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MyHVP Newsletter Volume 04 | Issue 01 | Jan-July 2017

KUALA LUMPUR GG2020 MEETING & GG2020 CONFERENCE July 16 - 18, 2017 Impiana KLCC Hotel, Kuala Lumpur

Deputy Minister of Higher Education, Datuk Dr. Mary Yap Kain Ching officiated the opening ceremony of the GG2020 Conference at Impiana KLCC Hotel, Kuala Lumpur.

“Moving Towards Zero Thalassaemia”


16th July 2017, the Global Globin 2020 Challenge (GG2020) annual meeting was held at the Impiana KLCC Hotel, Kuala Lumpur. The meeting was attended by 14 GG2020 members from nine countries. Several issues were discussed during the meeting, including the development of the GG2020 Thalassaemia Kit. On the following day, the inaugural conference on GG2020, with the theme of “Moving

Towards Zero Thalassaemia”, was held at the same venue. The conference was attended by a total of 60 participants, including 13 delegates from Brunei and Indonesia.

Contact us: | Secretariat Office: Human Variome Project Malaysian Node & South-east Asian Node School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia | Phone :(60) 097676543 / 6531 | Fax: (60) 097676543 | Email : | Website:

| See page 3

MyHVP Newsletter

Head’s Address

Board of Editors 2017

ISSN: 2550-1747 | Volume 04 | Issue 01| Jan-July 2017

Editor in Chief


Professor Dr. Zilfalil Alwi

Managing Editor Prof. Dr. Wan Zaidah Abdullah

Editorial Board Members

Prof. Ida Madieha binti Azmi Assoc. Prof. Dr. Muhammad Farid Johan Assoc. Prof. Dr. Endom Ismail Assoc. Prof. Dr Rosnah Bahar Dr. Nik Norliza Bt Nik Hassan Dr. Azlina bt Ahmad Annuar Mr. Abdul Halim Fikri Bin Hashim

English Editor Amyzar Alwi


02 Head’s Address 06 Calendar of events 03 Report 06 Postgradu 04 When a Geneti- ate cist Writes 08 Photo Diary © 2017. All rights reserved. The information in this newsletter is provided by the Malaysian Node of the Human Variome Project (MyHVP) members including South-east Asian Node (HVPSEA Node) for educational / information purpose only. It is not a substitute for professional medical care and medical advice. The contents express the opinions of the authors who alone are responsible for their view expressed. MyHVP does not accept any legal responsibility for their contents.

Writers, Invited!

MyHVP Newsletter is issued biannually. For the coming issue, we are going to invite the public from various fields and specialties in order to share with us, their experience in dealing with the issues of medicine or biomedicine. Writers may contribute their writing with these following criteria: 1. Length (Max. 1page A4 size, and it may be edited for our use) 2. The committee has the right to share your writing for further issues. 3. To suit the needs of the publication, and your writing won’t be returned 4. Emailed the article to

Published by

Malaysian Node of the Human Variome Project (MyHVP) School of Medical Sciences Universiti Sains Malaysia Health Campus 16150, Kubang Kerian, Kelantan, Malaysia Tel: +6097676531 /6543 | Email:

lobal Globin Challenge 2020 (GG2020) was initiated in 2014 with the first and subsequent annual meetings held at the UNESCO headquarters in Paris. This year, Kuala Lumpur became the first venue outside Paris to host the GG2020 annual meeting. The one-day meeting was held on July 16, 2017 and was followed by the international conference on GG2020 on July 17-18, 2017. The meeting, which was attended by representatives from 8 countries from Asia, the Middle East and Europe, discussed future GG2020 project planning and exchanged views on topics and issues related to hemoglobinopathies involving development, guidelines, ethics and education. The detailed report on this event is presented on page 1 and page 3 of this newsletter. Subsequent GG2020 meetings that will be organised by other HVP country nodes and GG2020 members include Egypt and Cyprus. A meeting in conjunction with the Conference of the African Society of Human Genetics will be held in Cairo, Egypt. The other GG2020 meeting at the Thalassemia International Federation (TIF) conference in Thessaloniki, Greece will be organised by members in Cyprus. Both meetings will be held in November. In future, it is hoped that more GG2020 members will take the opportunity to organise the GG2020 meeting in their respective countries especially those in regions where Thalassemia is prevalent.  

