Genetics


Tracking human genetic
disorders in the Arab world

A handful of researchers at the Centre for Arab Genomic Studies in Dubai are busy cataloguing all human genetic disorders in the Arab world. Some of their initial findings are surprising and are indicative of the benefits that can be reaped from this mammoth task. Callan Emery speaks to Dr Mahmoud Taleb Al Ali, director, and Dr Ghazi Omar Tadmouri, assistant director, of the Centre for Arab Genomic Studies, about the centre’s catalogue and their findings so far.

Genetic disorders in the Arab world are a major cause of mortality, disability and chronic disease. Several of these disorders, such as breast cancer, diabetes, hypertension, Down’s syndrome and blood disorders, such as beta and alpha thalassaemia and sickle cell disease, have reached epidemic proportions in certain countries in the region.

Historically in the Arab world little attention was given to genetic disorders as the healthcare focus was weighted towards infectious diseases which until recently have been the leading cause of mortality. However, since these diseases have been more or less brought under control, the focus has shifted to genetic disorders, which are are now the leading cause of neonatal mortality in the Arab world. Congenital disorders are the second main cause of infant mortality in the GCC countries.

In a decisive initiative to better understand the epidemiology of genetic disorders in the Arab world and to turn the tide on the financial burden and the human suffering they cause, the Centre for Arab Genomic Studies (CAGS) was established in Dubai on 25 June 2003, under the directive of H.H. Sheikh Hamdan Bin Rashid Al Maktoum, Deputy Ruler of Dubai and UAE Minister of Finance and Industry.

Dr Mahmoud Taleb Al Ali, director of CAGS, explained that the centre aims to work with colleagues in the region to alleviate the burden of genetic diseases in all Arab countries.

“So despite the centre being based in Dubai we are not limited to the UAE and we hope to play a regional role. In fact, we are already doing this.”

Objectives

CAGS has several objectives, the most important being the development of a comprehensive, open-access, database of genetic diseases in the Arab world – the Catalogue of Transmission Genetics in Arabs (CTGA). Others include: the bringing together of expertise and resources in the Arab world to facilitate genetic research; facilitating co-operation with global research and medical institutions; raising public awareness; and addressing ethical, legal and social issues related to genetic applications.

The centre also produces several publications regarding genetics in the Arab world. These can be downloaded for free from the CAGS website www.cags.org.ae

CAGS is responsible for hosting the biannual Pan Arab Human Genetics Conference. This year’s event was very well attended by leading experts in the field from more than 30 countries.

Arab world

Dr Taleb Al Ali explained that when complete the CTGA Database will cover the entire Arab world – Iraq, Syria, Jordan, Lebanon, Palestine, the countries on the Arabian peninsula, North Africa from Egypt to Morocco and Mauritania, as well as East Africa including Somalia, Djibouti and Eritrea, as well as the Comoros islands, in the south Indian Ocean.

“It will also include Arabs originating in these countries but living abroad, such as Lebanese living in Australia, Egyptians in Canada or Algerians living in France.”

Dr Ghazi Tadmouri, Assistant Director CAGS, said that to date they have completed cataloguing the UAE, Bahrain and Oman, and added that these will continue to be updated on a regular basis.



Resources

The data is largely drawn from published studies of genetic disorders in the region, he explained.

“Studies that we catalogue are all studies published in national and international peer-reviewed journals. We use these records exclusively as they provide the most robust information. We make a very few exceptions and will record the unpublished clinical observations of a physician if that person is highly recognised in the field,” said Dr Tadmouri.

“You should never underestimate the level and quality of the published work in local journals,” Dr Tadmouri noted. “Many of these journals, such as the Emirates, Bahrain, and Oman medical journals, have an international review board of eminent persons which gives them substantial credibility.

“Another point about the local journals is that in many cases the clinical studies are published with more detail than their international counterparts, as authors are not constricted by limited editorial space. International journals tend to push their authors to condense their information into a few pages. This is not the case with many local journals – so we find much more detail, which we appreciate a lot.”

