Lessons learned - resolving the enigma of genetic factors in IBS

IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi) genetic research and provides a vision on how to address and improve (epi) genetic approaches in this complex disorder in the future.This is the peer reviewed version of the paper: Gazouli, M., Wouters, M. M., Kapur-Pojskić, L., Bengtson, M.-B., Friedman, E., Nikčević, G., Demetriou, C. A., Mulak, A., Santos, J., & Niesler, B. (2016). Lessons learned—Resolving the enigma of genetic factors in IBS. Nature Reviews Gastroenterology & Hepatology, 13(2), 77–87. [https://doi.org/10.1038/nrgastro.2015.206]Published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/977

The mediterranean dietary pattern and breast cancer risk in Greek-Cypriot women: a case-control study

Background: Diet has long been suspected to impact on breast cancer risk. In this study we evaluated whether the degree of adherence to a Mediterranean diet pattern modifies breast cancer risk amongst Greek-Cypriot women. Methods: Subjects included 935 cases and 817 controls, all participating in the MASTOS case-control study in Cyprus. The study was approved by the Cyprus National Bioethics Committee. Information on dietary intakes was collected using an interviewer administered 32-item Food Frequency Questionnaire. Information on demographic, anthropometric, lifestyle, and other confounding factors was also collected. Adherence to the Mediterranean Diet pattern was assessed using two a-priory defined diet scores. In addition, dietary patterns specific to our population were derived using Principal Component Analysis (PCA). Logistic regression models were used to assess the association between the dietary patters and breast cancer risk. Results: There was no association with breast cancer risk for either score, however, higher consumptions of vegetables, fish and olive oil, were independently associated with decreased risk. In addition, the PCA derived component which included vegetables, fruit, fish and legumes was shown to significantly reduce risk of breast cancer (ORs across quartiles of increasing levels of consumption: 0.89 95%CI: 0.65-1.22, 0.64 95%CI: 0.47-0.88, 0.67 95%CI: 0.49-0.92, P trend < 0.0001), even after adjustment for relevant confounders. Conclusions: Our results suggest that adherence to a diet pattern rich in vegetables, fish, legumes and olive oil may favorably influence the risk of breast cancer. This study is the first investigation of dietary effects on breast cancer risk in Cyprus, a country whose population has traditionally adhered to the Mediterranean diet

Methylome Analysis and Epigenetic Changes Associated with Menarcheal Age

CAD received funding from EU-Europe aid grant CRIS 2009/223–507.The EPIC cohort is supported by the Europe Against Cancer Program of the European Commission (SANCO). The individual centres also received funding from: Denmark (Danish Cancer Society); France (Ligue centre le Cancer, Institut Gustave Roussy, Mutuelle Ge´ne´rale de l’Education Nationale, and Institut National de la Sante´ et de la Recherche Me´dicale (INSERM)); Greece (Hellenic Ministry of Health, the Stavros Niarchos Foundation and the Hellenic Health Foundation); Germany (German Cancer Aid, German Cancer Research Center, and Federal Ministry of Education and Research (Grant 01-EA-9401)); Italy (Italian Association for Research on Cancer and the National Research Council); The Netherlands (Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, and Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF)); Spain (Health Research Fund (FIS) of the Spanish Ministry of Health (Exp 96/0032) and the participating regional governments and institutions); Sweden (Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Skane); and the United Kingdom (Cancer Research UK and Medical Research Council UK and Breast Cancer Campaign). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mitochondrial superclusters influence age of onset of Parkinson’s disease in a gender specific manner in the Cypriot population: A case-control study

Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD).To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD.Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup.Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined

Dietary Intake, Mediterranean Diet Adherence and Caloric Intake in Huntington’s Disease: A Review