ment program has been held at 22 secondary schools and 2 universities. The program was implemented through forum by inviting specialists in the genetics field, haematology and members of parent support group to speak on thalassemia disease including its burden on patients and families and prevention. Through this program, it is hoped that the public awareness on thalassemia screening will be increased, befitting the theme of this program “Towards Zero Thalassemia”. Congratulations and a big thank you to the hardworking editorial board members for the publication of the eighth issue of the MyHVP newsletter. Last but not least, I invite all academics and researchers from institutions throughout Malaysia to join us in this exciting network of collaboration on a global scale. Thank you. Prof. Dr. Zilfalil Alwi

Head, Malaysian Node of the Human Variome Project (MyHVP)

EduVariome is one of the main activities in MyHVP aimed at promoting awareness of genetic screening especially for thalassemia patients as thalassemia is one of the most common genetic diseases in Malaysia and the southeast Asia region. Since its inception in 2014, EduVariome has been widely implemented in Kelantan and other states in Malaysia. To date, this community engageMyHVP Newsletter | Jan-July 2017| page 2

Report | continued from page 1 The Opening Ceremony on the 17th July 2017 began with the welcome remarks by the Chairman of GG2020 Conference, Professor Zilfalil Alwi, followed by the Chairman, Board of Directors of Human Variome Project (HVP), Professor Sir John Burn and the Dean of School of Medical Sciences, Universiti Sains Malaysia, Professor Dr. Shaiful Bahari Ismail. The event was officiated by the deputy minister of Higher Education, Datuk Dr. Mary Yap Kain Ching. This was followed by a performance from MyThal Club Universiti Kebangsaan Malaysia Medical Centre (UKMMC), a club involving thalassaemia patients, their families and medical practitioners. The Deputy Minister of Higher Education then witnessed the exchange ceremony of Memorandum of Understanding between Universiti Sains Malaysia and Global Variome which took place after the Opening Ceremony. Fifteen speakers from nine countries (Malaysia, Indonesia, Singapore, Thailand, India, Italy, Cyprus, Egypt and Pakistan) participated in this conference and shared their knowledge on thalassaemia during the symposia. In general, the symposia covered topics ranging from the epidemiology of thalassaemia disease and cutting-edge topics such as stem cell therapy. A total of 42 ePosters were present-

Memorandum of Understanding (MoU) between USM and Human Variome Project International Ltd (Global Variome) 17 July 2017, Impiana KLCC Hotel Kuala Lumpur Reported by Abdul Halim Fikri Hashim School of Medical Sciences, Universiti Sains Malaysia, Health Campus and a member of MyHVP


niversiti Sains Malaysia (USM) through the Malaysian Node of the Human Variome Project (MyHVP) under the School of Medical Sciences (PPSP) signed a Memorandum of Understanding (MoU) with UK-based Global Variome Limited. The MoU is undertaken for a collaboration involving the development of programs in research, publication, training and seminar.

ed at the conference and three best posters were selected at the end of the conference. Following the success of this inaugural conference, GG2020 hopes to make it an annual event and a bigger success in the future. Deputy Minister of Higher Education, Datuk Dr. Mary Yap Kain Ching delivering a speech during the opening ceremony of GG2020 Conference, held in Impianan KLCC Kuala Lumpur.

Prof. Sir John Burn delivering the keynote entitled “The Impact of Genetic Variation on Human Health� on the first day of conference. | Reported by Dr. Aisyah Ahmad

port services to international coordination work for the Human Variome Project (HVP) which was originally based in Melbourne, Australia. GVL acts as a legal instrument that enables the Human Variable Project to formally represent members of the HVP Consortium and carry out certain activities on behalf of the HVP members. GVL took over these functions from the previous entity, Human Variome Project International Limited in 2016. The MoU was signed for a three (3) year collaborative project effective of 17th July 2017. Through this MoU, both parties will further strengthen their cooperation in developing activities at a global level especially in the field of genomic and genetic medicine. HVP was represented by GVL Chairman, Prof. Sir John Burn who is also a member of the HVP Board of Directors. USM was represented by Dean of School of Medical Sciences, USM, Prof. Dr. Shaiful Bahari Ismail. | The Photo Diary: see page 8

