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Copyright © Richard C. Strange et al., 2021. Objective: Testosterone therapy (TTh) may reduce morbidity/mortality in men with adult-onset testosterone deficiency (TD), though some cardiovascular safety concerns remain. Increased hematocrit (HCT), a recognized effect of therapy, may be associated with cardiovascular disease and mortality. We examined HCT change (Δ) in men prescribed/not prescribed testosterone, and associations with mortality. Methods: We analyzed data from a prospective registry study with adult-onset TD patients: 353 men given testosterone undecanoate (TU) and 384 opting against TTh. Change in HCT after 12, 48, 72, and 96 months of TU and at final assessment was compared (nonparametric tests). The association between baseline HCT, ΔHCT, and mortality was studied using logistic and Cox regression. Results: HCT increased significantly (median change at final assessment: +5.0%) in men on TTh. HCT was higher (p = 0.021, rank-sum test) in those alive than in those who died, although median values were identical (49.0%). Baseline HCT and ΔHCT were inversely associated with mortality after adjustment for age in both logistic and Cox regression models. Men with final HCT >49.0% (median) suffered lower mortality than men with HCT ≤49.0%. Conclusions: A median HCT increase of 5.0% was associated with TTh, mostly within 48 months of commencing therapy. An increase in HCT (up to 52.0% at final assessment) was independently associated with reduced mortality, indicating current guidelines using a HCT value of 54.0% as a threshold for management change are appropriate until further study. No funding was received for this article.

Copyright © Nathan Lorde et al., 2021. Objective: Hematocrit (HCT)/hemoglobin (Hb) ratio in (%/g/dL) is around 3, with high fidelity between measured and derived Hb (applying the conversion using HCT) in various pathologies. We examined changes in HCT and Hb values and HCT/Hb, compared with baseline, in men with adult-onset testosterone deficiency (TD) given testosterone therapy (TTh). Materials and Methods: Data were analyzed from an observational, prospective registry study at various time points in 353 men with adult-onset TD receiving testosterone undecanoate (median follow-up: 105 months). After establishing baseline HCT/Hb, we compared (cf. baseline) changes in HCT, Hb, and HCT/Hb at 12, 48, 72, and 96 months. Regression analyses determined predictors of HCT and Hb change. Results: TTh was associated with (p < 0.0001) increases in median HCT and Hb; 44% to 49% and 14.5 to 14.9 g/dL at final assessment, respectively. Regression analyses showed that HCT change was associated with baseline HCT and testosterone levels, while Hb change was associated with baseline Hb, HCT, and testosterone levels. In the total cohort and subgroups, HCT/Hb increased significantly at all time points (p < 0.0001, cf. baseline) with over 90% of men demonstrating increases. Linear regression showed that the ratio of HCT change/Hb change (i.e., difference between HCT at the various time points and baseline value/difference between Hb at the various time points and baseline value), following TTh at each time point was higher than the baseline HCT/Hb ratio. Conclusion: HCT increase was greater than we anticipated from the established HCT/Hb of 3. We speculate that increased erythrocyte life span with associated higher Hb loss via vesiculation could account for our observation. This could have a bearing when using HbA1c as an indicator in men with adult-onset TD on TTh. No funding was received for this article.

Background: Klinefelter's syndrome (KS) is characterized by extra X chromosomes and features of primary hypogonadism including osteopenia and osteoporosis. Testosterone therapy (TTh) is widely used to treat men with KS and low serum testosterone/hypogonadal symptoms, though studies on its efficacy in improving bone density show varied outcomes. Materials and Methods: We studied the effects of TTh, bisphosphonates, and vitamin D/calcium in 38 men with KS and low testosterone, hypogonadal symptoms, and T-scores consistent with osteoporosis. Our aim was to investigate at the end of follow-up (median: 87 months, range: 27-147 months), associations between age, baseline total testosterone, and T-scores, and change in T-scores after treatment. Results: At final assessment, all men had T-score values outside the osteoporotic range (-1.1 standard deviation [SD],-1.8 SD). Baseline age but not median baseline testosterone appeared associated with change in T-score and T-score at final assessment. All men had dual-energy X-ray absorptiometry every 6 months and demonstrated continued improvement in T-scores after 3 months and up to 72 months. Baseline age and T-scores (stratified by median) were associated with change in T-score at final assessment. Compared with men ≥51 years, those aged

Background The nature and extent of inflammation seen in multiple sclerosis (MS) varies throughout the course of the disease. Changes seen in CD4+ T-helper cells in relapsing–remitting (RR) MS and secondary progressive (SP) MS might differ qualitatively and/or quantitatively. Objective The objective of this paper is to study the frequencies of all major CD4+ T-helper subtypes – Th17, Th22 and Th1 lineage cells – in relapse, remission and secondary progression alongside CCR6 status, a chemokine receptor involved in migration of these cells into the central nervous system. Methods We compared 100 patients (50 RRMS and 50 SPMS) and 50 healthy volunteers and performed flow cytometric analysis of lymphocytes in blood samples. Results We demonstrated raised frequencies of various cell types along the Th17 axis; Th17, Th17.1 (IL-17+ interferon gamma+) and dual IL-17+ IL-22+ cells in RRMS. Th22 and CCR6+ Th1 cells (nonclassical Th1) were also increased in RRMS. All these cells were CCR6+. Only Th17 frequencies were elevated in SPMS. Conclusions Increased frequencies of Th17 cells are implicated both in RRMS and SPMS. The CCR6 pathway includes Th17, Th22 and Th1 nonclassical cells, of which Th22 and Th1 cells represent the greatest subsets in MS.

