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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. [ABSTRACT FROM AUTHOR]

The article looks at research which examined the association between vitamin D receptor (VDR) polymorphisms and the risk of various cancers. The article discusses the structure of the VDR gene, single nucleotide polymorphisms, studies examining melanoma and prostate cancer, gene-environment interactions, and linkage disequilibrium patterns. According to the article, the potential benefits of exposure to ultraviolet light need to be evaluated against the risks for skin cancers from sunlight exposure.

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. [ABSTRACT FROM PUBLISHER]

Epidemiological studies have suggested that UV exerts a protective effect on prostate cancer. Accordingly, we determined, in 210 prostate cancer cases, whether parameters of exposure, skin type and polymorphism in MC1R, VDR and TYR were associated with the outcome parameters, histological grade, clinical stage and presence of bone metastases. We used logistic regression analysis, with correction for age and metastases, stage and grade in the models, to determine if the frequencies of individual factors were different in the patient groups. The development of metastases was not associated with UV exposure parameters. Paradoxically, patients with skin type 1 were at significantly reduced risk [P = 0.027, odds ratio (OR) 0.17, 95% CI 0.03–0.82] of developing metastases compared with cases with skin type 4. MC1R Val92/Val92 and VDR ff were associated with increased risk of metastases (ORs 4.30 and 4.98, respectively). Further, cumulative exposure (P = 0.005, OR 0.85/year) and increasing proportion of outdoor occupation (P = 0.001, OR 0.84/unit) were associated with reduced risk of advanced stage tumours. Skin types, MC1R or VDR genotypes were not significantly associated with advanced stage. None of the exposure parameters, skin types or genotypes were associated with tumour grade. While MC1R Val92/Val92 and VDR ff were only associated with bone metastases, TYR genotypes were associated with each of the outcome parameters. Thus, in logistic regression models that included age, but not advanced stage and high grade histology, TYR A1A2 was significantly associated with reduced risk of metastases (P = 0.033, OR 0.41). Similarly, in models that included age but not the other outcome parameters, associations between TYR A2A2 and high-grade and advanced stage were significant (P = 0.040, OR 0.41) or approached significance (P = 0.052, OR 0.44), respectively. These data indicate for the first time that pigmentation response to UV is associated with outcome in prostate cancer. [ABSTRACT FROM PUBLISHER]

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P= 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P= 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P= 0.001) and MC1R asp294/asp294 (P= 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P= 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor. [ABSTRACT FROM PUBLISHER]

We describe studies to assess the influence of polymorphism in the human glutathione S-transferase GSTM3 gene on susceptibility to high grade astrocytoma. Immunohisto-chemical studies using a GSTM3-specific antiserum identified expression of the GSTM3 subunit in astrocytes. The relative levels of expression of GSTM1 and GSTM3 in brain cytosols were determined after resolution of these enzymes using chromatofocusing. We found no differences in the level of GSTM3 activity in individuals with GSTM1 null and those with GSTMl-positive genotypes (GSTM1 A, GSTM1 B and GSTM1 A/B). A case-control study was performed to determine if GSTM3 alone or in combination with GSTM1 or GSTT1 influenced susceptibility to high grade astrocytoma. After correction for differences in age and gender, GSTM3 AA was not significantly different in cases compared with controls. No significant interactions between GSTM3 AA and GSTM1 null were identified. The significant interaction between GSTM3 AA and GSTT1 null appeared to result from the strength of the main effect (GSTT1 null). The data show that while GSTM3 is expressed in astrocytes and contributes significantly to total GST activity in human brain, it does not appear to influence susceptibility to high grade astrocytoma. Further, unlike lung, there appears to be no relationship between the level of GSTM3 activity in brain and GSTM1 genotype. [ABSTRACT FROM PUBLISHER]

The genetic factors that mediate the pathogenesis of multiple primary cutaneous basal cell carcinomas (BCC) are largely unclear. Thus, some patients suffer many BCC (>30) and/or rapid accrual (number of tumours/year from first presentation) of further lesions. We have studied, in 827 English Caucasians, the influence of polymorphism in carcinogen-metabolizing enzymes on susceptibility to this cancer. Accordingly, we describe, first, a cross-sectional analysis of the influence of GSTM1, GSTT1, CYP2D6 and CYP1A1 genotypes on tumour numbers, and secondly, a longitudinal analysis, in 169 of these cases, of the effect of these genes on tumour accrual. We have confirmed the expected importance of age and number of lesions at presentation, and male gender and skin type as risk factors. Furthermore, the cross-sectional analysis showed CYP1A1 m1m1 (P = 0.004; rate ratio 1.242) and CYP2D6 EM (P < 0.001, rate ratio 1.266) are associated with increased numbers of BCC. The longitudinal study showed, after adjustment for age and tumour number at presentation, that GSTT1 null (P< 0.001, rate ratio 2.677) and CYP2D6 EM (P< 0.001, rate ratio 2.154) were significant determinants of accrual while CYP1A1 Ile/Ile was associated with slower accrual than the Ile/Val and Val/Val genotypes (P = 0.008, rate ratio 0.690). We believe these are the first genetic factors to be associated with tumour accrual. No significant interactions between genotypes were identified, though the combinations GSTM1 null/skin type 1 (P < 0.001, rate ratio 2.702), CYP2D6 EM/male gender (P = 0.049, rate ratio 1.279) and CYP2D6 EM/blue+green eyes (P = 0.046, rate ratio 1388) influenced tumour numbers. Previous studies indicate the importance of effective repair of UV-damaged DNA in the pathogenesis of multiple BCC; indeed the influence of GSTM1 may result from its ability to utilize 5'-hydroxymethyluracil. However, the finding that CYP2D6 and CYP1A1 influence tumour numbers and accrual indicates detoxification of unknown molecules is important and supports the view that factors other than UV are important in the pathogenesis of BCC. [ABSTRACT FROM PUBLISHER]

Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in various cancers. Accordingly, we describe a group of case-control studies carried out to identify associations between GSTT1 genotypes and susceptibility to lung, oral, gastric and colorectal cancers. The frequencies of the putatively high risk GSTT1 null genotype were not increased in the lung, oral or gastric cancer cases compared with controls but the frequency of this genotype was significantly increased (P = 0.0011, odds ratio = 1.88) in the colorectal cancer cases. No significant interactions between the GSTT1 and GSTM1 null genotypes were identified in the cancer groups studied. Indeed, no significant associations between GSTM1 genotypes and susceptibility were identified though further evidence was obtained that the protective effect of GSTM1*A and GSTM1*B is not equal. The data complement studies showing that GSTT1 null is associated with an increased susceptibility to total ulcerative colitis and suggests that this enzyme is important in the detoxification of unidentified xenobiotics in the large intestine. [ABSTRACT FROM PUBLISHER]

The factors that determine progression of cervical intraepithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is a risk factor, suggesting polymorphism at loci that encode carcinogenmetabolizing enzymes such as glutathione S-transferase (GSTT1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CDS, high-grade CIN and SCC. The control group comprised women with normal cervical pathology suffering menorrhagia. We found the frequency of GSTT1 null in the control and case groups was not significantly different, though frequency distributions of combinations of the genotype with smoking in mutually exclusive groups in the high-grade CIN group and the other case groups were significantly different Interactive effects of GSTT1 null with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantly different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different However, inspection of our data does not indicate that GSTT1 null is a major factor mediating risk. Thus, comparison of χ values for the differences between frequency distributions in high-grade CIN and other groups shows that values for combinations of GSTT1 null with other factors are lower than those for equivalent combinations with smoking and CYP2D6 EM. Interestingly, the combination GSTT1 null/GSTM1 null did not appear to influence susceptibility to CIN or SCC. [ABSTRACT FROM PUBLISHER]

The frequency of the GSTM1 0 polymorphism at the glutathione S-transferase M1 locus has been determined in controls and patients with pituitary adenomas by using the polymerase chain reaction to amplify genomic DNA in the exon 4–5 region of the gene. The frequency of the genotype in patients with prolactinomas, non-functional adenomas, corticotrophinomas and somatotrophinomas varied between 52–67% compared with 44% in the controls. In the patients with prolactinomas the frequency of the genotype (67%) was significantly greater than in controls with odds ratio analysis indicating that GSTM1 0 individuals have a 2.56-fold greater risk of developing this adenoma. [ABSTRACT FROM PUBLISHER]

The suggestion that individuals with the GST1 0 phenotype have a greater susceptibility to carcinogens than those with other GST1 phenotypes has been examined by using a starch gel zymogram approach to compare the frequency of this phenotype in control subjects and a group of patients with adenocarcinoma of stomach and colon. A significantly greater proportion of the patients with adenocarcinoma demonstrated the null phenotype, odds ratio analysis indicating that individuals with this polymorphic variant have an ˜ 3-fold greater risk of developing these cancers. [ABSTRACT FROM PUBLISHER]

We describe studies to determine if susceptibility to pituitary tumours is associated with the putatively high risk GSTM1 null and CYP2D6 EM genotypes. Frequency distributions of these genotypes were similar in cases and controls though the frequency of CYP2D6 PM and GSTM1 B tended to be lower ( = 0.072 and = 0.095 respectively) in the tumour group. Immunopositivity for p53 was found in 18/97 tumours. In these samples GSTM1 null (39%) and CYP2D6 EM (56%) frequencies were not different to those in controls. The frequencies of CYP2D6 PM and GSTM1 B in the p53 immunonegative tumours tended to be lower ( = 0.055 and = 0.1185 respectively) than in controls. Mutations in and were studied using the polymerase chain reaction and allele specific oligonucleotide analysis. Eight of 19 somatotrophinomas demonstrated mutations in ; frequencies of GSTM1 null and CYP2D6 EM were similar to controls. No mutations were identified in 55-tumour studies. The data indicate the GSTM1 null and CYP2D6 EM genotypes are not associated with altered expression of p53 or, mutation of and in these adenomas and, suggest the CYP2D6 PM genotype is associated with a reduced risk of pituitary adenomas and, that confers greater protection than . [ABSTRACT FROM PUBLISHER]