World of Genomics: Greece

The next stop in our World of Genomics tour is Greece. Greece, officially known as the Hellenic republic, is one of the oldest nations in Europe. The county has given the world so much across all aspects of life from art to science. Greek architecture and art are exemplified by iconic structures like the Parthenon atop the Acropolis in Athens and the famous Aphrodite of Milos. Greek literature is renowned for its epic poems, such as the Iliad and the Odyssey. Classical Greek mythology is very well-known. Beloved stories include “The Twelve Labours of Hercules” and “Theseus and the Minotaur” as well as tales about Zeus, Poseidon and Athena.

Ancient Greek philosophers like Socrates, Plato and Aristotle used reason and logic to explore human morality and laid the foundations of Western thought. Science and mathematics were explored by Ancient Greek physicians like Hippocrates (the father of medicine) and philosophers like Pythagoras (the father of mathematics). The Ancient Greeks also commenced the Olympics in the 8^th century BC and Greece hosted the first modern Olympics in 1896.

Greece is also a top tourist destination, with delicious cuisines like moussaka and souvlaki and beautiful beach islands like Mykonos, Paros and Corfu. We have to mention the highly Instagram-able island of Santorini with its iconic whitewashed houses and vibrant blue domes. Here is your chance to find out more about Greece’s genomics landscape.

The population of Greece

Greece occupies the southern Balkan Peninsula. The country has more than 2,000 islands which make up 20% of the land area. Athens is the capital city of Greece and is home to approximately 30% of the population. The nation lies at the intersection of three continents – Europe, Asia and Africa. Greece is surrounded by the sea, except on its northern border. Albania, the Republic of North Macedonia, Bulgaria and Turkey border Greece to the north and northeast. Greece is bordered with the Aegean Sea to the east, the Mediterranean Sea to the south and the Ionian Sea to the west.

The rich culture of the classical Greek civilizations and the turbulent history, including multiple wars and invasions, are deeply ingrained into the country. These include the Persian invasions, the Peloponnesian Civil War, the establishment of Alexander the Great’s Empire, the Macedonian wars, conquests during the Byzantine era, four centuries of Ottoman rule, the Greek War of Independence and the Greco-Turkish War among others.

Greece mobilised 230,000 soldiers in World War One (WWI). 15,000 soldiers died and 45,000 soldiers were taken prisoner or were missing. During and after WWI (1913-1923), two successive governments of the Ottoman empire led the systematic persecution of Ottoman Greeks. This was called the Greek genocide and an estimated 1 million Greeks perished. In 1923, the governments of Greek and Turkey signed the “Convention Concerning the Exchange of Greek and Turkish Populations.” This resulted in a compulsory religion-based population exchange between the countries where approximately 2 million people were forcibly relocated. 1.5 million Greek Orthodox Christians in Turkey were settled in Greece and 500,000 Muslims in Greece were settled in Turkey. The country suffered greatly during World War Two (WWII). Total civilian and military deaths ranged from 300,000 to 800,000. Greece had one of the largest Jewish populations with approximately 72,000 Jews living in the country. By 1945, over 80% of the Greek Jewish population had been killed.

Greece joined the European Union (EU) in 1981. It was severely impacted by the global financial crisis in 2008, but it is now steadily recovering.. Greece has a high standard of living and is one of the most popular travel destinations in Europe.

Geographic and demographic information

Summary statistics

• Land area: 131,957 km²
• Gross domestic product (GDP):
  • Total: $216.24 billion
  • Per capita: $20,276.5

Population statistics

• Population size: 10,664,568 (2021)
• Birth rate: 8 per 1000 people (2020)
• Death rate: 12 per 1000 people (2020)
• Infant mortality rate: 4 per 1000 live births (2020)
• Life expectancy: 81 (2020)
  • Male 2020 estimate: 79 years
  • Female 2020 estimate: 84 years
• Ethnicities: The ethnic composition of Greece is challenging to quantify as data collection regarding ethnic minorities was abolished in 1951. It has been estimated that 98% of the population is Greek. The remaining 2% is made up of the following minority groups: Albanians, Turks, Macedonians, Armenians, Bulgarians, Romanis, Aromanians, Arvanites and Pomaks.