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.

BACKGROUND:\ud Serum sex hormone-binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM).\ud \ud OBJECTIVES:\ud To confirm the association of serum sex hormone-binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration.\ud \ud MATERIALS AND METHODS:\ud We studied 364 men (median age: 66 years) with T2DM over a median follow-up of 4.3 years using the Cox regression to study associations between sex hormone-binding globulin, age, total testosterone, and mortality.\ud \ud RESULTS:\ud Mortality was significantly and independently associated with sex hormone-binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone-binding globulin dichotomized by median values, the association of sex hormone-binding globulin with mortality was age-dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men ≤66 years/SHBG ≤ 35 nmol/L was 3.23%). In men >66 years, SHBG ≤ 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men ≤66 years, there was no significant difference between those with sex hormone-binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG ≤ 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories. Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT ≥ 12 (18.06%) and those with SHBG ≤ 35 nmol/L and TT < 12 nmol/L (13.79%).\ud \ud DISCUSSION:\ud Our data suggest sex hormone-binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone-binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone-binding globulin or low total testosterone individually.\ud \ud CONCLUSIONS:\ud Our findings are compatible with data suggesting the importance of sex hormone-binding globulin lies in mediating free testosterone levels.

No Abstract\ud \ud Keywords: Adult onset testosterone deficiency, Clinical guidelines, Laboratory performance, Testosterone therapy, Testosterone assays

INTRODUCTION Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded. AIM To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh. METHODS We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered. MAIN OUTCOME MEASURES The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit. RESULTS Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds. CONCLUSIONS TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups. Konig CS, Balabani S, Hackett GI, et al. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sex Med Rev 2019;XX:XXX-XXX.

The age-related fall in male testosterone levels can have clinical consequences. The concentration of serum-free testosterone, the putative bioactive moiety, is mediated by carrier proteins, especially SHBG.The aim of this study was to consider the nature of hormone binding to carriers with new insights into determining calculated free testosterone levels and review how SHBG and testosterone influence age-related mortality.Where possible, we focused on recent literature describing binding of testosterone to carrier proteins or, associations among age, SHBG, testosterone, and mortality. We then used logistic regression to study the impact of SHBG and total testosterone on age-related mortality in men with type 2 diabetes mellitus (T2DM).The association between mortality and age and SHBG and/or total testosterone was determined in a cohort of 364 men with T2DM leading to a graphical display of the impact of SHBG/testosterone levels on age-related mortality.Low total testosterone and high SHBG are independently associated with increased all-cause mortality. Our analyses support these findings showing that men with T2DM and a combination of total testosterone12 nmol/L and SHBG35nmol/L (odds ratio [OR]: 3.05; 95% CI: 1.43-6.53; P = .004) demonstrated an increased risk of mortality, independent of age (OR: 1.08; 95% CI: 1.06-1.11; P.001). We graphically demonstrated that the risk combination altered the relationship between age and mortality.Until free testosterone is precisely, accurately, and conveniently measured, calculated values may provide useful even if somewhat inaccurate estimates. We also suggest that SHBG and testosterone assays are standardized to allow establishment of diagnostic and treatment thresholds. Although it is possible that the association in men with T2DM, among the combination of SHBG and total testosterone and age-related mortality is driven by free hormone levels, it is so far, unproven. Sudarshan Ramachandran, Geoffrey I. Hackett, Richard C. Strange, et al. Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes. Sex Med Rev 2019;7:669-678.

SummaryBackground Low testosterone levels occur in over 40% of men with type 2 diabetes mellitus (T2DM) and have been associated with increased mortality. Testosterone replacement together with statins and phosphodiesterase 5 inhibitors (PDE5I) are widely used in men with T2DM. Purpose To determine the impact of testosterone and testosterone replacement therapy (TRT) on mortality and assess the independence of this effect by adjusting statistical models for statin and PDE5I use. Methods We studied 857 men with T2DM screened from five primary care practices during April 2007–April 2009. Of the 857 men, 175/637 men with serum total testosterone ≤ 12 nmol/l or free testosterone (FT) ≤ 0.25 nmol/l received TU for a mean of 3.8 ± 1.2 (SD) years. PDE5I and statins were prescribed to 175/857 and 662/857 men respectively. All-cause mortality was the primary end-point. Cox regression models were used to compare survival in the three testosterone level/treatment groups, the analysis adjusted for age, statin and PDE5I use, BMI, blood pressure and lipids. Results Compared with the Low T/untreated group, mortality in the Normal T/untreated (HR: 0.62, CI: 0.41–0.94) or Low T/treated (HR: 0.38, CI: 0.16–0.90) groups was significantly reduced. PDE5I use was significantly associated with reduced mortality (HR: 0.21, CI: 0.066–0.68). After repeating the Cox regression in the 682 men not given a PDE5I, mortality in the Normal T/untreated and Low T/treated groups was significantly lower than that in the reference Low T/untreated group. Mortality in the PDE5I/treated was significantly reduced compared with the PDE5I/untreated group (OR: 0.06, CI: 0.009–0.47). Conclusions Testosterone replacement therapy is independently associated with reduced mortality in men with T2DM. PDE5I use, included as a confounding factor, was associated with decreased mortality in all patients and, those not on TRT, suggesting independence of effect. The impact of PDE5I treatment on mortality (both HR and OR < 0.25) needs confirmation by independent studies.

