Distribution of 22 Single Nucleotide Polymorphisms in 13 Cytokine Genes in Malays, Chinese, and Indians in Peninsular Malaysia.

Introduction: Cytokines are cell signaling glycoproteins that are particularly important in immunity and inflammatory responses. Therefore, variations, such as single nucleotide polymorphisms (SNPs), in genes encoding for cytokines may have important consequences for their roles in health. Materials and Methods: A total of 222 unrelated, healthy, and un-admixed Malays (n = 97), Chinese (n = 77), and Indians (n = 48) with a median age of 30 years old (range 21-50) were typed for 22 cytokine gene SNPs: IL-1α -889 T/C, IL-1ß (-511 T/C, +3962 T/C), IL-1R pst1 1970 T/C, IL-1RA mspa1 11100 T/C, IL-4Rα +1902 G/A, IL-12 - 1188 C/A, IFN-γ +874 A/T, TGF-ß (cdn 10 C/T, cdn 25 G/C), TNF-α (-308 A/G, -238 A/G) IL-2 (+166 G/T, -330 T/G), IL-4 (-1098 T/G, -590 T/C, -33 T/C), IL-6 (-174 C/G, nt565 G/A), and IL-10 (-1082 G/A, -819 C/T, -592 A/C). This involved using well-established polymerase chain reaction procedures with sequence-specific primers and restriction fragment length polymorphism methods. Results: The majority of the screened cytokine gene SNPs are polymorphic in all three ethnicities. Exceptions include TGF-ß cdn 25 (G/C), IL-1ß +3962 (T/C), and TNF-α -238 (A/G), which were all observed to be monomorphic in Malays, Chinese and Indians. Many of the analyzed cytokine gene SNP genotypes deviated from Hardy-Weinberg equilibrium and the three ethnic study groups were all well-separated from reference Asian, African and European populations in a principal component analysis plot. Conclusion: We successfully typed 22 SNPs in 13 cytokine genes from genetic material collected from unrelated and un-admixed Malay, Chinese and Indian individuals in Peninsular Malaysia. These new cytokine gene population datasets reveal interesting contrasts with other populations.

Clinical and Haematological Parameters of Commonly Reported Non-deletional α-thalassaemia Mutations in Southeast Asia: A Review

@#Alpha (α)-thalassaemia is a common genetic disorder worldwide caused by the deletion and rarely non-deletional mutations of the α-globin gene. Nearly 70 types of non-deletional mutations have been reported worldwide, and this review focuses on the common ones affecting α-thalassaemia patients. The common mutations are initiation codon mutation, codon 30, haemoglobin (Hb) Constant Spring, Hb Quang Sze, Hb Adana and Hb Evora. The haematological parameters of non-deletional mutations usually show mild changes. However, a severe reduction in haemoglobin level, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), and mean corpuscular haemoglobin count (MCHC) has been observed among compound heterozygous HbH disease, involving both deletional and non-deletional mutations. Although non-deletional mutations are rarely reported, it requires the study of more cases to understand the clinical phenotypes that lead to severe clinical manifestations.

The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia.

Killer cell immunoglobulin-like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune-mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under-represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+ HLA-C in the Malaysian Chinese group, caused by the low frequency of C2+ HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high-resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies.

Acute Abdomen: Unmasked the Bleeding Site in Severe Haemophilia A

@#Haemophilia A is an inherited bleeding disorder, commonly involve soft tissues and joints. Gastrointestinal tract bleeding, are not uncommon but seldom highlighted. A 23-year-old male with underlying severe haemophilia A was presented with a generalised abdominal pain for 2 days, abdominal distension, diarrhoea and vomiting. He did not have any trauma to the abdomen. Abdominal examination revealed generalized tenderness with sign of guarding on palpation. Laboratory investigations revealed isolated, prolonged activated partial thromboplastin time (APTT) with normal total white blood cell count and haemoglobin level. In view of acute abdomen, which was not resolved by conservative treatment, an emergency laparotomy was done with FVIII concentrate and recombinant factor VII (rFVII) coverage. Intraoperative findings noted patchy gangrenous spots of about 30 cm in length in the small bowel. Histopathology examination revealed an evidence of haemorrhage within the submucosal and intramuscularis layer from the resected specimen. This case highlighted the possibility of gastrointestinal bleeding without prior trauma, which can be presented as acute abdomen in severe haemophilia patient.

