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We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.

Variations in serum prostate-specific antigen (PSA) have been ascribed to A/G nucleotide polymorphisms located at -158 bp (rs266882) and -4643 bp (rs925013), relative to the transcription start site within the promoter of the PSA gene. PSA is also an androgen receptor target (AR) gene and polymorphisms in AR gene are known to affect AR function. Our objective was to compare the impact of these A/G polymorphisms separately or in combination with AR CAG micro satellite on regulation of PSA secretion into seminal plasma and blood in young men. Leukocyte DNA was extracted from 291 conscripts and genotyping performed with the Sequenom Mass Array System. PSA was measured with an immunofluorometric assay. Linear regression analysis was used to test the association of polymorphism frequencies with serum and seminal plasma levels of PSA. PSA gene polymorphisms at -158 bp or -4643 bp did not alone influence total PSA (tPSA) levels in seminal plasma or in blood. Homozygotes for the A-allele at -158 bp in combination with CAG > 22 had significantly higher serum levels of tPSA than subjects carrying the G-allele (p = 0.01). In conclusion, the PSA gene polymorphisms did not importantly influence the levels of tPSA in seminal plasma or in blood. tPSA in serum was influenced by interactions between PSA promoter variants and AR CAG polymorphism.

Prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) are secreted by the prostate into seminal plasma and through leakage into blood. This leakage increases rapidly in prostate disease, and PSA is used worldwide as a marker of prostate cancer. PSA is activated in vitro by hK2, and cleaves the semenogelins in semen, which releases motile sperm, and low levels of PSA have been associated with low sperm motility. The present objective was to evaluate factors that might influence release of hK2 and PSA, and to study those two proteins with regard to their levels in seminal plasma and blood, and their association with sperm motility in young healthy men without prostate disease. PSA and hK2 were measured by immunofluorometric assay. Genomic DNA was prepared from peripheral leukocytes, and genotyping was performed with the Sequenom Mass Array System. Levels of hK2 and PSA were found to be associated with variants in the genes encoding hK2 (KLK2) and PSA (KLK3) in young men (mean age 18 years). The single-nucleotide polymorphisms (SNPs) rs198972, rs198977, rs198978, and “SNP2” in KLK2 were associated with lower hK2 levels in seminal plasma and serum in carriers of the TT genotype. In KLK3, the AA genotype in rs266882 in combination with CAG > 22 were correlated with higher total PSA (tPSA) in serum; rs2271094 and “SNP1" were associated with lower tPSA concentrations in seminal plasma from subjects homozygous for the common allele (A or G, respectively). Carriers of the common T allele in rs1058205 in KLK3, had higher amounts of tPSA in seminal plasma, higher concentrations of tPSA in serum, and a lower ratio of free to tPSA (%fPSA). Free PSA (fPSA) in blood showed ~17% co-variation with PSA in semen, whereas no relationship was found between levels of complexed PSA (cPSA) in blood and PSA in semen. In blood, levels of cPSA, but not fPSA, increased with age, which may reflect an increasing incidence of prostate disease. In men 19–40 years, an age when repr