Epidemiology of Haemoglobinopathies in Malaysia

15th September 2011

Multiracial

Multiracial population
Indigenous
West Malaysia
Proto-Malay, Negrito, Senoi

Malays Chinese Indians

Tamils Gujeratis Punjabis

East Malaysia
Sabah
Kadazandusun, Bajau, Murut

Sarawak
Dayaks, Iban, Bidayuh, Orang Ulu

Pakistanis Ceylonese

Malaysia: Population 28.2 million

Statistics 2010

Ethnic groups

Malaysian Citizens 91.8% Noncitizens 8.2%

Bumiputera 64.7% Others 0.7% Indians 7.3%

Chinese 24.6%

Statistics 2010

Origins

Indigenous people
50 000 years ago- Paleolithic (early stone age) Out of Africa theory Orang asli

Proto-Malays (Melayu Asli)

Mekong river migration

Cham- Malay

Cham- Malay language

Malay Sungai Cham Sungai English River Malay Lada Cham Lada English Pepper

Banyak
Bintang Manis Anjing Sedikit Ikan Orang

Banyak
Bintang Manis Anjing Sedikit Ikan Orang

More
Star Sweet Dog Less Fish People

Gunung

Gunung

Mountain
Bronze Tin Bitter Eye Here Water

Tembaga Tembaga Timah Pahit Mata Sini Ayer Tima Pahit Mata Ni Aya

Buat

Buat

Do

Bapa

Pak

Father

Malaysian-Chinese
15th century: Puteri Hang Li Po married Sultan Mansur Shah of Malacca 18th 19th century:
Hokkien from Fujian district > Penang and Malacca > rubber plantation Teochew from Chaoshan district > JB, Selangor > pepper plantation Hainanese from Hainan > Kemaman, Pulau Ketam > cooks Hakka from Guangdong and Fujian > Perak, Selangor > miners Cantonese from Guangdong and Guangxi > KL, Ipoh, Seremban, Sandakan > miners/ developers

Malaysian- Chinese

Malaysian-Indians
Early 20th century Brought in by the British as labourers
Tamils- plantation

Sri Lankan Tamils and Malayees: clerical

Punjabis- police force Gujeratis and Sindhis: textile business

80% of total Indian community are Tamils (South Indians)

Malaysian-Indians

Prevalence

Worldwide
Approx. 270 million people (4.5% of world population) carry abnormal Hb genes 400 million people in South East Asia (SEA) 50% of carriers are in SEA

South East Asia

Prevalence in Malaysia
Cross-sectional study in Tanjong Karang n= 111 screened 1 in 4 (25%) are carriers
Ainoon O, Malaysian J Pathol 1994

*About 4.5% are carriers for thalassaemia 4.5% of Malaysian-Chinese are carriers for 0 thalassaemia
Thalassemia Carrier Diagnosis in Malaysia, E. George, Ed., pp. 16, SP-Muda Printing Sdn Bhd, Kuala Lumpur, Malaysia, 1998

Pilot screening project, Form 4

Kota Belud, Jasin, Melaka Sabah 8 18 Timur Laut, P Pinang 37

No. secondary schools

No. pupils No. screened

trait HbE trait trait

1 592 3 062 1 242 (78%) 2 905 (94.9%)

92 (7.4%) 10 (0.8%) 108 (8.3%) 48 (1.65%) 99 (3.4%) 44 (0.03%)

7 281 4 273 (58.7%)

87 (2.0%) 86 (2.05) 223 (5.2%)

Safiah B, MOH 2005-2006

 thalassaemias

 thalassaemias
Present throughout SEA Higher in northern parts
30% in Chiengmai Province of Thailand vs. 0.5% in Indonesia

thal-2 is equally distributed

thal-1 is most frequent in Chiengmai (12.2%)

Fuchaeron S, Hemoglobin 1997

 thal-1
Deletion of both duplicated globin genes 17.5- 20kb deleted gene is not deleted Known as SEA 0 molecular defect (- - SEA)

Fuchaeron S, Hemoglobin 1997

 thal-2
2 types
Deletion of 4.2 kb DNA (leftward type, -4.2) Deletion of 3.7 kb DNA (rightward type, -3.7)

-3.7 most common in Malaysia

-4.2 only found in Malaysian-Chinese high frequencies of -4.2 in South China
Guangxi 58%, Jiangxi 29%
E. George, Thalassemia Carrier Diagnosis in Malaysia, 1998

Hb Constant Spring
1st isolated in a Chinese family from Constant Spring district of Jamaica in 1971 Mutation (TAA>CAA) of termination codon at position 142 of the 2-globin gene 172 amino acids (normal 141)

Unstable mRNA-CS
Milner PF, Lancet 1971

Hb Constant Spring
Most common in SEA In Malaysia, most common in Malays
Malays- 2.24% Chinese- 0.66% Indians- 0.16%

In Bangkok- 1.48%
Fuchaeron S, Hemoglobin 1997 Wee YC, J Obstet Gynaecol Res 2005

Hb H disease, n= 24
Type of thal - - SEA/- 4.2 - -SEA/- 3.7 - -SEA/CS TT Ethnic No. origin cases Chinese Chinese (5) Malay (2) Chinese (5) Malay (8) Chinese 3 7 13 1 Age (yr) Hb (g/dL) Av Av (range) (range) 28 8.0 (21- 40) (7.1- 9.9) 31.5 9.2 (12- 63) (8.2- 10.0) 22.5 8.5 (6- 35) (3.4- 10.7) 57 10.6 HbH (%) Av (range) 4.0 (2.0- 6.1) 6.7 (3.9- 12.1) 15.1 (4.0- 25.6) n.d.