Objective\ud To further characterise the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM). We aimed to determine firstly, if changes in cardiovascular disease (CVD) risk factors following TRT play a role, secondly whether the reduction in mortality is lost following TRT discontinuation and finally, the presence of subgroups where benefit may be greater.\ud \ud Materials and Methods\ud We studied 857 men with T2DM, screened for the BLAST RCT, over 3.8 years follow‐up. The men were stratified by testosterone levels; Group 1: total testosterone (TT) >12nmol/l and free testosterone (FT) >0.25nmol/l, Group 2: TT ≤12nmol/l or FT ≤0.25nmol/l and by TRT (Group 2 further stratified into those not on TRT (Group 2a) and 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.\ud \ud Results\ud TRT was not associated with improvements in the CVD risk factors. The CVD risk factors (baseline and changes during follow‐up) were not associated with mortality. Men in Group 1 and Group 2b demonstrated lower mortality (reference: Group 2a) even with CVD risk factors included in regression models. Mortality was lower in the Group 2b1 (6.2%) and Group 2b2 men (0%) compared to Group 2a men (16.9%). The lower mortality associated with Group 1 and Group 2b was primarily in older (>64.6 years) and less overweight (≤93.8Kg) men.\ud \ud Conclusions\ud 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.

The use of reference ranges is well established in medical practice and research. Classically, a range would be derived from the local healthy population and matched in age, gender, and other characteristics to the patients under investigation. However, recruiting suitable controls is problematic and the derivation of the range by excluding 2.5% at each end of the distribution results in 5% of the values being arbitrarily discarded. Thus, the traditional reference range is derived using statistical and not clinical principles. While these considerations are recognized by clinicians, it is often not realized that the application of whole population derived reference ranges to complex pathologies that comprise patient subgroups may be problematic. Such subgroups may be identified by phenotypes including genetic etiology, variations in exposure to a causative agent, and tumor site. In this review, we provide examples of how subgroups can be identified in diverse pathologies and how better management can be achieved using evidence-based action limits rather than reference ranges. We give examples from our clinical experience of problems arising from using the wrong reference ranges for the clinical situation. Identifying subgroups will often enable clinicians to derive specific action limits for treatment that will lead to customized management and researchers a route into the study of complex pathologies.

Introduction: Ischemic heart disease (IHD) has been associated with lower peak systolic velocity (PSV) on penile Doppler measurements [1]. This study establishes whether carotid ultrasound (US) PSV was associated with computational fluid dynamics (CFD) outputs, which in turn may contribute to IHD pathogenesis. Methods: A sample of 57 subjects (with IHD: 27, without IHD: 30) had US velocity profiles (left- common carotid artery) determined between 10–12 equi-spaced points. Bezier curve fitting was used to fit the profile through the measured velocity points for a normalised diameter. PSV was correlated against CFD results such as wall shear stress (WSS) [2]. Difference in PSV between individuals with/without IHD was studied via t-test. Linear regression was carried out to see if peak systolic velocity was associated with CFD outputs. Any significant associations were analysed within stratified groups (with/without IHD). Results: PSV was significantly lower (p = 0.042) in subjects with IHD (with IHD: 53.6±17.3 cm/s, without IHD: 62.8±16.1 cm/s). PSV was associated with carotid bulb average pressure drop (p < 0.001), area of average bulb WSS (

Although testosterone replacement treatment (TRT) can improve sexual function in many hypogonadal (HG) men with type 2 diabetes (T2DM), some show either no improvement or only in a limited number of domains. Indeed, it is often difficult for the clinician to offer an indication of the likely efficacy of TRT as little data exist on the proportion of TRT-treated men who will demonstrate improvement in domains such as sexual desire (SxD) and erectile function (EF). We describe in men with T2DM: firstly, the likelihood of improved sexual desire (SxD) and erectile function (EF) following TRT at various time points, and secondly, if probability of SxD change predicted likelihood of subsequent EF change. During a 30-week randomized controlled study of testosterone undecanoate (TU), 199 T2DM men with HG (189 men completing) identified from primary care registers (placebo (P): 107, TU: 92) were stratified using baseline total testosterone (TT)/free testosterone (FT) into Mild (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and Severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L) and placebo (P)- and TU-treated groups. Associations between TU, SxD and EF were investigated using chi-square and logistic regression analysis. The proportion of men with improved SxD after 6 weeks and EF improvement after 30 weeks was significantly higher following TU treatment compared to P, this particularly evident in Severe HG men. Changes in SxD and EF were significantly associated in all groups. Logistic regression showed that SxD change at 6 weeks predicted of EF change after 30 weeks. Our study confirms TRT leads to changes in SxD and EF at different time points and suggests SxD and EF changes are related. SxD change after 6 weeks predicting EF change at 30 weeks is possibly a useful clinical finding.

Background While many factors have been examined, male gender and older age at multiple sclerosis onset are among few variables consistently associated with increased disability. Interestingly, the association between onset age and disability may not be linear with some data suggesting a faster rate of accumulation of disability in patients aged more than 30 years at onset. Objective Explore the relationship between onset age and disability. Methods We studied 500 MS patients grouped by cut-offs in onset age. Disability was assessed using Multiple Sclerosis Severity Scale (MSSS) and, a model based on time to reach an Extended Disability Severity Score (EDSS) (progression model). Data were analyzed using linear and logistic regression. Results The association between disability (assessed by both MSSS and the progression model) and onset age was different in patients whose MS onset occurred after an age band of 30–35 years. Before this age range, changing age was not associated with changes in disability while during and after this age range, disability was increased. Conclusion We found a significant change in the relationship between disability and onset age after about 31 years supporting the idea that while onset age does not define a sharp cut-off, it can help define subgroups of patients with differing rates of accumulation of disability.

AIM To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Purpose of the study Statins and ezetimibe reduce low-density lipoprotein cholesterol (LDL-c) and cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-c by 50%–70% and might be useful in refractory patients. The National Institute for Health and Care Excellence (NICE) technology appraisal guidance (TAG) recommends use of these drugs in secondary prevention and familial hypercholesterolaemia (FH) at differing LDL-c thresholds. We have estimated the proportion of patients in whom this third-line drug might be useful. Study design We used data from a lipid-lowering audit programme to study 72 with FH and/or CVD of 271 patients referred over 12 months who failed to achieve target total cholesterol (TC) and LDL-c levels. All 72 patients were treated with ezetimibe, and 69 cases also received statins. We used LDL-c thresholds 1.5–5.5 mmol/L to estimate how many of these refractory patients could benefit from PCSK9 inhibitors. Results In 72 patients, TC and LDL-c targets were not met by 64 and 53 patients, respectively. We judged using the NICE TAG that only one patient (1.4% ezetimibe requiring and 0.4% total referrals) required a PCSK9 inhibitor. Conclusions We determined that the proportion of patients eligible for a PCSK9 inhibitor at various TC and LDL-c levels is modest. This may reflect the use of all available statins in UK lipid clinics often at non-daily frequency. We suggest that cost-effective use of PCSK9 inhibitors requires prescribing being restricted to clinicians working in specialised lipid clinics.

No abstract

Background: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. Objective: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. Methods: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). Results: CG294 with GG294 genotypes (rs1805009) (coefficient = —1.44, 95% CI —2.30, —0.59, mean MSSS ± SD = 4.33 ± 2.87) and AC84 (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62 ± 2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types 1/2 and 3/4, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. Conclusions: Multiple Sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type.

Familial clustering of autoimmune disease is well recognized and raises the possibility that some susceptibility genes may predispose to autoimmunity in general. In light of this observation, it might be expected that some of the variants of established relevance in one autoimmune disease may also be relevant in other related conditions. On the basis of this hypothesis, we tested seven single nucleotide polymorphisms (SNPs) that are known to be associated with type I diabetes in a large multiple sclerosis data set consisting of 2369 trio families, 5737 cases and 10 296 unrelated controls. Two of these seven SNPs showed evidence of association with multiple sclerosis; that is rs12708716 from the CLEC16A gene (P=1.6 x 10(-16)) and rs763361 from the CD226 gene (P=5.4 x 10(-8)). These findings thereby identify two additional multiple sclerosis susceptibility genes and lend support to the notion of autoimmune susceptibility genes. ispartof: Genes and immunity vol:10 issue:1 pages:11-14 ispartof: location:England status: published

Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more years, we studied the association of VDR single nucleotide polymorphisms (A/G1229, C/G3444, G/A3944, CC20965, CC30056, F/f30875, C/T48200, T/t65013) with outcome or disability. ff30875 frequency was lower in cases with EDSS ≥ 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% CI = 0.20–0.70). The association of ff30875 with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% CI = 0.14–1.34) and high exposure (odds ratio = 0.34, 95% CI = 0.16–0.73).

