CAG repeats are polymorphic nucleotide repeats present in the androgen receptor gene. Many studies have estimated the association between CAG repeat length and male infertility, but the conclusions are controversial. Previous meta-analyses have come to different conclusions; however, new studies have been published. An updated meta-analysis was conducted. PubMed, CBM, CNKI and Web of Science databases were systematically searched for studies published from 1 January 2000 to 1 October 2015. Case-control studies on the association between CAG repeat length and male infertility using appropriate methodology were included. Forty studies were selected, including 3858 cases and 3161 controls. Results showed statistically significantly longer CAG repeat length among cases compared with controls (SMD = 0.14; 95% CI, 0.02-0.26). Shorter repeat length was associated with a lower risk of male infertility compared with a longer repeat length in the overall analysis (OR = 0.79, 95% CI: 0.66-0.95). Moreover, CAG repeat length was associated with male infertility in Caucasian populations, but not Asian or Egyptian populations. Subgroup analysis revealed no significant difference in German populations, but CAG repeat length was associated with male infertility in China and the USA. There were no significant differences between cases and controls in azoospermia and severe oligozoospermia.

Impact of CAG repeat length in the androgen receptor gene on male infertility – a meta-analysis

CAG trinucleotide repeats in androgen receptor (AR) gene encode a polyglutamine tract in AR N-terminal transactivation domain. Studies have been conducted to evaluate the effect of CAG repeat length on male infertility, which have yielded contradictory results. This study aimed to explore the number of AR-CAG repeats in 150 fertile controls and 150 idiopathic infertile men, divided into four azoospermia, oligozoospermia, asthenozoospermia, and teratozoospermia subgroups. In addition, a meta-analysis was conducted based on previous studies to assess the association of the mentioned variation with male infertility in recent years. Polymerase chain reaction (PCR) targeting followed by an electrophoresis on polyacrylamide gel was used for AR-CAG genotype detecting. Moreover, a systematic search was performed in PubMed, Web of Science, Science Direct, and Google Scholar databases to collect eligible studies for meta-analysis purpose. According to the results, a significant association was observed between increased length of AR-CAG polymorphism and male infertility (p< 0.0001). Furthermore, there were similar significant associations in the azoospermia (p= 0.048), asthenozoospermia (p= 0.013) and teratozoospermia (p= 0.002) subgroups. In addition, meta-analysis on forty studies showed a significant association between AR-CAG polymorphism in the overall analysis (SMD= 0.199, 95 % CI= 0.112-0.287, p<0.001) and the Caucasian subgroup (SMD= 0.151, 95 % CI= 0.040-0.263, p= 0.008). Our results elucidated that long stretches of CAG repeat might lead to AR dysfunction, contributing to male infertility especially in the Caucasian population.

Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: a case-control trial and a meta-analysis.

The role of chromosome Y in chronic kidney disease (CKD) remains unknown, as chromosome Y is typically excluded from genetic analysis in CKD. The complex, sex-specific presentation of CKD could be influenced by chromosome Y genetic variation, but there is limited published research available to confirm or reject this hypothesis. Although traditionally thought to be associated with male-specific disease, evidence linking chromosome Y genetic variation to common complex disorders highlights a potential gap in CKD research. Chromosome Y variation has been associated with cardiovascular disease, a condition closely linked to CKD and one with a very similar sexual dimorphism. Relatively few sources of genetic variation in chromosome Y have been examined in CKD. The association between chromosome Y aneuploidy and CKD has never been explored comprehensively, while analyses of microdeletions, copy number variation, and single-nucleotide polymorphisms in CKD have been largely limited to the autosomes or chromosome X. In many studies, it is unclear whether the analyses excluded chromosome Y or simply did not report negative results. Lack of imputation, poor cross-study comparability, and requirement for separate or additional analyses in comparison with autosomal chromosomes means that chromosome Y is under-investigated in the context of CKD. Limitations in genotyping arrays could be overcome through use of whole-chromosome sequencing of chromosome Y that may allow analysis of many different types of genetic variation across the chromosome to determine if chromosome Y genetic variation is associated with CKD.

/pdf/the-challenges-of-chromosome-y-analysis-and-the-implications-gr02j4bolg.pdf

The Challenges of Chromosome Y Analysis and the Implications for Chronic Kidney Disease

OBJECTIVE
The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat.


DESIGN AND PATIENTS
A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men.


MEASUREMENT
Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique.


RESULTS
The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT.


CONCLUSION
To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.

Effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men

Assisted reproductive technology is a common procedure which helps millions of couples who suffer fertility problems worldwide every year. Screening for genetic abnormalities prior to such procedure is very important to prevent the transmission of harmful genetic mutations to future generations. Microdeletions within the azoospermia factor (AZF) region of the Y chromosome and the expansion of the CAG trinucleotides in the androgen receptor (AR) gene are among the susceptible causes of male infertility in different ethnic groups. Such association has never been studied in Jordan. In this study, we compared CAG repeat length between azoospermic infertile and normospermic fertile Jordanian males and we also screened the frequency of Y chromosome microdeletions in the same cohort. The study included 142 nonobstructive azoospermic cases and 145 normospermic controls. Results have shown that the median CAG repeat length in the azoospermic group is 19 ± 2 compared to 19 ± 1.5 (p = .6262) in the control group. Deletions within the Y chromosome AZF region were detected in 7 of 142 cases (4.93%) and no deletions were seen in the control group. The results of this study confirm the importance of the AZF region in normal spermatogenesis, whereas it shows no link between the length of CAG repeats in the AR gene and male azoospermia in Jordanian group examined.

Molecular analysis of CAG repeat length of the androgen receptor gene and Y chromosome microdeletions among Jordanian azoospermic infertile males.

Chromosome abnormalities, Y-chromosome microdeletions, and androgen receptor gene CAG and GGN repeat polymorphisms in infertile Chinese men featuring severe oligospermia and azoospermia were analyzed. Ninety-six fertile men and 189 non-obstructive infertile men, including 125 patients with azoospermia and 64 with severe oligozoospermia, were studied. Seventeen infertile men (9.0%) carried a chromosome abnormality. Twenty (10.6%) carried a Y-chromosome microdeletion. In the remainder of the patients and controls, GGN and CAG repeats were sequenced. Short GGN repeats (n 2.5-fold risk (OR = 2.539, 95%CI = 1.206-5.344, P < 0.05) of severe oligospermia and azoospermia. Our results confirmed the significant role of chromosome abnormalities, Y-chromosome microdeletions, and GGN repeats in Chinese male infertility.

/pdf/cytogenetic-and-molecular-analysis-of-infertile-chinese-men-3kg6dtd94h.pdf

Cytogenetic and molecular analysis of infertile Chinese men: karyotypic abnormalities, Y-chromosome microdeletions, and CAG and GGN repeat polymorphisms in the androgen receptor gene.

The non-recombining portion of the Y-chromosome contains numerous polymorphisms; therefore, it is now the most informative haplotyping system with wide-ranging applications. Idiopathic azoospermia and oligospermia are among the most important causes of male infertility. Different haplogroups may have different genetic backgrounds, which may be either susceptible or unsusceptible to idiopathic azoospermia or oligospermia. This study investigated the possible association between Y-chromosome haplogroup distribution and susceptibility to spermatogenic impairment. Peripheral blood was collected from 193 men with normozoospermia, 193 men with idiopathic azoospermia and 105 men with idiopathic oligospermia. All of the subjects underwent karyotyping, azoospermia factor (AZF) deletion analysis by 15 AZF-specific sequence-tagged sites and Y-chromosome haplotype analysis by 17 binary markers. Excluding men with AZF deletions and abnormal karyotypes, the remainder of these 3 groups was named Group i, Group ii, and Group iii, respectively. The comparisons of 17 Y-haplogroup distributions between Group i and Group ii, Group iii or Group ii + iii were performed with the SPSS V.18.0 software. Significantly different Y-haplogroup distributions were observed between Group i and Group ii in N1* (P = 0.002), between Group i and Group iii in F*, K*, P*, and O3* (P = 0.002, 0.001, 0.004, and 0.007, respectively), and between Group i and Group ii + iii in K*, N1* and O3* (P = 0.008, 0.012, and 0.009, respectively). These results suggest that Y-chromosome haplogroups play a role in spermatogenic impairment.

/pdf/association-study-between-y-chromosome-haplogroups-and-h53wi15jf1.pdf

Association study between Y-chromosome haplogroups and susceptibility to spermatogenic impairment in Han People from southwest China.

Stat5−/− CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation

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Cytogenetic and molecular analysis of infertile Chinese men: karyotypic abnormalities, Y-chromosome microdeletions, and CAG and GGN repeat polymorphisms in the androgen receptor gene.

Association study between Y-chromosome haplogroups and susceptibility to spermatogenic impairment in Han People from southwest China.

Stat5−/− CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation