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Pustika Amalia Wahidiyat
Faktor-faktor genetik pengubah manifestasi klinis thalassemia interaksi antara mutasi thalassemia polimorfisme dan SNPs pada klaster gen globin
"Latar belakang: Thalassemia dan hemoglobinopati merupakan kelainan gen tunggal terbanyak di dunia, termasuk di Indonesia dengan frekuensi pembawa sifat thalassemia-~ 3-10% dan HbE 1-36%. Thalassemia-WIThE adalah bentuk heterozigot ganda paling sering ditemukan dengan gejala klinis bervariasi, dari asimtomatik sampai berat. Beberapa faktor pemodifikasi telah diketahui memengaruhi manifestasi klinis. Faktanya pasien dengan jenis mutasi sarna dapat memiliki manifestasi klinis berbeda. Hal itu menunjukkan ada faktor pemodifikasi lain yang memengaruhi derajat manifestasi klinis. Tujuan: Meneari faktor-faktor genetik yang memengaruhi manifestasi klinis, antara lain MGP: bg2, bgll dan bg 200 yang diduga berhubungan dengan meningkatnya produksi HbF dan memengaruhi variasi manifestasi klinis. Metode penelitian: Penelitian dilakukan dengan metode belah lintang pada pasien thalassemia-~IHbE yang berobat ke Divisi Hematologi-Onkologi Dept. IKA dan Dept. IPD, RSCM, Lembaga Biomolekular Eijkman Jakarta, serta rumah sakit lain sejak bulan Desember 2006 sampai dengan Oktober 2008. Tahap I mendapatkan 293 subjek, terdiri atas 63 subjek ringan (skor <4), 101 subjek intermedia (skor 4-7,5), dan 129 subjek herat (skor ~7,5). Seluruh subjek menjalani pemeriksaan hematologi termasuk indeks eritrosit, morfologi eritrosit, analisis Hb dan feritin serum. Tahap IT dilakukan pemeriksaan jenis mutasi thalassemia-~, termasuk delesi besar gen globin-~ (HPFH tipe delesi), dan jenis mutasi thalassemia-a (co-inheritance dengan thalassemia-a dan triplikasi rantai globin-a) pada 192 subjek kelompok ringan dan berat. Tahap m dilakukan pemeriksaan HPFH nondelesi (polimorfismeXmnI-Gy) dan SNPs: bg2, bg11 dan bg200 pada 187 subjek kelompok ringan dan berat dengan mutasi-~o dan _~+beJat mumi. Pemeriksaan SNPs dilakukan dengan teknik RDB dan teknik sekuensing langsung. Basil penelitian dan pembabasan: Hasil penelitian menunjukkan jenis mutasi thalassemia-~ bukan faktor yang memengaruhi manifestasi klinis, kecuali mutasi IVS 1- nt5 (jenis mutasi-~+bera~ yang berhubungan dengan manifestasi klinis berat (P<0,05). Delesi satu gen globin-a (3.7 kb) berhubungan dengan manifestasi klinis ringan, sedangkan polimorfisme XmnI-G'Y tidak memengaruhi manifestasi klinis. Dari 3 buah SNPs, hanya bg200 yang berhubungan dengan manifestasi klinis (RR: 4,15 (1,22 < RR < 14,17) danp
Background: Thalassemia and hemoglobinopathy are the most common monogenic diseases in the world including Indonesia, with gene frequencies of ~-thalassemia 3-10% and for HbE 1-36%. Compund heterozygote ~-thalassemialHbE is one of the world's most common form, have a wide variation of clinical manifestations ranging from asymptomatic to transfusion-dependent. Several major modified genetic factors (MGP) which can influence the phenotype have been reported. The fact that patients with identical p-thalassemia mutations showed different clinical severity. This finding suggests that there are other MGP which contribute to the severity of the diseases. Purpose: To fmd ·several modifying gene factors including SNPs: bg2, bgll and bg200 which had tendency to increase HbF production and influences the clinical manifestations of p-thalassemialHbE. Materials and Methods: This was a cross sectional study to a total 293 subjects with pthalassemia/ HbE patients from Department of Child Health and Department of Internal Medicine, Cipto Mangunkusumo National Hospital, Eijkman Institute for Molecular Biology, Jakarta and other hospitals from December 2006 until October 2008. Phase I: Subjects were divided into mild (score <4, n=63), intermediate (score 4-7.S, n=101), and severe (score 2: 7.S, n= 129) using Thailand severity scoring. Hematological parameters including CBC, red cell indices and morphology, Hb analysis and serum ferritin were performed. Phase ll: 192 subj ects from mild and severe group were performed to characterize the ~thalassemia mutation, including large deletion of P-globin gene (deletion HPFH) and interaction of 0.thalassemia (deletion, non deletion a-thalassemia and a-globin gene triplication). Phase ill: XmnI-Gy polymorphisms and 3 SNPs: bg2, bgll and bg200 executed from 187 subjects of mild and severe groups with ~o - and ~~ -thalassemia mutation without any gene interaction. SNPs were performed by RDB and direct sequencing. Results: In this study types of p-thalassemia mutation are not the modifying factor contribute to the Clinical manifestation, except the · IVS I-ntS that correlate with severe clinical manifestations (p"
Jakarta: Fakultas Kedokteran Universitas Indonesia, 2009
D1765
UI - Disertasi Open  Universitas Indonesia Library
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Teny Tjitra Sari
Respons imun pada talasemia mayor dan pengaruh suplementasi seng terhadap kualitas respons imun pasca-splenektomi = Immune response of thalassemia major and zinc supplementation effects on immune response quality of post splenectomy thalassaemia major
"Latar Belakang: Respons imun berperan pada kerentanan pasien talasemia terhadap infeksi. Defisiensi seng pada talasemia akan memperburuk respons imun. Penelitian ini bertujuan mengetahui profil respons imun pasien talasemia mayor dan pengaruh suplementasi seng dan imunisasi pneumokokus pada respons imun pasien talasemia pasca-splenektomi.
Metode: Penelitian dilakukan di Pusat Thalassemia RSCM, Jakarta pada September 2013 ? Februari 2014. Studi observasi dengan metode belah lintang komparatif pada talasemia mayor sehat usia > 12 tahun dan HIV negatif non- dan pasca-splenektomi mendahului studi intervensi dengan metode randomized, double-blinded, controlled trial pada talasemia pasca-splenektomi yang dialokasikan menjadi kelompok seng 1,5 mg/kg/hr maksimum 50 mg, atau plasebo. Dua jenis imunisasi pneumokokus diberikan untuk menguji fungsi limfosit T. Luaran yang diukur adalah respons imun non-spesifik (jumlah dan fagositosis neutrofil) dan respons imun spesifik (kuantitatif dan kualitatif). Respons imun spesifik kualitatif mengukur produksi IgG pneumokokus, IL-2 dan TNF-α pasca pajanan PHA.
Hasil Penelitian: Median fagositosis neutrofil kelompok pasca-splenektomi 29,79 (4 sampai 81)% dan kelompok non-splenektomi 55,83 (2 sampai 133)% (p < 0,001). Kelompok pasca-splenektomi mempunyai jumlah netrofil, limfosit total, jumlah limfosit T, jumlah limfosit T CD4+ dan CD8+ yang lebih tinggi dibanding kelompok non- splenektomi. Tidak ada perbedaan respons imun spesifik kualitatif yang bermakna di antara pasien talasemia mayor. Setelah intervensi, hanya 18 dari 28 subjek kadar seng serum kelompok seng yang menjadi normal. Walaupun fagositositosis neutrofil hanya berubah dari 31,36 (4 sampai 81)% menjadi 30,44 (3 sampai 72)% (p = 0,554), namun terdapat kecenderungan perbaikan fagositosis neutrofil pada kelompok seng. Parameter respons imun lainnya tidak menunjukkan perubahan antara kelompok seng dan plasebo selama penelitian 12 minggu (p > 0,05).
Simpulan: Terdapat perbedaan respons imun antara pasien talasemia pasca-splenektomi dan non-splenektomi. Belum dapat dibuktikan pengaruh suplementasi seng pada hampir semua parameter respons imun pasien talasemia mayor pasca-splenektomi. Seng mungkin dapat direkomendasikan sebagai suplementasi, tetapi perlu penelitian lanjutan mengenai dosis dan lama pemberian yang tepat untuk perbaikan respons imun pasien talasemia mayor pasca-splenektomi.
Introduction: Immune response plays a role in increasing thalassemia patient?s susceptibility to infections. Zinc deficiency in thalassemia patients will alter immune response. The aim of this study is to evaluate immune response of thalassemia major and zinc supplementation effects on immune response quality of post-splenectomy thalassemia major.
Methods: This study was conducted at Thalassaemia Centre, Cipto Mangunkusumo Hospital Jakarta on September 2013 ? February 2014. An observational study using comparative cross-sectional method was done in healthy non- and post-splenectomy thalassemia major aged > 12 year and HIV negative. Then, it was followed by an interventional study using randomized, double-blinded, controlled trial, on post- splenectomy subjects, which were assigned to receive 1.5 mg/kg/d maximum 50 mg/d zinc or placebo. Moreover, 2 type of immunization were also administered in order to assess T lymphocyte function. The outcomes were non-specific (neutrophil count and phagocytosis) and specific immune response (quantitave and qualitative). Qualitative specific immune response measured by detecting IgG pneumococcal, IL-2 and TNF-α after PHA exposure.
Results: Median of neutrophil phagocytosis on post-splenectomy and non-splenectomy were 29.79 (4 to 81)% and 55.83 (2 to 133)% (p < 0.001). Post-splenectomy subjects have higher neutrophil count, total lymphocyte count, lymphocyte T count, lymphocyte T CD4+ and CD8+ than non-splenectomy. There is no significant difference on qualitative specific immune response among thalassemia major. Following the intervention, only 18 out of 28 subjects of zinc group had normal plasma zinc. There was a trend of neutrophil phagocytosis improvement on zinc group despite a little shifting on those value, from 31.36 (range 4 to 81)% to 30.44 (3 to 72)% (p = 0.554). Other immune response parameters showed no different changes between two groups after 12 weeks supplementation (p > 0.05).
Conclusions: There were significant differences on immune response of post- splenectomy and non-splenectomy patients. The significant changes on almost all of immune response parameter after zinc supplementation have not been proved yet. Addition of zinc supplementation may be recommended, but it need further study to evaluate the dose and duration of supplementation to improve immune response in splenectomised thalassemia major patients."
Jakarta: Fakultas Kedokteran Universitas Indonesia, 2014
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UI - Disertasi Membership  Universitas Indonesia Library