Expression of the glutathione S-transferase, GSTP1, is associated with phase 1 detoxification of the products of oxidative stress. Recently, GSTP1 expression has been implicated in the regulation of cell proliferation and apoptosis through direct interaction with the c-Jun N-terminal kinase, (JNK). GSTP1 is polymorphic and allelic variants have been associated with disease susceptibility and clinical outcome. However, the influence of GSTP1 alleles on proliferation and apoptosis has not been studied previously. To investigate this, we have examined the effects of inducible expression of wild-type GSTP1*A and mutant GSTP1*C haplotypes on cell proliferation and apoptosis in NIH3T3 fibroblasts. Cells expressing GSTP1*A displayed increased doubling times and a delayed G1-S phase transition compared with cells expressing GSTP1*C. Both GSTP1*A and GSTP1*C haplotypes protected cells from undergoing apoptosis when exposed to oxidative stress. However, analysis of JNK status revealed that only GSTP1*C expression led to a reduction in JNK activity compared with GSTP1*A-expressing cells and non-induced cells. We further examined the effect of GSTP1 alleles on colony-forming efficiency (CFE) in soft agar following exposure to oxidative stress and found that GSTP1*A-expressing clones had increased CFE compared with non-induced and GSTP1*C-expressing clones. Our data suggest that GSTP1 alleles have differential effects on proliferation and apoptosis; GSTP1*A reduces cellular proliferation and protects against apoptosis through a JNK-independent mechanism. In contrast, GSTP1*C does not influence cellular proliferation but protects cells from apoptosis through JNK-mediated mechanisms.

Vitamin D receptor (VDR) polymorphisms are prostate cancer risk candidates. We determined if SNPs in haplotype block sub-regions C2 (SNPs C2-1, G/C(3436), C2-2, A/G(3944)) or C1 (C1-1, C/T(20965), C1-2, C/T(30056)) are associated with risk in an ultraviolet radiation (UVR)-dependent manner. In men with very low exposure, SNPs in both sub-regions were associated with risk. Various haplotypes in haplotype block C including G(3436)-A(3944)-C(20965)-C(30056), (G or C)-A-C-C and G-A-(C or T)-C were significantly associated with increased risk (odds ratios between 1.95 and 2.37). These findings suggest various block C SNPs are associated with prostate cancer risk via a mechanism involving exposure to sunlight.

Ultraviolet radiation exposure increases basal cell carcinoma (BCC) risk, but may be protective against prostate cancer. We attempted to identify exposure patterns that confer reduced prostate cancer risk without increasing that of BCC. We used a questionnaire to assess exposure in 528 prostate cancer patients and 442 men with basal cell carcinoma, using 365 benign prostatic hypertrophy patients as controls. Skin type 1 (odds ratio (OR)=0.47, 95% CI=0.26-0.86), childhood sunburning (OR=0.38, 95% CI=0.26-0.57), occasional/frequent sunbathing (OR=0.21, 95% CI=0.14-0.31), lifetime weekday (OR=0.85, 95% CI=0.80-0.91) and weekend exposure (OR=0.79, 95% CI=0.73-0.86) were associated with reduced prostate cancer risk. Skin type 1 (OR=4.00, 95% CI=2.16-7.41), childhood sunburning (OR=1.91, 95% CI=1.36-2.68), regular foreign holidays (OR=6.91, 95% CI=5.00-9.55) and weekend (OR=1.17, 95% CI=1.08-1.27) but not weekday exposure were linked with increased BCC risk. Combinations of one or two parameters were associated with a progressive decrease in the ORs for prostate cancer risk (OR=0.54-0.25) with correspondingly increased BCC risk (OR=1.60-2.54). Our data do not define exposure patterns that reduce prostate cancer risk without increasing BCC risk.

Recent studies suggest ultraviolet radiation (UVR)/vitamin D is protective against the development of multiple sclerosis (MS). We determined if outcome in MS is associated with the surrogate for host pigmentation, skin type, and parameters of UVR exposure. We used a validated questionnaire to determine skin type and UVR exposure during childhood (0-16 years), and early adult life (17-40 years), in 448 Caucasians with MS. Outcome was assessed using the Kurtzke Expanded Disability Status Score (EDSS) and Multiple Sclerosis Severity Scale (MSSS). We studied the association of skin type and exposure with dichotomized values of EDSS (< and ≥6) and MSSS (continuous variable) using logistic and linear regression analyses, respectively. Sex, onset age and MS duration were significantly associated with outcome in all patients. In 169 females with established disease (≥10 years), sun sensitive skin types 1 and 2 were associated with reduced risk of EDSS ≥6 (odds ratio =0.50; 95% CI = 0.26-0.97), and higher MSSS values (coefficient = -0.86; 95% CI = -1.67 to -0.05). Parameters of UVR exposure were not significantly associated with outcome. These preliminary data show an association between skin type and disability in female MS patients. They are compatible with independent studies suggesting that exposure mediates MS pathogenesis via vitamin D. Further studies are required to properly assess these potentially important findings. Multiple Sclerosis 2007; 13: 369-375. http://msj.sagepub.com

The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.