George E, Hemoglobin 1992

Common thalassaemia syndromes

HbH (- -/- ) HbH-CS (- -/CS) Hb AE-Barts (- -/- , E) Hb EF-Barts (- -/- , EE) Homozygous CS (CS/CS) Hb Barts hydrops fetalis (- -/- -)

 thalassaemias

Spectrum of thalassaemia mutations in Malays and Malaysian-Chinese

Malays
IVS 1-5 (G>C)
*IVS 1-1 (G>T)

%
19.4

Chinese
IVS 2-654 (C>T)

%
49.8
23.4

50.0 *Codon 41-42 (-TCTT)

*Codon 17 (A>T)
*Codon 35 (-C)

13.9
8.3

-28 (A>G)
*Codon 17 (A>T)

13.3
10.1

*Codon 41-42 (-TCTT)

IVS 2-654 (C>T)

5.6
2.8

*Codon 71-72 (+A)

-29 (A>G)

2.1
1.3

George E, Hemoglobin 1992 E. George, Thalassemia Carrier Diagnosis in Malaysia, 1998

Our neighbours

Fuchaeron S, Hemoglobin 1997

Fuchaeron S, Hemoglobin 1997

George E, Hemoglobin 1992

Kadazandusun
Deletional -thalassaemia Nondeletional thal -thal
*22 B-thal mutations

-3.7

-4.2 - - SEA - - FIL - - THAI HbCS HbQS

Kada 42 zan dusun n= 125 33.6%

Filipino deletion 0 16

12.8%
Jin-Ai MAT, J Biomed Biotech 2010

Spectrum of thalassaemia mutations in Northern Indians

5 mutations account for > 90%
IVS 1-5 (G>C) IVS 1-1 (G>T) del 619 bp codon 41/42 (-TCTT) codon 8/9 (+G)

Kazazian HH, EMBO J 1984 Garewal G, BJH 1994

Carrier frequency in India <1-17%

1. Jammu and Kashmir 8. Gujarat 2. Himachal Pradesh 9. Maharashtra 3. Uttarakhand 10. Goa 4. Punjab 11. Madhya Pradesh 5. Haryana 12. Chhattisgarh 6. Uttar Pradesh 13. Bihar 7. Rajasthan 14. Jharkhand 15. West Bengal 22. Meghahrya 16. Orissa 23. Arurachal Pradesh 17. Karnataka 24. Assam 18. Andhra Pradesh 25. Nagaland 19. Kerala 26. Manipur 20. Tamil Nadu 27. Mizoram 21. Sikkim 28. Tripura Chouhan DM 1992

Hb E
Mutation at position 26 on the globin gene Replaces glutamic acid by lysine Limited to mainland SEA Borders joining Thailand, Laos and Cambodia: Hb E triangle

Hb E triangle

Hb Malay
Codon 19 (Asn to Ser) (A>G) Common in Malays and Southern Thailand More severe than Hb E

Yang KG, BJH 1989

Common thalassaemia syndromes

thalassaemia major (00) thalassaemia intermedia (++) Hb E thalassaemia (E+, E0) Compound heterozygous Hb Malay Compound heterozygous thalassaemia

Comparison of Hb levels and Hb analysis

Mild + -thal/ HbE Severe + -thal/ HbE
Hb E -28/HbE CD 19/HbE IVS II- IVS 1-5/HbE 654/HbE

No.
Hb type

39
EE

16

13
EF 6.6 0.9 57.5 11.6 39.2 13.7

5
EF 7.9 1.0 52.2 8.0 47.7 8.0

EFA EF+Malay 9.5 1.5 9.2 2.8 58.2 3.4 3.4 1.1

Hb (g/dL) 11.4 1.2 Hb E (%) Hb F (%)

95.2 57.1 5.9 2.1 4.8 2.1 10.1 5.6

Fuchaeron S, Hemoglobin 1997

GA()0

and G(A)0- thal

Both reported in Malaysia G(A)0 found in Cantonese subjects GA()0 found in Thais Hb F between 9.9- 16.6%

Trent RJ, BJH 1984 George E, Hemoglobin 1986

Patient numbers

Total no. patients = 5115

Mytalasemia registry, Sept 2011

540

500
1341

Mytalasemia registry, Sept 2011

Mytalasemia registry, Sept 2011

Mytalasemia registry, Sept 2011

Mytalasemia registry, Sept 2011

50 100 150 200

x 101

Mytalasemia registry, Sept 2011

Affected new births in Malaysia

5% carrier frequency for -thal, 3% for 0-thal and 10% for Hb E Using Hardy-Weinberg equation for recessively inherited single gene disorder

Taking birth rate at 500,000 births/year

Calculate:
350 homozygote thal births/ year 120 hydrops per year 937 Hb E- thal births/year

Summary
Thalassaemia is the most common inherited single gene disorder in the world 50% of thalassaemia carriers are in South East Asia Thalassaemia syndromes were originally confined to the tropics

Changing epidemiology
SEAsians are now scattered all over

Summary
In Malaysia, the Chinese, Malays and indigenous people are commonly affected Hb E, Hb Malay and Hb Constant Spring more common in Malays 0-thal more common in Chinese

Summary
The common hemoglobinopathies/ thalassaemias in Malaysia are:
thalassaemia major thalassaemia intermedia Hb E thalassaemia Hb H disease Hb H- Constant Spring

Summary
With a high prevalence of about 5%, screening for thalassaemia should be undertaken Screen for -thal, 0- thal, Hb E

>50% die by age 30 years

Loss of productivity

Estimated life-time cost: >RM1 million/patient

Health burden

The end