“Also, some of these local journals include local experiences from the region which are very important because they can be more easily applied in the Arab countries compared to many solutions emanating from the industrialised world. This means that the local journals can have strong regional application,” Dr Tadmouri added.


The United Arab Emirates

Data collection for the UAE, the first country to be surveyed, was completed in late 2005. Data was collected from international databases, such as OMIM (Online Mendelian Inheritance in Man), International bibliographies, such as PubMed, national biographies, such as Saudi MedBase (this is not available online, but on CD), the Emirates Medical Journal and mined hospital records.

“We identified 240 genetic disorders in UAE,” Dr Tadmouri said.

“This was much more than we had anticipated and it gave a new perspective to the dimension of the problem in the UAE.

“When I arrived in the UAE at the beginning of the establishment of the database in 2004, I met several colleagues working in the field and was getting contradictory replies to the question of how many genetic disorders they were dealing with. Each one gave me a figure of between 30 and 60 diseases. It turned out that each was speaking from their own perspective. The paediatricians were talking about diseases specific to paediatrics; cardiologists were talking about diseases specific to cardiology and so on. The reality, however, is the sum of all of these. So the figure was much higher than we expected and this surprised everyone.

“What compounded this surprise was that the data only referred to 20% of the population as the focus was only on UAE nationals and the expatriate Arab population in the country. “Of course, it is not only the number of disorders that is important, but also the prevalence rate. Some are quite rare, while others are epidemic.”

Arab Council

The next step was to begin indexing data from other countries in the region. To assist this procedure, the Arab Council for CAGS was established in 2006, which includes known scientists in the field from 13 countries in the region.

“All of them were aware of the need for a database to catalogue genetic diseases in the Arab world. By explaining the details of how data is collected, many were inspired to start contributing to the database, and although the enthusiasm has continued and we get regular contributions from across the Arab world every month, we still have a need for more contributions,” said Dr Tadmouri.

He explained that, despite the voluntary contributions, the best process to accumulate this data is to use a step-wise model.

“This means conducting thorough country-by-country surveys which will give us a better, clearer picture in a much shorter time.”

Bahrain

“We chose Bahrain as the first country to test our decentralised model of data collection, because it is a small place with a small population.”

This involved the collection of data in Dubai (international journals, OMIM) and Manama (local journals, medical records), and the digitisation, review, standardisation and curation of the data in Dubai.

“We completed the indexing in late 2006 and found 109 genetic disorders.” After this success CAGS adopted the decentralised system approach to collecting data.

Oman

“Oman was the next logical target as it neighbours the UAE and we thought possibly shares many of the same genetic diseases.

“We finished cataloguing the data earlier this year and found 271 genetic diseases described in the sultanate – the most we have found in a single country so far.”

Qatar and Kuwait

CAGS plans to index genetic disorders in Qatar and Kuwait next.

Dr Tadmouri said that Kuwait is an important source of information as it includes a well established governmental genetic centre that has been operational for the past 27 years.

“We expect this will keep us busy for the next year or two. Then we will move on to Yemen and Saudi Arabia, before moving out of the GCC countries.”



Molecular analysis

The CTGA Database does not only include data on genetic disorders, but also records that describe the genes and mutations causing these diseases.

“Unfortunately in the Arab world this information is very limited,” said Dr Tadmouri. “For example, in the UAE we have 240 diseases, but only 28 have a known genetic background.

In Bahrain we recoreded 109 diseases, but only 14 related genes have been identified. In Oman there are 271 diseases, but only 58 related genes.

“This indicates that more molecular analysis needs to be conducted. What we have are many clinical studies, but very little molecular analysis to identify the genetic mutation responsible for the disease. Clinical studies are relatively inexpensive to carry out, but molecular analysis requires sophisticated technology and knowledge and is considerably more expensive to conduct.