Healthcare system

The healthcare system in Greece was founded in 1983. It is called the National Healthcare Service or Εθνικό Σύστημα Υγείας (ΕΣΥ/ESY). The system is highly centralised. It is financed by the state budget, social insurance contributions and private health insurance. In 2019, the health expenditure for Greece was 7.84% of its GDP – this was lower than the EU average of 9.9%. The healthcare system is funded by taxes (60%) and private expenditure (40%). The National Organisation for the Provision of Health Services (EOPYY) was established in 2011. It merged Greek insurance institutions, forming a single unified health insurance fund. The organisation manages the fund and purchases health services for patients covered by the ESY. Regulation and planning of the ESY and EOPYY is conducted by the Ministry of Health.

The Greek constitution considers health to be a social right. Thus, access to healthcare is free for those who cannot afford it (and have legal status). However, due to long-running financial issues, free access is becoming increasingly unfeasible and the quality of healthcare services is deteriorating. The healthcare system of Greece received a moderate score on the World Index of Healthcare Innovation (WIHI) and the quality of healthcare was deemed poor. The country ranked 27^th overall out of 31 countries in the WIHI.

Greece’s healthcare system is increasingly being privatised. The private sector has contracts with the EOPYY to provide primary and outpatient care and diagnostic services. 45% of hospitals are privately owned and 35% of hospital beds are within private hospitals.

The EOPYY provides a standardised benefits package, which includes various health services: ambulatory health care, diagnostic procedures, medical tests, physiotherapy, pharmaceutical care, dentistry and dental care, hospital care, obstetric care and childbirth. Even though many services seem to be included, not all aspects of the care are covered. Patients often have to pay out-of-pocket for pharmaceuticals, dental care and home care.

Health priorities

Smoking is very common in Greece. 25% of adults smoke daily. This is one if the highest smoking rates in the EU. Tackling smoking became a serious public health priority. It was difficult to enforce a ban on smoking in public places until October 2019 when a new tobacco control action plan was introduced. As a part of the plan, a media campaign was organised to drive changes in the attitude to smoking and also to promote awareness of the action plan. The government introduced a strict anti-smoking law. The law banned smoking in all public indoor places, healthcare facilities, schools, restaurants, taxis, open-air sports arenas and playgrounds.  Heavy fines and specialised inspectors were used to enforce the regulations.

Obesity rates in adults are equal to the EU average. However, childhood obesity has been growing. In 2019, 15% of all deaths in Greece were attributed to dietary risks (low fruit and vegetable consumption and high sugar and salt consumption). The Greek government introduced policies and actions to tackle the dietary risks. A maximum of 2% salt content in dry matter and food reformulation was introduced to reduce salt consumption. To promote healthy eating, there has been a tax on high-sugar content food since 2013 and there are fruit schemes in schools. Physical activity is also promoted to all members of society: specific programmes encourage physical activity among the elderly, physical education is mandatory in primary and secondary schools and incentives have been introduced for companies to encourage walking and cycling to work.

In 2018, the leading causes of death were circulatory diseases (approximately 33%), followed by cancer (approximately 25%). Ischaemic heart disease and stroke accounted for 11% and 10% of deaths, respectively. Lung cancer was the most common cause of death from cancer at 6%. With the more comprehensive and stricter anti-smoking legislation, it is hoped that deaths from circulatory diseases will reduce.

The burden of cancer is also high in Greece. However, the country does not have a national cancer registry. This means that managing and analysing data on cancer patients is challenging and based on incomplete data from regional registries. The Ministry of Health have announced plans to create a national cancer patient registry, which is to be connected to the National Digital Health Record. A national cancer plan has not been developed, but a specific plan for lung cancer is in development (since November 2021). The National Lung Cancer Control Strategy is aligned with Europe’s Beating Cancer Plan and focusses on prevention, early detection, diagnosis, treatment and improving quality of life.

Genomic medicine capabilities

In the early 1960’s, two university-affiliated hospitals in Athens began providing genetic services: the ‘Aghia Sophia’ Children’s Hospital and the ‘Alexandra’ Maternity Hospital. The Choremion Research Laboratory (CRL) is a lab in the First Department of Paediatrics at the ‘Aghia Sophia’ Children’s Hospital (affiliated with the University of Athens). The department pioneered prenatal diagnosis in Greece and the CRL was the first to diagnose chromosomal disorders in 1976.

The Department of Medical Genetics (DMG) is within the CRL. The DMG is a major public academic genetics centre and plays an important role in active teaching and research. Genetic testing methods for carrier screening and prenatal diagnosis of most genetic disorders in Greece were introduced by the DMG. In addition to genetic testing and analysis, the department also provides genetic counselling. Genetic services are currently offered by over 24 public and private institutions.

