All of the polymorphisms were genotyped by PCR-restriction fragment length polymorphisms (PCR-RFLP). Genotype and allele frequencies were analyzed by SPSS13.0 software. RESULTS: There were significant differences in both allele and genotype frequencies of -857C/T of TNF-alpha gene between the schizophrenia and control groups (P< 0.05). The allele T of -857C/T in schizophrenia group was significantly higher than that in control group (chi-square was 9.414, P=0.002, OR=1.511, 95%CI:1.160-1.969). In addition, there were significant differences in the positive and negative syndrome scale (PANSS) total score and negative symptoms between the patients with different -857C/T genotypes, and the negative symptom score of TT genotype was significantly higher than that of CC genotype (P<0.05). CONCLUSION: There is an association between -857C/T of TNF-alpha gene and schizophrenia, individuals with T allele of -857C/T are susceptible to schizophrenia, and there is an association between -857C/T and negative symptom score.

[Identification of a novel lymphotoxin-alpha (LTA) gene associated with ankylosing spondylitis in Ningxia population].

Lymphotoxin-alpha (LTA) gene has been reported to have a genetic association with systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis. However, the association of LTA with ankylosing spondylitis (AS) has not reported. By case-control study, we carried out the high density limited genome scanning to the HLA class III region about 58 kb in Ningxia population (case 300 and control 385). In this study, 33 SNPs in LTA were genotyped in Ningxia population. We analyzed these SNPs and the haplotypes covering LTA. Only the distribution of TCC haplotype which contains mutation allele of LTA rs909253 was statistically significant(P=0.0005). The C allele frequency of the LTA rs909253 T/C polymorphism was higher in AS cases than that in the controls (28.5% versus 19.7%, P=2×10-4) in Ningxia population. The results suggest that there is a relevance between LTA and the susceptibility of AS, and we identified that the LTA polymorphism may be associated with AS in Ningxia population.

[Genetic polymorphism of twelve Y chromosomal short tandem repeat loci in Chinese Hui ethnic group].

OBJECTIVE: To obtain the genetic polymorphism of Y chromosomal short tandem repeat (Y-STR) loci in Ningxia Hui population. METHODS: Blood samples were collected from 150 unrelated healthy male individuals of Ningxia Hui ethnic group. Twelve Y-STR loci were amplified in one tube by using the PowerPlex System STR Amplification Kit, and the genotypes were determined using Genescan and Genotype software of ABI377 DNA sequencer and the frequency of alleles and haplotypes of Ningxia Hui ethnic was obtained. RESULTS: Seventy-five alleles were observed at 12 Y-STR loci. The frequency ranged from 0.0067-0.7067 and the gene diversity ranged from 0.4446-0.8877. Totally 148 different haplotypes were found, which were unique in 150 males. Two haplotypes were shared by 2 males respectively. The haplotype diversity was 0.9864. CONCLUSION: The 12 Y-STR loci are highly polymorphic in Ningxia Hui population and are suitable for genetics and forensic research.