Christiana A. Demetriou

Single-nucleotide polymorphisms in one-carbon metabolism genes, Mediterranean diet and breast cancer risk: a case-control study in the Greek-Cypriot female population

Single-nucleotide polymorphisms (SNPs) within genes of the one-carbon metabolism pathway have been shown to interact with dietary folate intake to modify breast cancer (BC) risk. Our group has previously demonstrated that the Mediterranean dietary pattern, rich in beneficial one-carbon metabolism micronutrients, protects against BC in Greek-Cypriot women. We aimed to investigate whether SNPs in the MTHFR (rs1801133 and rs1801131) and MTR (rs1805087) genes modify the effect of the Mediterranean dietary pattern on BC risk. Dietary intake data were obtained using a 32-item food-frequency questionnaire. A dietary pattern specific to the Greek-Cypriot population, which closely resembles the Mediterranean diet, was derived using principal component analysis (PCA) and used as our dietary variable. Genotyping was performed on subjects from the MASTOS study, a case–control study of BC in Cyprus, using TaqMan assays. Adjusted odds ratios (ORs) were estimated using logistic regression analyses. High adherence to the PCA-derived Mediterranean dietary pattern further reduced BC risk with increasing number of variant MTHFR 677T alleles (ORQ4vs.Q1 for 677TTxa0=xa00.37, 95xa0% CI 0.20–0.69, for 677 CTxa0=xa00.60, 95xa0% CI 0.42–0.86). Additionally, high adherence to the Mediterranean dietary pattern decreased BC risk in subjects with at least one MTR 2756A allele (ORQ4vs.Q1 for 2756AAxa0=xa00.59, 95xa0% CI 0.43–0.81, for 2756AGxa0=xa00.59, 95xa0% CI 0.39–0.91) and in subjects with the MTHFR 1298CC genotype (ORQ4vs.Q1 0.44, 95xa0% CI 0.30–0.65). Overall P-interaction values, however, were not statistically significant. Our study suggests that these MTHFR and MTR SNPs may act as effect modifiers, highlighting their biological significance in the association between Mediterranean diet, the one-carbon metabolism pathway and BC.

MnSOD and CAT polymorphisms modulate the effect of the Mediterranean diet on breast cancer risk among Greek-Cypriot women

PurposeOxidative stress arises due to a cellular imbalance in oxidants and antioxidants and/or due to an altered activity of antioxidant enzymes, caused by SNPs. Oxidative stress increases susceptibility to breast cancer (BC) risk, and we previously showed that the Mediterranean diet (MD), which is rich in antioxidants, reduces BC risk in Greek-Cypriot women. Here, we investigated the effect of MnSOD (p.Val16Ala, rs4880) and CAT (-262C>T, rs1001179) SNPs on the association between the MD and BC risk in the case–control study of BC MASTOS in Cyprus.MethodsDietary intake data were obtained using a 32-item food frequency questionnaire, from which a dietary pattern was previously derived, using principal component analysis. This pattern included high loadings of vegetables, fruit, legumes and fish, a combination that closely resembles the MD and was used as our dietary variable.ResultsHigh vegetable intake lowered BC risk in women with at least one MnSOD Val allele (ORHigh vs. Low for Val/Valxa0=xa00.56, 95xa0%xa0CI 0.35–0.88, for Val/Alaxa0=xa00.57, 95xa0% CI 0.39–0.82), or one CAT -262C allele (ORHigh vs. Low for -262CCxa0=xa00.66, 95xa0% CI 0.47–0.92, for -262CTxa0=xa00.53, 95xa0% CI 0.35–0.81). High fish intake conferred a decreased BC risk of CAT -262CC women (ORQ4 vs. Q1 0.66, 95xa0% CI 0.47–0.92) compared with the CAT -262TT women and low fish intake (ORQ2 vs. Q1 2.79, 95xa0% CI 1.08–7.17). Additionally, high fish intake reduced BC risk in MnSOD Val/Val women (ORQ4 vs. Q1 0.63, 95xa0% CI 0.40–0.98). p interaction values were, however, not statistically significant.ConclusionOur results demonstrate that the antioxidative effects of the MD against BC risk may be enhanced by the wild-type alleles of the MnSOD or CAT SNPs among Greek-Cypriot women.

The association between IgG and IgM antibodies against cardiolipin, β2-glycoprotein I and Domain I of β2-glycoprotein I with disease profile in patients with multiple sclerosis

Antiphospholipid antibodies (aPL) occur in patients with multiple sclerosis (MS) with a number of studies reporting elevated levels; their exact prevalence and pathogenic role remain unclear. Epidemiological studies associate MS with an increased risk of deep venous thromboembolism and stroke; overlapping clinical features with APS. Antibodies against the first domain - Domain I (DI) - of β2glycoprotein I (β2GPI), show the most clinical significance and evidence for pathogenicity in the antiphospholipid syndrome (APS), but have not yet been investigated in MS. Serum from a well-defined cohort of 127 MS patients and 92 healthy controls were tested for IgM and IgG antibodies against cardiolipin (CL), β2GPI and DI. Higher frequency of IgM and IgG anti-CL were found in MS patients (18.1% and 21.3%), compared to controls (1.1% in both cases, p<0.0001). We report that anti-DI antibodies were associated with MS patients, with 6.3% and 7.1% positive for IgM and IgG, respectively, compared to controls, 1.1% (p<0.05). IgM anti-CL antibodies were elevated in secondary progressive MS and primary progressive MS compared to relapse-remitting MS, (p<0.005). This study enrolled the largest number of patients with definite MS for studying the association with aPL. Although we confirmed IgM and IgG anti-CL antibodies occur in patients with MS, this is the first study that identified anti-DI antibodies in MS patients. This new finding may prove valuable and future studies are required to evaluate its role as a potential risk factor of thromboembolic phenomena in MS.

Sex-specific age association with primary DNA transfer

Practicing forensic scientists who are called to provide expert witness testimony are often asked to explain both the presence and the absence of DNA on objects that have been handled by perpetrators with bare hands. Unwashed hands, depending on what they have come in contact with previously, may become the vehicle of both primary and secondary transfer of DNA. In this study, we investigated the propensity of primary and secondary transfer of DNA from unwashed bare hands of 128 individuals onto plastic tubes. Our experiments, carried out in triplicate, have shown that DNA was not detected on all the touched tubes, secondary transfer of DNA, through unwashed hands, was small, and in the majority of cases primary DNA transfer could be distinguished from secondary DNA transfer. A statistically significant association was demonstrated between percent DNA profile deposited on plastic tubes, through unwashed hands, and the age of male individuals.

Mediterranean diet-gene interactions: a targeted metabolomics study in Greek-Cypriot women.

SCOPEnA high adherence to the Mediterranean diet (MD) was previously associated with a decreased risk of breast cancer (BC) among Greek-Cypriot women. Additionally, particular polymorphisms were shown to modulate this MD-BC association. Herein, we aimed to investigate the effect of polymorphisms-MD interactions on the levels of specific metabolites that could be related to dietary adherence or enzymatic activity, which is itself modulated by polymorphisms.nnnMETHODS AND RESULTSnGreek-Cypriot women who were BC controls and had the lowest or the highest MD adherence (vegetables, fruit, legumes, fish) as assessed by principal component analysis (n = 564) were included. Participants were previously genotyped for nine polymorphisms of the one-carbon metabolism, oxidative stress, and xenobiotic metabolism. The serum levels of 14 metabolites that are key players in the aforementioned pathways were measured by UPLC-MS/MS. ANCOVA was used to assess polymorphism-MD interactions on metabolites levels within a multivariate linear regression model. Statistically significant interactions between GSTM1 (where GST is glutathione S-transferase) deletion polymorphism and MD on flavin mononucleotide and on 5-methyltetrahydrofolate (5-MTHF) concentrations were observed. The MTHFR rs1801133 interacted significantly with MD on 5-MTHF concentration.nnnCONCLUSIONnSerum levels of flavin mononucleotide and 5-MTHF were shown to be influenced by interactions between GSTM1 deletion or MTHFR (rs1801133) polymorphisms and a dietary pattern, characteristic of MD.

The synergistic effect between the Mediterranean diet and GSTP1 or NAT2 SNPs decreases breast cancer risk in Greek-Cypriot women