Despite the well-recognised role of vitamin D in a wide range of physiological processes, hypovitaminosis is common worldwide (prevalence 30%-50%) presumably arising from inadequate exposure to ultraviolet radiation and insufficient consumption. While generally not at the very low levels associated with rickets, hypovitaminosis D has been implicated in various very different, pathophysiological processes. These include putative effects on the pathogenesis of neoplastic change, inflammatory and demyelinating conditions, cardiovascular disease (CVD) and diabetes. This review focuses on the association between hypovitaminosis D and the metabolic syndrome as well as its component characteristics which are central obesity, glucose homeostasis, insulin resistance, hypertension and atherogenic dyslipidaemia. We also consider the effects of hypovitaminosis D on outcomes associated with the metabolic syndrome such as CVD, diabetes and non-alcoholic fatty liver disease. We structure this review into 3 distinct sections; the metabolic syndrome, vitamin D biochemistry and the putative association between hypovitaminosis D, the metabolic syndrome and cardiovascular risk.

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.

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (70 versusor =70 years at diagnosis), in the patients diagnosed70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Background Patients with basal cell carcinoma (BCC) frequently develop further tumors during follow-up. Objective We sought to elucidate the relative effects of pattern of ultraviolet radiation exposure, and site and histologic type of the first tumor, on the rate of increase in BCC numbers. Methods We used negative binomial regression analysis to study the association of selected variables on the rate of increase in BCC numbers in 266 Caucasian patients who first presented with a tumor on the head/neck or trunk with nodular or superficial histology. Results Patients with an initial truncal BCC with superficial histology demonstrated significantly faster increases in BCC numbers than did patients with other site and histology combinations. Conclusions These data indicate that site and histology define subsets of patients with BCC.

Summary We have examined the association of the CCND1 A/G 870 polymorphism with susceptibility and outcome in 174 German patients with oral SCC (OSCC). The CCND1 G 870 allele frequency was increased in cases (G 870 = 0.65) when compared to controls ( n = 155, G 870 = 0.54) and the distribution of CCND1 genotypes were significantly different ( p = 0.014). Using logistic regression, correcting for age, gender and tobacco consumption, an increased frequency of the CCND1 GG 870 genotype was observed in the OSCC cases ( p = 0.025, OR 3.37, 95% CI 1.61–9.80). No significant associations were observed between CCND1 A/G 870 and tumour histological factors. Our data suggests that the CCND1 GG 870 genotype is associated with increased susceptibility to OSCC. The involvement of cyclin D1 polymorphism in mechanisms of SCC development may differ in the different sub-sites of the head and neck.

Maternal factors are known to influence the heritability and expression of asthma and atopy. We report the association of maternal, paternal and proband GSTP1 genotype with lung function in 145 Caucasian children with asthma. GSTP1 Val105/Val105 and Ala114/Val114 genotypes in the child were associated with non-significant increases in lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio). Paternal genotype had no influence on lung function in the child. In contrast, maternal GSTP1 Val105/Val105 genotype was significantly associated with offspring lung function and was strongly predictive of FEV1/FVC (Val105/Val105 105.2%, Ile105/Val105 and Ile105/Ile105 97.9% p=0.006) and maternal GSTP1 Ala114/Val114 genotype was associated with significantly higher FEV1 (Ala114/Val114 109.0%, Ala114/Ala114 99.0% p=0.008), and FEV1/FVC ratios (Ala114/Val114 104.1%, Ala114/Ala114 98.2% p=0.04). The associations between maternal GSTP1 Val105/Val105 genotype and FEV1/FVC and maternal GSTP1 Ala114/Val114 genotype and FEV1 remained significant (p=0.003 and p=0.007) after correction for child and maternal atopic status, passive smoke exposure, smoking during pregnancy, individual and paternal GSTP1 genotype and was independent of transmission to the child. These data support the hypothesis that maternal GSTP1 genotype can act as a specific risk factor which has ex utero consequences for children with asthma. As a child's genotype is not independent of maternal genotype, effects seen in candidate gene studies may be due at least in part to this phenomenon.

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/A 1 5 6 ), exon 10 (c.932G>A, dbSNP1799793:g.G>A; designated G/A 3 1 2 ), and exon 23 (c.2251A>C, dbSNP13181:g.A>C; designated A/C 7 5 1 ) 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 AA 1 5 6 (odds ratio [OR]=0.61, 95% confidence interval [CI]=0.37-1.01, P=0.052) and AA 3 1 2 (OR=0.65, 95% CI=0.40-1.05, P=0.08) were linked with reduced risk. A 1 5 6 -A 3 1 2 and A 1 5 6 -A 3 1 2 -A 7 5 1 haplotype frequencies however, were significantly lower in cases than controls (OR=0.12, 95% CI=0.05-0.31, P

Loss of function of the human patched gene (PTCH) is common and critical in basal cell carcinoma (BCC) development. Indirect evidence suggests polymorphism in PTCH mediates BCC risk. We studied 659 BCC cases and 300 controls to determine if exon 2(318), 3(429), 11(1552), 12(1665), 12(1686), 14(2199) and 23(3944) and intron 9(1336-135) and 15(2560+9)PTCH variants were sufficiently common for use in case-control studies, and if selected markers were associated with risk. Intron 15(2560+9) and exon 23(3944) variants were studied further. Their genotype frequencies were not significantly different in controls and cases, though frequency of the G(2560+9)-C(3944) haplotype was lower in all cases (odds ratio=0.44, p=0.009) and those stratified by BCC site and rate of development of further tumours. This association was not mediated by the extent of UVR exposure. We confirmed the robustness of these findings by showing these associations demonstrated similar odds ratios in two groups of randomly selected cases and controls, and using the false positive report probability (FPRP) approach described by Wacholder et al. (2004). The FPRP value (0.168) was in the noteworthy category. These data, showing for the first time that PTCH polymorphism mediates susceptibility, are compatible with reports showing that PTCH haploinsufficiency influences development of BCC precursor lesions.