HVPI is a non-governmental organization (NGO) which works with UNESCO to establish a global effort to collect, consolidate and arrange genomics data, clinical differences and individual phenotype towards disease from all ethnic groups throughout the world and enable the information to be shared widely. The goal of this project is to facilitate assessment and accessibility of genetic diseases from countries throughout the world by doctors and researchers. The goal is also to provide doctors and researchers the latest sources to assist in their daily clinical practice as well as biomedical research. Global Variome Limited (GVL) is a non-governmental organization (NGO) which has taken over HVP management in 2016. Based in the United Kingdom, GVL was established in 2016 to provide sup-

MOU Exchange Ceremony between USM and Human Variome Project

MyHVP Newsletter | Jan-July 2017| page 3

When a Geneticist Writes Glucose-6-phosphate dehydrogenase (G6PD) deficiency - the intricate realtionship between haematology, pharmacogenetics and malariology Written by: Prof. Dr. Narazah Mohd Yusoff, MBBS, PhD Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Penang, Malaysia.


lucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymopathy worldwide. It affects approximately 400 million people, the majority of whom are at risk for malaria [1-4.] The G6PD enzyme helps red blood cells function normally. Without enough G6PD enzyme to protect the red blood cells, a sufficient amount of reduced glutathione cannot be produced. This will result in oxidative stress. The clinical expression of G6PD-deficient individuals are mostly asymptomatic, but they can have episodic acute haemolytic anaemia (AHA) or a few can have chronic haemolysis when they are exposed to certain infection or drugs. In neonates with G6PD deficiency, decreased bilirubin elimination may play a role in the development of jaundice [5-6]. As such the clinical expression of G6PD-deficient individuals encompasses a spectrum of syndromes. The gene for G6PD is located on the X chromosome (band X q28) [7] and has been cloned and sequenced [8-10]. The G6PD locus shows a considerable degree of genetic heterogeneity and at least 186 distinct alleles involving mutations leading to single amino acid substitutions or deletions, scattered throughout the entire coding and non-coding region have been identified [11, 12, 13]. Most of the variants occur sporadically, although some, such as the G6PD Mediterranean and the G6PD A-202A/376G variants, exist with an increased frequency in certain populations [14, 15]. Almost three billion people are at risk of contracting the Plasmodium vivax infection globally [16, 17] . Beyond Africa, it is the predominant cause of malaria [18]. Recent evidence suggests considerable morbidity and mortality associated with vivax malaria due to its association with recurrent episodic presentations [19- 21] since complete eradication of Plasmodium vivax is not be feasible without systematic treatment of the dormant liver forms (hypnozoites) of the parasite [22]. Currently, the only available treatment to kill hypnozoites is primaquine (PQ), which causes dose-dependent haemolysis in patients with G6PD deficiency [23]. G6PD deficiency is common in areas of endemic malaria [24] thus the WHO anti-malarial treatment guidelines recommend that wherever possible routine testing for G6PD deficiency should be undertaken prior to PQ-based radical cure. However, if testing is not available, an individual risk–benefit assessment should guide the decision whether to administer without testing or withhold PQ [25]. Thus, implementing routine testing for G6PD deficiency is challenging for countries which do not test

for G6PD deficiency on routine basis and often, PQ is not prescribed [26, 27]. Pharmacogenetics is described as genetically determined variations in how individuals respond to drugs, with regards to the therapeutic and adverse effects. Historically this concept arose when it was discovered that the ability to taste phenylthiocarbamide (PTC) was shown to be inherited [28]. But it was with the discovery of G6PD deficiency as the biochemical basis of PQ sensitivity that this became a prototype study case in pharmacogenetics [29]. Soon, it became clear that G6PD deficiency was also the biochemical defect underlying favism as a cause of AHA [30]. Subsequently, in the 1960s and 1970s, numerous drugs other than PQ were reported as possible triggers of AHA in G6PD-deficient individuals. The main features of drug-induced AHA are well known [31]. In the steady state, the blood of a G6PD-deficient individual is normal, drug-induced AHA is the paradigm of a pharmacogenetics event: haemolysis results from the action of an exogenous factor on latently but intrinsically abnormal red cells [32]. An increasing number of countries in Asia have set themselves the ambitious goal to eliminate Plasmodium vivax malaria: in order to do this, PQ is needed. .However, there is a consensus among malaria experts that eliminating Plasmodium vivax will prove more technically challenging than eliminating Plasmodium falciparum [33] as this involves critical decision-making on need for prescription of PQ in G6PD deficient individuals. This situation has escalated from a circumscribed pharmacogenetics problem to a major public health issue. In principle, there are two solutions i.e. either to give PQ regardless, and let the G6PD deficient individuals bear the consequences, with the hope that appropriate medical supervision and intervention will be available when necessary. Secondly the option is to test for G6PD, and then either exempt those who are G6PD-deficient from receiving PQ, or give them PQ under supervision [32]. Meanwhile, WHO recently recommended an important change for one of the two indications for PQ mentioned above where the stated dose of PQ has been decreased. Subsequently there is evidence that the gametocytocidal action may be sufficient, and the AHA caused in G6PD-deficient individuals will be certainly much milder [34]. AHA in G6PD-deficient individuals remains a unique case in pharmacogenetics, where a specific enzyme deficiency is the single determinant of a severe, potentially life-threatening side effect [32]. MyHVP Newsletter | Jan-July 2017| page 4