Decades of research and experimental studies have investigated Huntington&rsquo;s disease (HD), a rare neurodegenerative disease. Similarly, several studies have investigated whether high/moderate adherence to the Mediterranean Diet and specific macro and micronutrients can decrease cognitive loss and provide a neuroprotective function to neurons. This review systematically identifies and examines studies that have investigated Mediterranean Diet adherence, micro- and macronutrients, supplementation and caloric intake in people with HD, in order to identify if dietary exposures resulted in improvement of disease symptoms, a delay in age of onset or if they contributed to an earlier age of onset in people with HD. A systematic search of PubMed, Directory of open access journal and HubMed was performed independently by two reviewers using specific search terms criteria for studies. The identified abstracts were screened and the studies were included in the review if they satisfied predetermined inclusion criteria. Reference screening of included studies was also performed. A total of 18 studies were included in the review. A few studies found that patients who had high/moderate adherence to Mediterranean Diet showed a slight improvement in their Unified Huntington&rsquo;s Disease Rating Scale and Total Functional Capacity. In addition, people with HD who had high Mediterranean Diet adherence showed an improvement in both cognitive and motor scores and had a better quality of life compared to patients who had low Mediterranean Diet adherence. Furthermore, a few studies showed that supplementation with specific nutrients, such as triheaptanoin, L-acetyl-carnitine and creatine, had no beneficial effect on the patients&rsquo; Unified Huntington&rsquo;s Disease Rating Scale score. A few studies suggest that the Mediterranean Diet may confer a motor and cognitive benefit to people with HD. Unfortunately, there was little consistency among study findings. It is important for more research to be conducted to have a better understanding of which dietary exposures are beneficial and may result delaying age of onset or disease progression in people with HD

Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

Huntington&rsquo;s disease is a rare neurodegenerative disease caused by a cytosine&ndash;adenine&ndash;guanine (CAG) trinucleotide expansion in the Huntingtin (HTT) gene. Although Huntington&rsquo;s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The CACNA1I gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified AF198444 to be common between the rewired genes and DEGs of symptomatic HD. CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1 and RBM15 between the DEGs of pre-symptomatic and DEGs of symptomatic HD and CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2 and Y16709 between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-&beta;) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca2+) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca2+, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset

Lifestyle habits of adults during the COVID-19 pandemic lockdown in Cyprus: evidence from a cross-sectional study

Background: The COVID-19 pandemic and the widespread adoption of virus control measures have inevitably disrupted efforts to address lifestyle risk factors for non-communicable diseases (NCD). This study aimed to explore the effects of COVID-19 lockdown on all lifestyle medicine pillars, namely diet, physical activity, sleep, stress, social support and use of risky substances. Methods: This was a cross-sectional study on a convenient sample of adults who resided in Cyprus during the Spring 2020 lockdown. Participants completed an anonymous online questionnaire comprised of six validated tools regarding the following lifestyle behaviours before and during lockdown: adherence to the Mediterranean diet, physical activity, stress and social support levels, sleep pattern and use of risky substances such as smoking and alcohol. Paired before and during lockdown comparisons for each lifestyle pillar were undertaken using Wilcoxon Signed-Rank test and Bowker symmetry Test where response was numerical (non-parametric data) and categorical respectively. Furthermore, stratified analyses for sociodemographic characteristics were performed. Results: Out of 745 participants, 74% were female and median age was 39 years. Overall participants reported significantly higher perceived stress score (22 v 25, p < 0.01), lower social support score (71 v 68, p < 0.001), and worse sleep quality score (4 v 5, p < 0.01) during lockdown. Mediterranean diet (MD) adherence was moderate and increased significantly only in those practicing religious fasting (score of 6 v 7, p < 0.01). Total minutes spent sitting increased (120 v 180, p < 0.01) although overall physical activity score did not significantly change. Smoking intensity increased during lockdown whilst frequency of alcohol consumption decreased (ptrend = 0.03 and < 0.01, respectively). Conclusion: Various lifestyle factors were adversely affected by the COVID-19 lockdown in Cyprus. Evidence from this study supports development of holistic lifestyle interventions during and following the pandemic to reduce short and long-term NCD risks by building on lifestyle behaviour strengths and addressing longstanding and emerging gaps and needs

Social inequality in obesity in an Eastern Mediterranean population: evidence from a national health survey in Cyprus