While sunlight is critical in basal cell carcinoma (BCC) pathogenesis the relationship between exposure and tumor site and histology is unclear. We determined if tumor site (trunk or head/neck) or histology (nodular or superficial) is determined by exposure pattern. In 66 cases with truncal and 362 patients with head/neck BCC at first presentation, average hours exposure/year, intermittency score, childhood sunburning and skin type were not significantly associated with tumor site or histology. However, often sunbathing was associated with a five-fold increased risk of truncal BCC. Average sunbathing score was significantly greater in 22 cases with truncal compared with 325 cases with head/neck nodular tumors and also in 44 cases with superficial truncal compared with superficial head/neck BCC. Thus, sunbathing determined tumor site but not histology.

Gene-environment interactions have been extensively studied in lung cancer. It is likely that several genetic polymorphisms cooperate in increasing the individual risk. Therefore, the study of gene-gene interactions might be important to identify high-susceptibility subgroups. GSEC is an initiative aimed at collecting available data sets on metabolic polymorphisms and the risks of cancer at several sites and performing pooled analyses of the original data. Authors of published papers have provided original data sets. The present paper refers to gene-gene interactions in lung cancer and considers three polymorphisms in three metabolic genes: CYP1A1, GSTM1 and GSTT1. The present analyses compare the gene gene interactions of the CYP1A1*2A, GSTM1 and GSTT1 polymorphisms from studies on lung cancer conducted in Europe and the USA between 1991 and 2000. Only Caucasians have been included. The data set includes 1466 cases and 1488 controls. The only clear-cut association was found with CYP1A1*2A. This association remained unchanged after stratification by polymorphisms in other genes (with an odds ratio [OR] of approximately 2.5), except when interaction with GSTM1 was considered. When the OR for CYP1A1*2A was stratified according to the GSTM1 genotype, the OR was increased only among the subjects who had the null (homozygous deletion) GSTM1 genotype (OR = 2.8, 95% CI = 0.9-8.4). The odds ratio for the interactive term (CYP1A1*2A by GSTM1) in logistic regression was 2.7 (95% CI = 0.5-15.3). An association between lung cancer and the homozygous CYP1A1*2A genotype is confirmed. An apparent and biologically plausible interaction is suggested between this genotype and GSTM1.

After first presentation with a basal cell carcinoma (BCC), patients demonstrate interindividual diversity in the rate of development of further BCCs (number/year of follow-up). The mechanism for this variation is unknown. In this study, we evaluated whether PTCH variants mediate this phenomenon. We used negative binomial regression analysis to identify associations between BCC numbers/year and host characteristics, parameters of exposure to ultraviolet radiation (UVR), and PTCH exon 121686 C/T, intron 152560+9 G/C, and exon 233944 C/T genotypes and haplotypes in 279 BCC cases who presented with an initial tumor on the head/neck. PTCH genotypes were not significantly associated with BCCs/year, although cases with two copies of the C1686-C3944 haplotype developed significantly fewer BCCs/year than those without this haplotype (rate ratio = 0.44; 95% CI = 0.27–0.71). Cases with one copy of T1686-T3944 developed more BCCs/year (rate ratio = 2.46; 95% CI = 1.27–3.97) than those without the haplotype. We found no significant associations between BCCs/year and the other PTCH haplotypes studied. We reexamined the association of C1686-C3944 with BCCs/year in a model that included UVR exposure parameters (sunburning in childhood, sunbathing score, intermittency of exposure between 40 and 60 years of age, exposure in hours/year) and skin type, gender, and age at first presentation. The association between C1686-C3944 and BCCs/year remained significant (rate ratio = 0.44; 95% CI = 0.26–0.73 for two copies of the haplotype). The data show that allelic variation in PTCH contributes to the rate of development of BCC. Environ. Mol. Mutagen., 2004. © 2004 Wiley-Liss, Inc.

Low sunlight exposure confers increased prostate cancer risk. In a study conducted in northern England, we investigated how combinations of exposure measures affect this risk. Recursive partitioning was used to identify combinations of exposure parameters that distinguished 453 prostate cancers from 312 benign hypertrophy patients. Sunbathing score most significantly defined cancer patients; 78.7% men with low scores (/=3.0) and 40.2% men with high scores (8.0) had cancer. These subgroups were stratified by childhood sunburning, holidays in a hot climate and skin type such that subgroups with a 13.0-fold increased risk of cancer were identified.

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 PC 20 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 PC 20 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 PC 20 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.