When a Geneticist Writes The geographical correlation of distribution of G6PD deficiency with the historical endemicity of malaria suggests that G6PD deficiency has risen in frequency through natural selection by malaria [35, 36]. Thus, there exists an intricate relationship whereby malaria selects for G6PD deficiency and PQ is an effective antimalarial, however G6PD-deficient individuals are sensitive to PQ [37]. In conclusion, G6PD deficiency must always be considered in the differential diagnosis of haemolytic anaemia; and we should be mindful of G6PD deficiency whenever we prescribe a potentially haemolytic drug [32]. G6PD deficiency is still a public health issue and G6PD testing must be made available when administering PQ in areas where G6PD deficiency has a high prevalence [32]. References 1. Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, et al. Spatial distribution of G6PD defciency variants across malaria-endemic regions. Malar J. 2013; 12:418. 2. Ruwende C, Khoo SC, Snow RW, Yates SN, Kwiatkowski D, Gupta S, et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 1995; 376:246. 3. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371:64. 4. Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev 2007; 21:267. 5. Kaplan M, Muraca M, Hammerman C, Vilei MT, Leiter C, Rudensky B, Rubaltelli FF. Bilirubin conjugation, reflected by conjugated bilirubin fractions, in glucose-6-phosphate dehydrogenase-deficient neonates: a determining factor in the pathogenesis of hyperbilirubinemia. Pediatrics. 1998 Sep;102(3): E37 6. Kaplan M, Hammerman C. Glucose-6 phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol. 2004 Oct; 28 (5):356. 7. Kirkman HN, Hendrickson EM. Sex-linked electrophoretic difference in Glucose-6-phosphate dehydrogenase. Am J Hum Genet 1963; 15:241. 8. Martini G, Toniolo D, Vulliamy T, et al. Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 1986; 5:1849. 9. Persico MG, Viglietto G, Martini G, et al. Isolation of human glucose 6-phosphate dehydrogenase (G6PD) cDNA clones: primary structure of the protein and unusual 5’ non-coding region. Nucleic Acids Res 1986; 14:2511. 10. Takizawa T, Huang IY, Ikuta T, Yoshida A. Human glucose-6 phosphate dehydrogenase: primary structure and cDNA cloning. Proc Natl Acad Sci U S A. 1986; 83(12):4157. 11. Beutler E. G6PD deficiency. Blood. 1994; 84:3613. 12. Beutler E, Vulliamy TJ. Hematologically important mutations: glucose-6-phosphate dehydrogenase. Blood Cells Mol Dis. 2002; 28:93. 13. Minucci A, Moradkhani K, Hwang MJ, Zuppi C, Giardina B, Capoluongo E. Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the “old” and update of the new mutations. Blood Cells Mol Dis. 2012; 48:154. 14. Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A- Blood. 1989; 74:2550. 15. Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. G6PD deficiency: global distribution, genetic variants and primaquine therapy. Adv Parasitol. 2013; 81:133 16. Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, Temperly WH The International Limits and Population at Risk of Plasmodium vivax Transmission in 2009. PLoS Negl Trop Dis. 2010

