The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia

Recent studies on young men from the general population have demonstrated geographic and ethnic differences in semen quality. The aim of this study was to investigate whether reported ethnic differences in semen quality might be associated with the maternally derived CAG and GGN polymorphisms in the androgen receptor gene or paternal ethnicity. In total 114 military conscripts from Latvia were included in the study. Information on maternal and parental ethnicity was collected by questionnaires. CAG and GGN repeats were analysed by direct sequencing of leukocyte DNA. Men with Latvian mothers (n = 83) had marginally shorter CAG repeat length (21.6 ± 2.9) as compared with those with non-Latvian mothers (22.9 ± 3.2, n = 31), not reaching statistical significance (p = 0.053). Sperm concentration did not differ significantly between these two groups (76 ± 59 and 70 ± 52, p = 0.9 respectively). In contrast, significantly higher sperm concentration and total sperm count were found in men with Latvian fathers (n = 77) as compared with men with non-Latvian fathers (n = 37) (80 ± 61 vs. 62 ± 48, p = 0.035, for sperm concentration and 225.7 ± 209 vs. 158.4 ± 134.4, p = 0.002, for total sperm count respectively). CAG repeat length did not correlate with any semen parameters in the whole population. However, GGN repeat length correlated with semen volume: men with GGN > 23 presented with higher semen volume (3.2 ± 2.1) as compared with men with GGN = 23 (2.6 ± 1.3, p = 0.04) or GGN < 23 (2.0 ± 1.2, p = 0.006). We conclude that GGN repeat length has an impact on semen volume, whereas differences in sperm numbers are associated with the paternal ethnicity.Peer reviewe

Trinucleotide (CAG) repeat polymorphism of the androgen receptor gene in human disease

Ph.DDOCTOR OF PHILOSOPH

Genetic analysis of male infertility

Approximately one in twenty men has impaired spermatogenesis due to mutation of genes involved in the establishment or maintenance of fertility. Our understanding of male infertility is complicated by the variable phenotypes produced by similar genetic changes, largely due to the practise of screening a single fertility gene in isolation. This thesis aimed to increase our understanding of the role of synergistic mutations in relation to differences in semen quality. Each sample was analysed for mutation in: CAG trinucleotide repeat variation in the X-linked androgen receptor (AR) gene, micro deletion within the three Y chromosome azoospermic factor (AZF) regions, and CAG trinucleotide repeat variation and exonuclease domain mutation in the nuclear polymerase gamma (POLγ gene. These genes have been associated with reduced semen quality in past research. Each gene region was amplified by polymerase chain reaction (PCR), followed by sequencing. Suspected AZF micro-deletions were confirmed by Southern blot hybridisation. Associations with semen quality were evaluated using either a t-test or Gtest for independence at α=0.05. Yq AZF micro-deletions were observed in 6.6% (14/211) of men with poor semen quality but not in normozoospermic samples (0/104); P<0.001). Micro-deletion frequency was greatest in azoospermic and severely oligoasthenozoospermic individuals (15% and 11.5%, respectively). AR CAG repeat length ranged from 9-38 CAG repeats in the normozoospermic population (n=98) and 13-31 CAG repeats in men with poor semen quality (n= 119). Variation in AR CAG trinucleotide repeat number was not significantly related to poor semen quality (P>0.05). Variation in POLγ CAG repeat number was not significantly different between normozoospermic men (n=93) and men with poor semen quality (n= 182); P>0.05. No nucleotide changes were observed in any of the three POLγ exonuclease motifs (n=83 normozoospermic and 191 non-normozoospermic motif, 61 and 65 motif II, and 60 and 64 motif III). Although most gene regions did not show an association with poor semen quality on their own, there was a general trend towards greater severity of impaired spermatogenesis with the presence of both Yq micro-deletion and mitochondrial DNA substitutions or moderately expanded AR CAG repeats. These results support the idea that male infertility is a complex process, due to many factors, some of which act dominantly and others act in concert