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Objectives: We describe studies determining the association between testosterone therapy (TTh) and mortality. Materials & methods: We used a registry database of 737 men with adult‐onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10‐year follow‐up. We compared associations between testosterone undecanoate (TU), cardio‐metabolic risk factors and mortality using non‐parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio‐metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio‐metabolic risk. Results: During a median follow‐up interquartile range (IQR) of 114 (84–132) months, 94 of the 737 men died. TU (ref: non‐treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14–0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high‐risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. Conclusions: This study with long follow‐up confirms that TTh is associated with lower mortality in men with adult‐onset TD. This association was evident only in men with greater cardio‐metabolic risk factors who demonstrated greater benefit. [ABSTRACT FROM AUTHOR]

Background: Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult‐onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy. Objectives: Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT. Materials and methods: A randomized double‐blind trial approach was used to recruit and randomize men with T2DM and adult‐onset TD into placebo and TRT‐treated groups. Multiple regression was used to study differences between groups. Results: Baseline SHBG and change in SHBG (∆SHBG) were inversely related in the TRT group. Both median values of SHBG and age mediated the effect of TRT on ∆SHBG depending on whether baseline values were ≤ or>median (28.1 nmol/L, 63 years, respectively). In men with both SHBG ≤ 28.1 nmol/L and age ≤ 63 years (subgroup 1), TRT was positively associated with ∆SHBG (c = 4.67, 95%CI 1.17‐8.16, P =.010) while in those with SHBG > 28.1 nmol/L and age > 63.1 years (subgroup 4) the association was inverse (c = −7.07, 95%CI −11.64 to −2.49, P =.003). The association between TRT and change (∆) in waist circumference, HbA1c and International Index of Erectile Function (IIEF) score differed between subgroups; in subgroup 4 but not subgroup 1, the therapy was significantly associated with ∆waist circumference, ∆HbA1c and ∆IIEF. Discussion: Though the mechanism remains unclear, our finding of different responses to TRT in terms of change in waist circumference, HbA1c and IIEF score supports the concept of subgroups in men with T2DM and adult‐onset TD. Conclusion: Our approach may provide a basis for identifying men who will or will not derive benefit from TRT though a larger study is required. [ABSTRACT FROM AUTHOR]

Objectives: To further characterize the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM), by determining, firstly, if changes in cardiovascular disease (CVD) risk factors after TRT play a role, secondly, whether the reduction in mortality is lost when TRT is discontinued and, finally, the presence of subgroups where benefit may be greater. Materials and Methods: We studied 857 men with T2DM, screened for the BLAST randomized controlled trial, over 3.8 years of follow‐up. The men were stratified first by testosterone levels: group 1: total testosterone (TT) >12 nmol/L and free testosterone (FT) >0.25 nmol/L; Group 2: TT ≤12 nmol/L or FT ≤0.25 nmol/L. Group 2 was further stratified into those not on TRT (Group 2a) and those on TRT (Group 2b). Group 2b was further stratified by whether TRT was discontinued (Group 2b1) or not (Group 2b2). The principal outcome, mortality, was studied using Cox regression. Results: We found that TRT was not associated with improvements in CVD risk factors. CVD risk factors (baseline and changes during follow‐up) were not associated with mortality. Men in Group 1 and Group 2b were found to have lower mortality (reference: Group 2a), even with CVD risk factors included in the regression models. Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%). The lower mortality associated with Group 1 and Group 2b was observed primarily in older (>64.6 years) and less overweight (≤93.8 kg) men. Conclusions: The benefits associated with normal testosterone levels and TRT (even after discontinuation) do not appear to be related to improvements in the CVD risk factors studied. In view of TRT having greater impact in men of lower weight, better outcomes may be achieved with concurrent TRT and weight reduction programmes. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor ( VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A1229 (SNP 1), A/G3944 (SNP 2), T/C30875 (SNP 3), C/T48200 (SNP 4) and C/T65013 (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41–0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1-2, G-G (odds ratio = 0.63, p = 0.039), SNPs 2-3 G-C (odds ratio = 0.45, p = 0.008) and SNPs 1-2-3 G-G-C (odds ratio = 0.44, p = 0.006), but not SNPs 1-3, G-C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes). These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2. [ABSTRACT FROM AUTHOR]

Cutaneous basal cell carcinoma (BCC) risk is mediated by interactions between ultraviolet radiation (UVR) and host factors, including DNA repair efficiency. We investigated the association between BCC risk and SNPs in exon 6 (c.466C>A, dbSNP238406:g.C>A; designated C/A156), exon 10 (c.932G>A, dbSNP1799793:g.G>A; designated G/A312), and exon 23 (c.2251A>C, dbSNP13181:g.A>C; designated A/C751) of the nucleotide excision repair gene, XPD ( ERCC2; excision repair cross-complementing repair deficiency, complementation 2 [xeroderma pigmentosum D]). XPD genotype frequencies were not significantly different in 509 cases and 379 controls, although AA156 (odds ratio [OR]=0.61, 95% confidence interval [CI]=0.37-1.01, P=0.052) and AA312 (OR=0.65, 95% CI=0.40-1.05, P=0.08) were linked with reduced risk. A156-A312 and A156-A312-A751 haplotype frequencies however, were significantly lower in cases than controls (OR=0.12, 95% CI=0.05-0.31, P<0.001; OR=0.10, 95% CI=0.03-0.33, P<0.001). We confirmed the robustness of these findings by showing significant associations of the haplotypes with risk in two randomly selected equal sized groups of cases and controls and, using the false positive report probability (FPRP) approach (FPRP values<0.001 and<0.004, respectively). A156-A312 was similarly associated with reduced risk in subgroups, including cases with no family history of skin cancer, with only BCC on the head/neck, and those with a high rate of increase in BCC numbers. The association was not dependent on gender, age, or extent of UVR exposure. A156-A312 was found in 6.3% of controls and the corresponding risk haplotype, C156-G312 (OR=1.65, 95% CI=1.21-2.26, P=0.002) in 35.4% of controls. We interpret these data as showing that XPD SNP mediate susceptibility to BCC. Hum Mutat 25:353-359, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose–response slopes (DRS) and PC20 values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7–18 years. Correction of bronchial challenge results, expressed as both DRS and PC20 values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC20 methacholine <8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRS c 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor (VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A(1229) (SNP 1), A/G(3944) (SNP 2), T/C(30875) (SNP 3), C/T(48200) (SNP 4) and C/T(65013) (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41-0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1-2, G-G (odds ratio = 0.63, p = 0.039), SNPs 2-3 G-C (odds ratio = 0.45, p = 0.008) and SNPs 1-2-3 G-G-C (odds ratio = 0.44, p = 0.006), but not SNPs 1-3, G-C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes). These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2.