Aug; 4(8): e774. 17. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg. 2007; 77:79. 18. WHO world malaria report 2016. Geneva World Health Organization; 2016. 19. Douglas NM, Lampah DA, Kenangalem E, SimpsonJA, Poespoprodjo JR, Sugiarto P, Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study PLoS Med. 2013 Dec; 10(12): e1001575. Published online 2013 Dec 17. doi: 10.1371/journal.pmed.1001575. 20. Douglas NM, Pontororing GJ, Lampah DA, Yeo TW, Kenangalem E, Poespoprodjo JR, Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia. BMC Med. 2014; 12: 217. Published online 2014 Nov 18. doi: 10.1186/s12916-014-0217-z. 21. Burdam FH, Hakimi M, Thio F, Kenangalem E, Indrawanti R, Noviyanti R, Asymptomatic Vivax and Falciparum Parasitaemia with Helminth Co-Infection: Major Risk Factors for Anaemia in Early Life. PLoS One. 2016; 11(8): e0160917. Published online 2016 Aug 9. doi: 10.1371/journal.pone.0160917. 22. Roy M, Bouma MJ, Ionides EL, Dhiman RC, Pascual M. The potential elimination of Plasmodium vivax malaria by relapse treatment: insights from a transmission model and surveillance data from NW India. PLoS Negl Trop Dis. 2013;7:e1979. 23. Ashley EA, Recht J, White NJ. Primaquine: the risks and the benefits. Malar J. 2014;13:418. 24. Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Medicine 2012; 9: e1001339 25. WHO. Guidelines for the treatment of malaria. 3. Geneva: World Health Organization; 2015. 26. Chu CS, White NJ. Management of relapsing Plasmodium vivax malaria. Expert Rev Anti-Infect Ther. 2016;14:885–900. doi: 10.1080/14787210.2016.1220304. 27. Vivax Working Group Targeting vivax malaria in the Asia Pacific: the Asia Pacific Malaria Elimination Network Vivax Working Group. Malar J. 2015;14:484. doi: 10.1186/s12936-015-0958-y. 28. Blakeslee, A.F. Genetics of sensory thresholds: taste for phenylthiocarbamide. Proceedings of the National Academy Sciences USA.1932; 18: 120. 29. Motulsky, A.G. Drug reactions, enzymes and biochemical genetics. Journal of the American Medical Association. Journal of the American Medical Association. 1957; 165: 835. 30. Sansone, G. & Segni, G. Nuovi aspettidell’alterato biochimismo degli eritrociti dei favici: assenza pressoche‘completa della glucos-6-P deidrogenasi. Bollettino della Societa‘Italiana di Biologia Sperimentale. 1958; 34: 327. 31. Luzzatto, L. & Poggi, VE. Glucose 6-phosphate dehydrogenase deficiency. In: Hematology of Infancy and Childhood 2009; pp. 883–907. Saunders, Philadelphia. 32. Lucio Luzzatto, Elisa Seneca G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. British Journal of Haematology. 2014; 164: 469. 33. Feachem RGA Malaria Elimination Group. San Francisco: The Global Health Group; 2009. Shrinking the malaria map: a guide on malaria elimination for policy makers. 34. White NJ, Qiao LG, Qi G, Luzzatto, L. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malaria Journal. 2012; 11: 418. 35. Allison AC, Glucose-6-phosphate dehydrogenase deficiency in red blood cells of East Africans Nature. 1960; 188:532. 36. Motulsky AG, Metabolic polymorphisms and the role of infectious diseases in human evolution Hum Bio. 1960; 32:28. 37. Luzzatto, L. The rise and fall of the antimalarial Lapdap: a lesson in pharmacogenetics. Lancet. 2010; 376: 739.

MyHVP Newsletter | Jan-July 2017| page 5

Postgraduate Collagen 1 alpha 1 (COL1A1) gene as potential genetic markers for osteoporosis in thalassemia patients Ms. Noor Diana Abdul Rashid Department of Paediatrics, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan


halassemia patients showed a wide variety of phenotypic severity which are variations in anemia, growth development, hepatosplenomegaly and transfusion requirements. The blood transfusion dependent thalassemia patients required a regular blood transfusion early throughout life to survive but later had developed many complications including the bone disease. One of the most common bone diseases in transfusion dependent Thalassemia patient is osteoporosis. Osteoporosis is characterized by low bone mass and micro architectural deterioration of bone tissue, leading to enhanced bone fragility and higher frequency of fractures which can be determined by measurement of bone mineral density (BMD).

