Institutional Profile: Golden Helix Institute of Biomedical Research: interdisciplinary research and educational activities in pharmacogenomics and personalized medicine

The Golden Helix Institute of Biomedical Research is an international non-profit scientific organization with interdisciplinary research and educational activities in the field of genome medicine in Europe, Asia and Latin America. These activities are supervised by an international scientific advisory council, consisting of world leaders in the field of genomics and translational medicine. Research activities include the regional coordination of the Pharmacogenomics for Every Nation Initiative in Europe, in an effort to integrate pharmacogenomics in developing countries, the development of several National/Ethnic Genetic databases and related web services and the critical assessment of the impact of genetics and genomic medicine to society in various countries. Also, educational activities include the organization of the Golden Helix Symposia®, which are high profile scientific research symposia in the field of personalized medicine, and the Golden Helix Pharmacogenomics Days, an international educational activity focused on pharmacogenomics, as part of its international pharmacogenomics education and outreach efforts

A critical view of the general public's awareness and physicians' opinion of the trends and potential pitfalls of genetic testing in Greece

Aim: Progress in deciphering the functionality of the human genome sequence in the wake of technological advances in the field of genomic medicine have dramatically reduced the overall costs of genetic analysis, thereby facilitating the incorporation of genetic testing services into mainstream clinical practice. Although Greek genetic testing laboratories offer a variety of different genetic tests, relatively little is known about how either the general public or medical practitioners perceive genetic testing services. Materials & methods: We have therefore performed a nationwide survey of the views of 1717 members of the general public, divided into three age groups, from all over Greece, and residing in both large and small cities and villages, in order to acquire a better understanding of how they perceive genetic testing. We also canvassed the opinions of 496 medical practitioners with regard to genetic testing services in a separate survey that addressed similar issues. Results: Our subsequent analysis indicated that a large proportion of the general public is aware of the nature of DNA, genetic disorders and the potential benefits of genetic testing, although this proportion declines steadily with age. Furthermore, a large proportion of the interviewed individuals would be willing to undergo genetic testing even if the cost of analysis was not covered by healthcare insurance. However, a relatively small proportion of the general public has actually been advized to undergo genetic testing, either by relatives or physicians. Most physicians believe that the regulatory and legal framework that governs genetic testing services in Greece is rather weak. Interestingly, the vast majority of the general public strongly opposes direct-access genetic testing, and most would prefer referral from a physician than from a pharmacist. Conclusion: Overall, our results provide a critical evaluation of the views of the general public with regard to genetics and genetic testing services in Greece and should serve as a model for replication in other populations

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the <i>TWIST1</i> and <i>EFNB1</i> Genes

Introduction: Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify. Objective: The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the FGFR1-3, TWIST1, and EFNB1 genes. Results: Genetic analysis identified 3 novel mutations, c.413T&gt;C - p.(Leu138Pro) [p.(L138P)] in TWIST1, the previously reported c.373G&gt;A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in EFNB1 gene as well as 6 previously known mutations and a heterozygous TWIST1 gene deletion. The 2 novel mutations within EFNB1 gene arose de novo, but the novel mutation p.(L138P) within TWIST1 gene was inherited from the patient’s father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for TWIST1 gene. Conclusions: The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis. </jats:sec

Elevation of Fetal Hemoglobin (HbF) by Novel Alkylating Agents in Human Erythroid Cells; Synergistic Effects with Established HbF-Inducing Agents.

Abstract Pharmacological induction of fetal hemoglobin (HbF) is beneficial for some patients with β-thalassemia and also ameliorates the severity of pain episodes in sickle cell anemia, mainly by hydroxyurea (HU). However, refractoriness or poor response of some patients treated with HU triggered research for other drugs. In the present study, we evaluated the effects of novel steroidal alkylating agents EA80, XK4 and CS on HbF induction in CD34+ cell cultures from normal donors. Furthermore, we examined the effects of these agents combined with HU, hemin (HE) and butyric acid (BU) on HbF modulation in adult erythroid cells. CD34+ cells from normal donors cultured in serum-free StemSpan medium were exposed to EPO (4 u/ml) + SCF (100ng/ml). Different concentrations of EA80 (0.1–1μM), XK4 (0.1–10 μM) and CS (0.1–1μM) were added to the cultures at day 6 (proerythroblast stage), then cells were washed and harvested 1– 3 days later. The effect of the drugs on cell number was measured by the trypan blue exclusion technique. The number of Hb-containing cells were determined using the benzidine-HCl procedure. EA80, over a wide range of concentrations (0.1–0.8μM), did not compromise cell survival. Continuous exposure of CD34+ to EA80 had a dose (up to 0.4μM)- and-time dependent effect on cell number as well as on globin mRNA levels. Treatment of CD34+ cells with EA80 at 0.4μM for 3 days was followed by a two-fold increase in cell number and a 1.5-fold in benzidine-positive cells. Qualitative and quantitative RT-PCR evaluation of globin-mRNA transcripts in CD34+ demonstrated that EA80 (0.4μM) caused a time- and dose-dependent increase in gamma globin mRNA (1– 3 days: 1.5 to 2.0-fold). The addition of HU and HE in combination with EA80 in normal CD34+ cell cultures led to a 20–30% increase in cell number by day 9. Furthermore, the combination of EA80 with either HU or HE was accompanied by an increase in γ-mRNA content (1.5 and 2.5-fold, respectively).No significant difference was detected in the level of both adult globin mRNAs. In contrast, BU addition had no effect either on erythroid cell proliferation or γ-mRNA levels. The addition of XK4 had a dose dependent effect on cell number and γ-globin mRNA transcripts [highest effect (2.0–5.0-fold) at 5 and 10μM]. Addition of EA80 (0.4μM) concurrently with varied concentrations of XK4 (0.1–10μM) caused a x2–4-fold increase in gamma globin content (highest effect at 5/10μM). For both drugs, the levels of β-and α-mRNAs in normal CD34+ cell cultures were not affected by dose. The addition of the third drug, CS at concentrations between 0.1 and 1μM proved toxic (reduced cell number and γ-globin mRNA transcripts). Our findings suggest that the beneficial effect of EA80 and XK4 might be threefold: increasing cell number affecting preferentially the rate of transcription of γ-globin mRNA, acting synergisticallly with HE and HU, most likely through transcriptional and posttranscriptional mechanisms. These results indicate that novel alkylating agents EA80 and XK4, either alone or in combination with other HbF-augmenting drugs, might provide a potentially useful treatment for patients with β-hemoglobinopathies with poor or no response to established Hb-F inducing agents.</jats:p

Institutional Profile: Golden Helix Institute of Biomedical Research: interdisciplinary research and educational activities in pharmacogenomics and personalized medicine.

The Golden Helix Institute of Biomedical Research is an international nonprofit scientific organization with interdisciplinary research and educational activities in the field of genome medicine in Europe, Asia and Latin America. These activities are supervised by an international scientific advisory council, consisting of world leaders in the field of genomics and translational medicine. Research activities include the regional coordination of the Pharmacogenomics for Every Nation Initiative in Europe, in an effort to integrate pharmacogenomics in developing countries, the development of several national/ethnic genetic databases and related web services and the critical assessment of the impact of genetics and genomic medicine on society in various countries. Educational activities also include the organization of the Golden Helix Symposia(®), which are high-profile scientific research symposia in the field of personalized medicine and the Golden Helix Pharmacogenomics Days, an international educational activity focused on pharmacogenomics, as part of its international pharmacogenomics education and outreach efforts