Nationwide newborn screening (NBS) began in 1973/1974. The screening programme is quite limited. As of 2020, the Institute of Child Health was the only laboratory that conducted NBS tests. Only 4 disorders are tested in the screening panels: phenylketonuria, glucose-6-phosphate dehydrogenase deficiency, galactosemia and congenital hypothyroidism. Although 100% of newborns are screened, sample analysis takes longer (6-8 days) than many countries in the EU where it takes 1-5 days.

The availability of genetic counselling in Greece is very limited. It is mainly provided in certain public genetic units, but most services are largely private. For example, seven out of eight molecular diagnostic labs, which conduct genetic tests for hereditary cancer, are in the private sector. The infrastructure for genetic counselling services in Greece is largely absent. Specific genetic counselling training programmes are not present and Greek legislation does not recognise the profession. Formal positions for genetic counsellors or medical geneticists are not available. This is because genetic counselling is usually provided by the treating physicians and the clinical laboratory geneticists. The lack of national guidelines means that they follow international guidelines from organisations such as NICE and ESMO. Even though some patients are referred to healthcare providers that have some training in the field, a framework for regular and systematic sessions and quality assessment procedures are not in place.

A nationwide survey-based study, published in 2022, assessed the genetic service provisions (mainly in cancer) in Greece from the perspective of physicians. 84% of respondents said their institutions did not have a clinical genetics department. Around 76% of the physicians referred their patients for genetic counselling to other departments or to healthcare professionals with training. 68.8% of respondents said they had either little or no formal training with cancer genetics counselling.

Biobank networks facilitate biomedical research initiatives in Greece. There are several biobanks in Greece which have different research purposes. The First Department of Pathology, which is in the Medical School of the National and Kapodistrian University of Athens, hosts the largest tissue collection and mainly focuses on malignant diseases for diagnostic purposes. The Laboratory of Medical Genetics of the University of Athens (based at the ‘Aghia Sophia’ Children’s Hospital) holds an important tissue collection of DNA samples for genetic diseases. The National Retrovirus Reference Centre (NRRC) focusses on virological research, particularly in HIV/AIDS, hepatitis, and oncogenic viral cancers. It has an active biobank contain 370,000 samples of various biological nature (DNA, plasma, biopsies and others).

Notable projects

• National Thalassemia Prevention Program: The nationwide government sponsored programme started in 1974 to address diagnosis and clinical management of thalassemia, which is the most frequent genetic disorder in Greece. It is implemented through 23 prevention units across Greece and is free. Since the programme began, 12,000 at risk couples have had a healthy child. There has been an 81.1% reduction in new cases of beta-thalassaemia and an 84.6% reduction in new cases of sickle cell syndromes. 
• EPIC (European Prospective Investigation into Cancer and Nutrition) – Greece: A European-wide prospective cohort study that was initiated by the International Agency for Research on Cancer – World Health Organization (IARC-WHO). Greece joined in 1994. The study was designed to investigate the effect of certain factors (diet, nutritional status, lifestyle and environment) on the incidence of cancer and other chronic diseases. 28,572 Greek participants were recruited into the study and follow up studies to investigate disease endpoints are ongoing.
• The Genome of Greece (GoGreece) Initiative: A long-term national genomics project that was launched in 2010. The initiative facilitates the implementation of genomic medicine in Greece through various objectives. This includes characterising the allelic structure of the Greek population, including isolated populations in the islands and mountainous regions, to identify rare pathogenic variants. So far, samples from over 20,00 people have been collected and 600 individuals have been sequenced. The initiative also has social public health genomic activities. This includes addressing ethical and societal issues around implementing genomic medicine in Greece and improving genomics education both in healthcare and school settings.
• BeginNGS Greece: A pilot programme that aims to use rapid whole genome sequencing to screen newborns for approximately 400 treatable genetic diseases. The national public healthcare organisation in Greece is working with two organisations to recruit 1,000 families to participate in the pilot programme.
• 1+ Million Genomes (1+MG) Initiative: Greece joined the 1+MG initiative in 2018. The Europe-wide initiative aims to facilitate cross-border access to genomic data. Greece is a full member of BBMRI-ERIC and EMBL, putting them in a good position to rapidly implement the initiative’s objectives.