In this study, the measurement of bone mineral density and the study of polymorphism in COL1A1 gene as genetic marker may identify thalassemia patients who are at higher risks to develop osteoporosis and pathologic fractures. Thus, the clinicians can provide preventive measurement for osteoporosis in thalassemia patients. This gene also has potential to be explored in other bone related diseases such as postmenopausal osteoporosis, idiopathic osteoarthritis, high myopia susceptibility, and ostegenesis imperfecta in different ethnics of different populations.

In addition, genetic factors are believed to play a role in the development of low bone mass and osteoporotic fractures which are seen as regulator genes of BMD. However, this has not been thoroughly observed in thalassemia-induced osteoporosis (Voskaridou and Terpos, 2013). These genes are known as tertiary modifying factors, while not being involved in the hemoglobin synthesis. However, they can cause variation in the progression of the thalassemia disease. Many genes were previously associated with osteoporosis such as collagen type I alpha 1 (COLIAI), vitamin D receptors, estrogen receptors and interleukin-6 (IL-6). The COL1A1 gene (as showed in figure 1) is highlighted in this study because the collagen type I play role as the main component of the bone matrix. A G to T polymorphism in the regulatory region of the COLIA1 Figure 1: adapted from at a recognition site for transcription factor Sp1 has been reported associated with osteoporotic fractures. The polymor- ry#alpha_1-COL1A1 phism are detected by using restriction fragmentation length polymorphism-polymerase chain reaction (RFLP-PCR) method. Alleles with a G-base at the Sp1 binding are defined as ‘S’, while alleles with a T-base are defined as ‘s’. Many studies have shown that patients with ‘s’ allele are mostly have reduced BMD and osteoporotic fractures in several populations.

Calendar of Events 19 September 2017 | Annual General Meeting of Malaysian Node of the Human Variome Project (MyHVP) USM, Health Campus, Malaysia 25 - 27 September 2017 | 12th Malaysia International Genetics Congress Hotel Bangi-Putrajaya, Malaysia 29-31 October 2017 | The 2017 Annual Meeting of Indonesian Society of Human Genetics (InaSHG) Yogyakarta, Indonesia 9-12 November 2017 | Second International Conference on Founder Population Kochi, Kerala, India 17-19 November 2017 | 14th International Conference on Thalassaemia & Haemoglobinopathies & 16th TIF International Conference for Patients & Parents, Thessaloniki, Greece MyHVP Newsletter | Jan-July 2017| page 6

Postgraduate Genetic analysis of beta globin gene (HBB) and Gamma Globin gene (HBG2) in transfusion dependent HBE/β-Thalassemia patients Sarifah Hanafi1, Muhammad Farid Johan2, Rosnah Bahar2, Ariffin Nasir1 Department of Paediatrics, School of Medical Sciences, Health Campus, 16150 Kubang Kerian, Kelantan 2 Department of Haematology, School of Medical Sciences, Health Campus, 16150 Kubang Kerian, Kelantan 1