“We are trying to promote molecular analysis as we will never fully understand the disease without understanding its genetic background,” said Dr Tadmouri. “However,” he added, “there is a growing movement in the region, apparent in the latest publications, toward genetic molecular analysis to identify the genes involved in the disorder.

We are now increasingly getting a mix of published clinical observation and genetic molecular analysis.”

Benefits of the CTGA

Dr Taleb Al Ali explained that through these records CAGS can help decision makers make informed decisions based on the most accurate available information to determine which genetic disorders are epidemic, which ones are rare and which ones need to be dealt with urgently.

“And on this basis they will be in a good position to devise a strategic plan of action for the health sector of any specific country for which the data is available.” He added that the database also assists in the dissemination of information and acts as a tool to further educate physicians and the general population at large.

Dr Tadmouri explained: “If you read through the text of a specific record and you want to collaborate with someone who has worked on that genetic disorder described in the document, the database provides a means of accessing the researcher in the reference section of the record.” Since its inception four years ago the database has had some 400,000 online visitors. CAGS expects this to pass the 500,000 mark by the end of this year.

Dr Tadmouri pointedGeneticists working on out that CAGS is getting a lot of appreciation for giving local publications international recognition. Some of these smaller publications are not published online but are referenced in the CTGA database.

Contributions

CAGS receives on daily basis a variety of publications from scientists in the Arab world or abroad to be considered for the CTGA Database. Curators create about 30 entries and update an equivalent number each month with an average of 5-10 publications reviewed per day.

Geneticists working on genetic disorders in Arabs are requested to contribute to the growth of the CTGA Database. A CTGA Database Information Submission Form is available online.

Websites
CAGS - www.cags.org.ae
OMIM - www.ncbi.nlm.nih.gov/omim
 

The CTGA database

Dr Ghazi Tadmouri, Assistant Director of CAGS, explained the structure of the Catalogue of Transmission Genetics in Arabs (CTGA) database. The online database is freely available to anyone who has an interest in the subject.

At the time of going to press the database had 1,246 records of genetic diseases throughout the Arab world.

Records can be accessed via a webbased search of the database from the frontpage which will generate a list of related genetic disorders. Each record has the following information:

1. Name of the disease
2. Alternate names of the disease
3. WHO classification (global standard)
4. The OMIM number – with link to the record of the disease on the OMIM Database. (OMIM is the Online Mendelian Inheritance in Man Database of human genes and genetic disorders developed by staff at Johns Hopkins in the United States)
5. A computer-generated map which shows in which countries in the region the disease has been recorded. “This does not mean the disease does not occur in the other countries, but that we have not found it in those countries. We have yet to complete surveys for some of these countries,” Dr Tadmouri pointed out.
6. A general description of the disease – what its symptoms look like, any possible treatment modalities, possible diagnostic procedures, prevalence rates worldwide, etc. This section gives all details that could be relevant to that disease.
7. The Molecular Genetics section describes the genetic root of the disease and describes the genes and mutation involved – “if they are known”.
8. Epidemiology of the disease in the Arab world (the heart of the database). This section provides descriptive information about the disease country by country in the Arab world in alphabetical order. Within each country all the clinical descriptions are put in chronological order from the oldest to the latest study.
9. Lastly, the References section provides links to PubMed – where researchers can access the full text of the study (providing they have access to PubMed) or just the reference to the journal if it is not published online, as is the case with a number of smaller regional journals.

“This is evidence that consanguinity is directly linked to the abundance of recessive genetic disorders compared to dominant ones. Previously it has only been surmised theoretically. But with growing evidence this theory is crystallising. As we continue to index genetic disorders for each country in the region, we believe this evidence will grow stronger and stronger.

“This is the power of the database – being able to decipher trends and facts that were hitherto unknown or unproven,” Dr Tadmouri said.

“Programmes to prevent consanguinity, in the UAE for example, will have little success because the genetic pool is small. Of about 1 million nationals in the UAE, only about 500,000 are fertile. That is about 250,000 men and 250,000 women. It is not very many. And with government restrictions that nationals should only marry nationals, the situation is exacerbated.