Notable organisations and companies

• U-PGx (Ubiquitous pharmacogenomics) consortium: Greece is a member of this consortium of seven European countries, which aims to introduce pharmacogenomics testing in standard patient care. The consortium has planned a genomic data initiative to conduct large-scale pre-emptive pharmacogenomics testing. The aim is to investigate whether genotyping pharmacogenomic markers is feasible, cost-efficient and improves patient outcomes.
• The Greek Genome Centre (GGC): The GCC was established by the Biomedical Research Foundation of the Academy of Athens (BRFAA). The centre is equipped with advanced sequencing technology and high-performance computing capacity to advance genomic projects both nationally and internationally.
• BBMRI-GR (Biobanking and Biomolecular Resources Research Infrastructure -Greece): The BRFAA is the coordinator of BBMRI-GR, which is a Europe-wide biomedical consortium. The consortium aims to standardise Greek biobanking procedures with other member countries and connect existing collections with other European centres to facilitate multi-centre studies.
• The Hellenic Association of Medical Geneticists (HAMG): HAMG was established in 1982 by a group of scientists specialising in the field of medical genetics. It was the first representative association for Greek geneticists, marking a historical event in the development of genetics in Greece. All medical specialities are represented in the association. The goals of the association are to promote genetics in Greece by facilitating research initiatives and collaborations and also achieving recognition for geneticists by national authorities. 

Notable individuals

• Professor Stylianos Antonarakis: Antonarakis has conducted universally recognised research on genetic mutations in hereditary diseases. His lab is renowned in Europe for its contribution to genetic research. He is particularly noted for his work on chromosome 21 and Down’s Syndrome.
• Professor Fotis C. Kafatos: Kafatos was a Greek developmental and molecular biologist. He made significant contributions to the genetics and genomics fields. His most significant contribution was the development of cDNA cloning, which is the basis of many modern molecular biology techniques. Kafatos was the founder of the University of Crete and held several influential positions in the genomics sphere including Director General of the European Molecular Biology Laboratory and the first President of the European Research Council.
• Associate Professor Theodora Hatziioannou: Hatziioannou is a Greek-American Virologist. She created the first HIV-1-based virus that can induce AIDS-like symptoms in primates. Previous studies used simian immunodeficiency viruses in primates, which hindered the study of HIV because it was not the same virus. This has furthered animal studies of HIV/AIDS in a way that was not possible before.
• Dr Georgios Papanikolaou and Andromachi Mavrogeni: Papanikolaou was a Greek physician who pioneered cytopathology and early cancer detection. Together, Papanikolaou and his wife, Mavrogeni, famously developed the Pap smear. His initial studies were on female guinea pigs but he needed human females to verify his techniques. Mavrogeni volunteered for her husband’s experiments and also managed his lab. His findings were published in 1943 and since then, the cervical cancer death rate has dropped significantly across the world.

The future genomics landscape

Precision medicine initiatives in Greece are increasing. The General Secretariat for Research and Innovation (GSRI) is the public service that plans and implements research, technological development and innovation policy in Greece. It supports and supervises research centres that can boost economic growth and innovation. A recent initiative involves long-term plans with the Hellenic Network of Precision Medicine(HNPM). The objectives concern the operation of accredited biobanks, regarding clinical data collection and establishing specialised departments for molecular and genetic analysis using next-generation sequencing.

Biobanking initiatives are expanding and becoming more organised in Greece. This is through the Greek Research Infrastructure for Personalised Medicine and the establishment of a national population biobank network. This aims to promote collaboration among researchers in future biobanking activities.

Legislation regarding biobanking is also becoming clearer. Greek legislation states that the “processing of special categories of data is permitted, among other reasons, for the purpose of ‘preventive medicine.” This will enable retrospective biobank research in Greece, which is currently hindered due to issues surrounding the lack of patient consent at the time of tissue collection about potential use in future biomedical research.

References

• European Observatory of Health systems and Policies, Greece Health system review 2017, https://www.euro.who.int/__data/assets/pdf_file/0006/373695/hit-greece-eng.pdf
• Fountzilas et al. Physicians’ experience, practice and education, on genetic testing and genetic counseling: a nationwide survey study in Greece, Familial Cancer. 2022
• Koracin et al. Current Status of Newborn Screening in Southeastern Europe, Frontiers in Paediatrics, 2021
• Manoli & Fryssira, Medical genetics and genomic medicine in Greece: achievements and challenges, Molecular Genetics and Genomic Medicine, 2015
•  OECD, State of health in the EU – Greece country health profile 2021, https://www.oecd.org/health/greece-country-health-profile-2021-4ab8ea73-en.htm
• Tzortzatou & Siapka. Mapping the biobank landscape in Greece, GDPR and Biobanking. 2021