bE/β-thalassemia is the most common severe form of β-thalassemia in Asia including Malaysia and globally, comprised approximately 50% of clinical severe β-thalassemia disorders. It has various clinical manifestations ranging from very mild anemia to severe manifestation similar to beta thalassemia major. Many different syndromes are observed in HbE/β-thalassemia. Several genetic modifiers have been reported to play important role in ameliorating phenotypic variability. The true reasons underlying this phenotypic variability remain largely obscure. The most reliable and predictive factor of the disease phenotype is the nature of the β-globin gene mutation itself. However, the degree of severity is also affected by other genetic modifiers. For instance, the elevating of HbF level as an ameliorating factor of β-thalassemia becomes more evident. Therefore, an attempt have been made to investigated the role of primary genetic modifiers on hematological parameters and secondary genetics modifiers on HbF and disease severity. A cross sectional study was designed to revealed the spectrum of β-globin gene mutations among HbE/β-thalassemia patients, subsequently correlate the identified mutations with hematological parameters such as HbF, MCV, MCH. The project also were designed to discovered the frequency of Xmn1-Gγ Polymorphism and to associate the polymorphism with HbF level and disease severity. A total of 204 HbE/β-thalassemia patients were randomly selected at Hospital USM and Ministry of Health hospitals in Malaysia. MARMS-PCR and CSGE were performed to screen β-globin gene mutations. PCR-RFLP was performed to identify Xmn1-Gγ polymorphism. All the genotyping results were confirmed and validated by DNA sequencing. The results obtained were analyzed using SPSS version 22 and STATA SE. Out of 204 subjects screened, 152 subjects were diagnosed as HbE/β-thalassemia. Thirteen compound heterozygous mutations were successfully identified. The most prevalent compound heterozygous mutations were CD 26 (G-A) & IVS 1-5 (G-C) (36.2%), CD 26 (G-A) & CD 41/42 (-TTCT) (26.9%) and compound heterozygous CD 26 (G-A) & IVS 1-1 (G-T (11.8%). Two previously unreported rare mutations which are prevalent in Algerian populations, compound heterozygous CD 26 (G-A) & IVS 1-2 (T-C) and compound heterozygous CD 26 (G-A) & IVS 1-2 (T-A) were also discovered. The prevalent compound heterozygous mutations were statistically significant with MCH (p=0.033) and HbF level (p=0.008). Xmn1-Gγ gene polymorphism were found in 74 (54.8%) out of 135 HbE/β-thalassemia patients. Majority of them were CT heterozygous (51.1%), 45.2% were identified as CC homozygous and 3.7% subjects were identified as TT homozygous genotypes. Fisher exact test showed that Xmn1-Gγ polymorphism has no statistical relationship with HbF level and clinical phenotype of HbE/β-thalassemia patients. This study gives a potential insight of the impact of genetic modifiers on genotype heterogeneity and clinical severity of the disease. A better understanding of the mechanism underlying the variety of phenotypes of this disease may lead to the direction for a better future management plans. References 1. Borgna-Pignatti, C. (2007). Modern treatment of thalassaemia intermedia. Bitish journal of haemotology, 138 (3), 291-304 2. George, E. (2013). HbE A β-Thalassemia in Malaysia in Malaysia: Revisited. Journal of Haematology & Thromboembolic Diseases. 3. Ganguly, A., Rock, M.J & Prockop, D. J (1993). Confirmation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR product and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proceeding of the National Academy of Sciences, 90(21), 10325-10329. 4. Hassan, s., Ahmad, R., Zalaria, Z., Zulkafli, Z. & Abdullah, W. Z. (2013). Detection of β-globin Gene mutations Among β-thallassaemia Carriers and patients in Malaysia: Application of Multiplex Amplification Refractory Mutation System- Polymerase Chain Reactions

the detection of β-globin mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia. American Journal of blood research, 4(1), 33. 6. Sherva, R., Sripichai, O., Abel, K., Ma, Q., Whitacre, J., Angkachatchai, V., Makarasara, W., Winichagoon, P., Svasti, S. & Fucharoen, S. (2010). Genetic modifiers of Hb E/ β 0 Thalassemia identified by a two-stage genome-wide association study. BMC medical genetics, 11 (1), 51. 7. Weatherall, D. (2001). Phenotype-genotype relationships in monogenetic disease: lessons from the thalassaemias. Nature Reviews Genetics, 2 (4), 245-255.

5. Hanafi, S., Hassan, R., Bahar, R., Abdullah, W. Z., Johan, M.F., Rashid, N. D., Azman, N. F Nasir, A., Hassan, S. & Ahmad, R. (2014). Multiplex amplification refractory mutation system (MARMS) for MyHVP Newsletter | Jan-July 2017| page 7

Photo Diary Key events in in the first half of 2017 (January - July) Photographs below were taken during January - July 2017













Photo 1

Photo 2 - 4

Photo 5 - 6

Photo 7 - 12

Human Genome Meeting 2017

EduVariome at SMK Bandar Kuala Krai

MOU Exchange Ceremony between USM and HVP

Feb 5-7, 2017

March 29, 2017

July 17, 2017

Kuala Lumpur GG2020 Meeting & GG2020 Conference 2017 July 17-18, 2017

Barcelona, Spain

Kelantan, Malaysia

Kuala Lumpur, Malaysia

Kuala Lumpur, Malaysia

MyHVP Newsletter | Jan-July 2017| page 8

MyHVP Newsletter | Volume 4 | Issue 1 | Jan - July 2017  
MyHVP Newsletter | Volume 4 | Issue 1 | Jan - July 2017