Transfusion Medicine and Molecular Genetic Methods.

Transfusion procedures are always complicated by potential genetic mismatching between donor and recipient. Compatibility is determined by several major antigens, such as the ABO and Rhesus blood groups. Matching for other blood groups (Kell, Kidd, Duffy, and MNS), human platelet antigens, and human leukocyte antigens (HLAs) also contributes toward the successful transfusion outcomes, especially in multitransfused or highly immunized patients. All these antigens of tissue identity are highly polymorphic and thus present great challenges for finding suitable donors for transfusion patients. The ABO blood group and HLA markers are also the determinants of transplant compatibility, and mismatched antigens will cause graft rejection or graft-versus-host disease. Thus, a single and comprehensive registry covering all of the significant transfusion and transplantation antigens is expected to become an important tool in providing an efficient service capable of delivering safe blood and quickly locating matching organs/stem cells. This review article is intended as an accessible guide for physicians who care for transfusion-dependent patients. In particular, it serves to introduce the new molecular screening methods together with the biology of these systems, which underlies the tests.

Familial antithrombin III deficiency in a Malay patient with massive thrombosis

Patients with low antithrombin III (AT III) has increased risk for arteriovenous thromboembolic (TE) disease. We report a 28-year-old Malay lady who presented with spontaneous right calf pain and swelling of one week duration. She was on oral contraceptive pills and had a history of travelling for a long distance prior to the presentation. Her brother who was diagnosed with AT III deficiency had arterial thrombosis at a young age. She was diagnosed as having right popliteal vein thrombosis by ultrasound and treated with subcutaneous fondaparinux. While on treatment, she developed massive bilateral pulmonary embolism (PE). Thrombophilia study showed reduced AT III activity (38μl/dl) and normal results for protein C, protein S, activated protein C resistance and lupus anticoagulant assays. This patient has heterozygous AT III deficiency added with significant acquired factors responsible for the TE events. Those with AT III deficiency may have resistance to heparin therapy and require higher doses of heparin.

Detection of β-globin Gene Mutations Among β-thalassaemia Carriers and Patients in Malaysia: Application of Multiplex Amplification Refractory Mutation System– Polymerase Chain Reaction

Background: β-thalassaemia is one of the most common single-gene disorders worldwide. Each ethnic population has its own common mutations, accounting for the majority of cases, with a small number of mutations for the rarer alleles. Due to the heterogeneity of β-thalassaemia and the multi-ethnicity of Malaysians, molecular diagnostics may be expensive and time consuming. Methods: A simple polymerase chain reaction (PCR) approach involving a multiplex amplification refractory mutation system (MARMS) and one amplification refractory mutation system (ARMS), consisting of 20 β-globin gene mutations, were designed and employed to investigate β-thalassaemia patients and carriers. Results: Out of 169 carriers tested with the MARMS, Cd 41/42 (–TTCT), Cd 26 (A–G) HbE, IVS 1–1 (G–T), and IVS 1–5 (G–C) were the most common mutations, accounting for 78.1%. Among the Malays, Cd 26 (A–G) HbE, Cd 41/42 (–TTCT), IVS 1–1 (G–T), and IVS 1–5 (G–C) were the most common mutations, accounting for 81.4%, whereas Cd 41/42 (–TTCT) and IVS 2–654 (C–T) were most common among the Chinese (79.1%). Conclusion: We propose the use of this cheap, easy to interpret, and simple system for the molecular diagnostics of β-thalassaemia among Malaysians at the Institute for Medical Research (IMR)