Background. We aimed to explore socioeconomic factors associated with obesity among adults and to investigate social inequality in obesity prevalence in Cyprus. Study design. Cross-sectional study Methods. We conducted a survey among 3,021 Greek-Cypriots aged 25-64 years, collecting self-reported demographics, health behaviors, socioeconomic characteristics and anthropometric measurements. We performed univariable and multivariable (adjusting for demographics and health behaviors) sex-specific Poisson’s regression with robust variance, reporting adjusted prevalence ratios (PRs) and 95% confidence intervals. Results. The prevalence of obesity was 22% among males and 17% among females. According to univariable analyses, higher obesity prevalence was associated with increased age, decreased physical activity and decreased alcohol consumption in both genders. In addition, obesity was associated with refugee status and former smoking in males and with a higher healthy diet score in females. There was a clear linear decrease in obesity prevalence each step up the socioeconomic hierarchy in both genders. In the fully adjusted model, a clear inverse gradient in obesity prevalence by educational attainment was observed in females (p=0.002), while, in males, lower obesity prevalence remained significantly associated with the highest level of family-net income and educational attainment (aPR:0.48; 95% CI:0.27-0.84 and aPR:0.46; 95% CI:0.25-0.84, respectively). Occupational social class was not associated with obesity. Conclusions. This study highlights striking social inequalities in obesity in an Eastern Mediterranean population, which only recently moved from rural living to high levels of development. We recommend that public health interventions should address education - and income-related barriers, as a means of tackling health inequalitie

Weight gain in early infancy impacts appetite regulation in the first year of life. A prospective study of infants living in Cyprus

BACKGROUND: Eating behaviour is associated with weight gain in infancy and childhood. Few studies found a bi-directional association between weight gain and eating behaviour development in childhood but there is little data on the association in early infancy, a period critical for the programming of obesity risk. OBJECTIVE: We investigated the bi-directional association between appetite traits and weight gain during the first year of life. METHODS: Participants were part of a cohort of 432 infants born in Cyprus. Appetite traits were measured using the BEBQ or the CEBQ at age 2-4 weeks, 6 and 12 months. Weight and length were collected at birth, 4 weeks, 6 and 12 months. Multivariable linear regression was used to analyse associations between appetite traits at 2-4 weeks and 6 months and weight for age Z-score change (WFAZC) between 4 weeks-6 months and 6-12 months. Associations were also analysed in the opposite direction, between WFAZC from birth to 4 weeks, 4 weeks to 6 months, 6-12 months and appetite traits at 4 weeks, 6 months and 12 months. RESULTS: Satiety responsive (SR) at 2-4 weeks was associated with lower WFAZC from 4 weeks to 6 months (β=-0.17; 95%CI: -0.30, -0.04) and SR at age 6 months was associated with lower WFAZC from 6 to 12 months (β=-0.09; 95%CI: -0.17, -0.02). WFAZC from 4 weeks to 6 months was associated with higher EF at 12 months (β=0.11; 95%CI: 0.01, 0.20), higher FR at 12 months (β=0.17; 95%CI: 0.04, 0.30) and lower SR at both 6 (β=-0.11; 95%CI: -0.21, -0.01) and 12 months (β=-0.14; 95%CI: -0.24, -0.03) CONCLUSIONS: We found a bi-directional association between weight gain and appetite traits in infancy, suggesting that the effect of postnatal weight gain on obesity development is partly mediated by programming of appetite traits

Retrospective longitudinal study of ALS in Cyprus: Clinical characteristics, management and survival.

INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease. There is heterogeneity of clinical phenotypes while a clinical characterization of ALS in Cyprus is still lacking. The aim of this 30-year retrospective study of ALS in Cyprus is to determine the demographic characteristics of patients, the clinical features of the disease, the uptake of supportive therapies and factors influencing survival. METHODS:All ALS patients seen at the Cyprus Institute of Neurology and Genetics from January 1985 until July 2015 were included. Medical records of eligible patients were used for data extraction and compilation of an ALS database. Clinical features were compared between gender categories using univariate tests, while survival was assessed using Kaplan-Meier curves. Cox proportional hazards models were used to identify prognostic factors for survival. RESULTS:One hundred and seventy-nine ALS patients were included in the study, of whom 7 had a positive family history. Most clinical characteristics of ALS did not differ from what is observed in other European countries. However, some clinical characteristics were unique to our population, such as an increased acceptability and utilisation of supportive treatments such as gastrostomy. CONCLUSIONS:Overall, clinical characteristics of patients with ALS in the Republic of Cyprus do not differ from other European counties. Our study demonstrates a high acceptance and utilisation of supportive interventions enhancing survival, in the context of a multidisciplinary approach offered in the single tertiary centre that services the whole Cypriot ALS population. The findings of this paper are of value to the health professionals treating ALS in Cyprus