Recent studies have proposed that exposure to ultraviolet radiation (UVR) protects against development of some internal cancers including that in prostate. This effect may be mediated by UVR-induced cutaneous synthesis of vitamin D. It is also proposed that ability to pigment in response to UVR will influence susceptibility to prostate cancer through its effects on vitamin D synthesis. We wished to determine first, whether ability to pigment, as assessed by skin type, influences the extent of exposure to UVR, secondly, whether skin type is associated with prostate cancer susceptibility and thirdly, whether such an effect is mediated by the extent of UVR exposure. We studied 453 prostatic adenocarcinoma and 312 benign prostatic hypertrophy (BPH) patients using a validated questionnaire to assess two parameters of exposure; months of cumulative exposure per year and adult sunbathing score. We used analysis of variance to show that cancer cases with sun-sensitive skin (skin type 1) had lower cumulative exposure per year (P = 0.014) and sunbathing scores (P < 0.0001) than those with type 4, possibly because of a tendency to avoid exposure. Further, cumulative exposure per year and sunbathing score were significantly lower in cancer compared with BPH patients (P < 0.001 and P < 0.001, respectively). While the proportion of subjects with skin types 1 and 2 was lower in cancer than BPH patients, these were not significantly different (logistic regression analysis, skin type 1 versus type 4; P = 0.11). We used recursive partitioning to determine if skin type influenced susceptibility to prostate cancer in subgroups stratified by exposure. Analysis of the data showed that in men with low sunbathing scores, skin type 1 conferred protection compared with skin types 2-4 (OR = 4.78, 95% CI 3.01-8.25, P < 0.0009). These findings indicate that susceptibility to prostate cancer is in part determined by extent of exposure to UVR and that ability to pigment mediates this effect.

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

BACKGROUND The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for single head and neck cancer. In patients with multiple cancer development a cumulation of genetic risk factors can be assumed. METHODS Accordingly, we have examined genotype frequencies at GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and TNF loci, in patients with single and multiple squamous cell carcinoma (SCC) of the head and neck, and controls. RESULTS GSTT1 0 was increased in multiple SCC patients (36.8 %) compared with single SCC patients (21.2 %) and controls (22.2 %). GSTM3 AA was more frequent in the single SCC patients (76.6 %) and multiple SCC patients (82.1 %) compared with controls (66.5 %) but lacked significance. The TNF allele B3 was significantly increased in the single SCC group (B3-allele: 22.5 %, B3/B3 : 10.8 %) and showed a further cumulation in the multiple SCC group (B3 : 30.3 %, B3/B3 : 15.8 %). CONCLUSIONS Patients suffering from multiple SCC development showed a cumulation of high risk genotypes at GST and TNF gene loci. Specific genetic variations could not be determined.

Patients with a basal cell carcinomas (BCC) have an increased risk of further tumors. We studied the individual and combined impact of gender, skin type and allelic genes cytochrome P450 (CYP2D6), vitamin D receptor (VDR), tumor necrosis factor-alpha, TNF-α) on the rate of increase in BCC numbers after first presentation. Individually, male gender, skin type 1, CYP2D6 EM, VDR TT and TNF-α GG were associated with more BCC/year (rate ratio (RR) 1.20–1.36) while RR for associations of combinations of two, three and four variables were greater than in their reference categories (RR 1.32–1.90, 2.20–2.84, 3.06–5.49, respectively). The data show that different factors mediate the numbers of BCC/year in males and females and, the individual contributions of variables to risk is modest.

Basal cell carcinoma (BCC) patients demonstrate marked variation in tumour numbers and site. Previous studies also show an association between age at first BCC presentation and development of BCC on the trunk. In this study we have investigated the association between age at first presentation and the rate of development of truncal and non-truncal tumours in 747 patients with BCC. We used negative binomial regression analysis to show that increasing age at first presentation was associated with an increased rate of BCC development (rate ratio 1.01/year, 95% CI 1.01-1.02, P < 0.001). In particular, development of tumours was greater in cases aged 60.0-69.9, 70.0-79.9 and 80.0-89.9 years than in those 40.0-49.9 years (P = 0.05, 0.01 and 0.039, respectively). While few cases aged over 70 years of age first present with a truncal BCC, the numbers of BCC/year were greater than in those with a head/neck BCC. The data suggest different genetic factors mediate the appearance of BCC in patients of different ages particularly those aged above and below 60 years.

Basal cell carcinoma is the most common cancer in Caucasians and its incidence is rising. Whilst not life threatening, the tumor can cause substantial morbidity and because of long follow-up, it places a major burden on healthcare agencies worldwide. Patients with the disease demonstrate wide phenotypic diversity with respect to tumor numbers, rate of tumor appearance and site. The factors involved in patient susceptibility to basal cell carcinoma are not well understood although exposure to ultraviolet radiation in sunlight appears critical. In this review we discuss the role of environmental and genetic factors on predisposition to basal cell carcinoma and illustrate how stratification of the basal cell carcinoma cohort into high-risk subgroups is helpful in identifying factors significant in disease susceptibility.