“Further, as cities like Dubai and Abu Dhabi grow the nationals are being pushed into small pockets of the city. They are clustering within the city and you will find that they will marry within these small clusters – to their neighbours and their work colleagues. So the pool is small and this will keep magnifying rare genetic disorders despite any work that is done to prevent consanguinity.”

However, he said there are other ways to prevent the spread of autosomal recessive disorders through various preventive programmes such as premarital and neonatal genetic screening. The UAE has a newborn screening programme for nationals for four major disorders.

And premarital screening for thalassaemia and sickle cell anaemia is now a prerequisite in order to complete marriage documents. By looking at statistics derived from the database, CAGS is now in a position to offer consultation regarding the key genetic diseases for which screening should be carried out. “Of course screening cannot be carried for all genetic disease.

Some of them are due to environmental factors, such as Downs syndrome which can be the result of having offspring at a late age. Education can help here,” Dr Tadmouri added.

The practice of consanguineous marriage

Arabs probably practiced consanguinity since ancient times before the introduction of Islam in the 7th century. Unlike what is widely thought, Islam does not advocate or encourage consanguineous marriages. The holy sermons of the Prophet Mohammad Hadith state that “close marriages will often produce weak children”.

In the Arab World, the custom of consanguineous marriage results from cultural and historical, rather than religious reasons. Mistakenly, the preference for consanguineous marriage is thought to be restricted to Islamic Arab communities. In some Christian communities (such as Lebanon) consanguinity is also common.

The Arabian culture and history as well as the geographical concentration of many population groups in small and isolated areas promoted the tradition of consanguineous marriages. Many families consider the choice of consanguineous marriage between close relatives as a way to maintain the unity of family assets. Marriage with a relative is also preferred because of the comparative ease with which premarital negotiations can be conducted and the greater stability of consanguineous union due to the advanced relationship between the female partner and her in-laws.

Studies indicate that several factors influence consanguinity rates in Arabs. These factors include urban-rural residence ratios of families, education levels, and time trend. Studies in Jordan, Egypt, Lebanon, Oman, and Tunisia demonstrated a higher tendency of unions among rural than urban inhabitants.

In some Arab countries, it is evident that the higher the level of education of the female partner, the lower the consanguinity rate. On the contrary, in some societies, highly educated men are more likely to be married to cousins. A plausible explanation is that since a son with higher education becomes a more valuable asset, he is pressured to remain within the family.

While a declining trend of consanguineous marriages has been documented in Bahrain, Lebanon, Kuwait, and Syria, a stable trend has been reported in Jordan and Oman. Surprisingly, consanguineous marriages in Algeria and Yemen are increasing in the present generations compared to previous generations. The reason for the rising trend in consanguinity can be attributed to the increase in the availability of cousins due to high fertility.

In the United Arab Emirates, consanguinity rates vary according to race, tribe, economic class, isolation of the society, and secular exposure. Despite the improvements in education, general economic conditions and health status of the population, consanguinity rate in the UAE has increased from 39% to 50.5% in one generation. Moreover, the comparison of the two generations in terms of cousin marriage preferences suggests the continuation of the same patterns in the two generations. The most common has been and still is first cousin marriages (26.2%). Indeed, parents who were consanguineous were significantly more likely to give their children away to consanguineous spouses. Interestingly, consanguinity is more common among women with educated husbands (secondary or university/ high) than among women with less educated husbands.

Consanguinity rates are not identical throughout the main cities of the UAE. The level of consanguinity is higher in Al-Ain (54.2%) than in Dubai (39.9%). In both cities, first cousin marriage is the commonest type (28.2% in Al-Ain versus 20.7% in Dubai). In Abu Dhabi, the consanguinity rate stands at about 32%. In addition, the increase in consanguinity rate is higher in Dubai (10.42%) than in Al-Ain (7.49%).

– Credit: CAGS



 Date of upload: 23rd July 2008

                                  
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