PurposeXenobiotic metabolism is related to the interplay between diet and breast cancer (BC) risk. This involves detoxification enzymes, which are polymorphic and metabolise various dietary metabolites. An important characteristic of this pathway is that chemoprotective micronutrients can act not only as substrates but also as inducers for these enzymes. We investigated whether functional GSTP1 (p.Ile105Val-rs1695), NAT2 (590G>A-rs1799930) SNPs and GSTM1 and GSTT1 deletion polymorphisms could modulate the effect of the Mediterranean diet (MD) on BC risk, in Greek-Cypriot women.MethodsGenotyping was performed on women from the MASTOS case–control study of BC in Cyprus. A 32-item food-frequency questionnaire was used to obtain dietary intake information. A dietary pattern, which closely resembles the MD (high loadings of vegetables, fruit, legumes and fish), was previously derived with principal component analysis and was used as our dietary variable.ResultsGSTT1 null genotype increased BC risk compared with the homozygous non-null GSTT1 genotype (OR 1.21, 95xa0% CI 1.01–1.45). Increasing adherence to the MD reduced BC risk in women with at least one GSTP1 Ile allele (OR for Ile/Ilexa0=xa00.84, 95xa0% CI 0.74–0.95, for Ile/Valxa0=xa00.73, 95xa0% CI 0.62–0.85) or one NAT2 590G allele (OR for 590 GGxa0=xa00.73, 95xa0% CI 0.63–0.83, for 590 GAxa0=xa00.81, 95xa0% CI 0.70–0.94). p interaction values were not, however, statistically significant.ConclusionThe homozygous null GSTT1 genotype could be a risk allele for BC among Greek-Cypriot women. The anticarcinogenic effects of the high adherence to MD against BC risk could also be further enhanced when combined with the wild-type alleles of the detoxification GSTP1 or NAT2 SNPs.

Monitoring opioid and benzodiazepine use and abuse: Is oral fluid or urine the preferred specimen type?

BACKGROUNDnOral fluid (OF) has become an increasingly popular matrix to assess compliance in pain management and addiction settings as it reduces the likelihood of adulteration. However, drug concentrations and windows of detection are not as well studied in OF as in urine (UR). We compared the clinical utility and analytical performance of OF and UR as matrices for detecting common benzodiazepines and opioids.nnnMETHODSnOF and UR concentrations of 5 benzodiazepines and 7 opioids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 263 paired OF and UR specimens. UR creatinine was measured and prescription medications were reviewed.nnnRESULTSnThe benzodiazepines 7-aminoclonazepam, lorazepam, and oxazepam exhibited statistically higher detection rates in UR. For opioids, 6-AM was statistically more likely to be detected in OF, while hydromorphone and oxymorphone were statistically more likely to be detected in UR. Chemical properties including glucuronidation explain preferential detection in each matrix, not UR creatinine nor prescription status.nnnCONCLUSIONnWe found that OF is the preferred matrix for 6-AM, while UR is preferred for 7-aminoclonazepam, lorazepam, oxazepam, hydromorphone, and oxymorphone. However, OF should be considered if the risk of adulteration is high and use and/or misuse of benzodiazepines, hydromorphone, and oxymorphone is low.

The Mediterranean Diet and Breast Cancer Risk

Abstract There is ample evidence that the Mediterranean diet reduces breast cancer risk, despite the fact that evidence across studies and populations has not been consistent. The protective effect of the Mediterranean diet is in line with the fact that some of its key components, such as fruit, vegetables, folate, and olive oil, have also been shown to have beneficial effects with regard to breast carcinogenesis. The mechanisms through which these components are hypothesized to exert their protective effects include epigenetics and more specifically DNA methylation; antioxidant functions; biological response modification; and antiestrogenic, antiproliferative, and antiangiogenic activities. Additionally, nutrigenetics and metabolomics studies on the association between Mediterranean diet adherence and breast cancer further support the protective effects of this dietary pattern. Further research to investigate the effects of intensity and timing of exposure and to elucidate the mechanistic pathways involved in the relationship is essential. The answers to these questions will provide biomarkers for prevention and early detection and targets for therapy, establishing the causality of the association and supporting adherence to the Mediterranean diet as a prevention strategy for breast cancer.

Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective

Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis.

Epidemiology of Huntington Disease in Cyprus: A 20‐Year Retrospective Study

Huntington disease (HD) is most prevalent among populations of western European descent and isolated populations where founder effects may operate. The aim of this study was to examine the epidemiology of HD in Cyprus, an island in southern Europe with extensive western European colonization in the past. All registered HD patients in the Cyprus, since 1994, were included. Detailed pedigrees and clinical information were recorded and maps, showing the geographic distribution of HD, were constructed. Requests for genetic testing were also examined. The project identified 58 clinically manifested cases of HD belonging to 19 families. The 16 families of Cypriot origin were concentrated in a confined geographical cluster in southeast Cyprus. In 2015, prevalence of symptomatic HD was 4.64/100u2009000 population, while incidence was 0.12/100u2009000 person‐years. Prevalence displayed a marked increase during the past 20u2009years. Disease characteristics of HD patients were similar to those reported in western European populations. Lastly, the uptake of predictive and/or prenatal testing was limited. HD disease characteristics, incidence and prevalence in Cyprus were comparable to western European populations. Together with the geographical clustering observed, these results support the possibility for a relatively recent founder effect of HD in Cyprus, potentially of western European origin.