Commenced in January 2007
Paper Count: 31113
Investigation of Genetic Epidemiology of Metabolic Compromises in ß Thalassemia Minor Mutation: Phenotypic Pleiotropy
Abstract:Human genome is not only the evolutionary summation of all advantageous events, but also houses lesions of deleterious foot prints. A single gene mutation sometimes may express multiple consequences in numerous tissues and a linear relationship of the genotype and the phenotype may often be obscure. ß Thalassemia minor, a transfusion independent mild anaemia, coupled with environment among other factors may articulate into phenotypic pleotropy with Hypocholesterolemia, Vitamin D deficiency, Tissue hypoxia, Hyper-parathyroidism and Psychological alterations. Occurrence of Pancreatic insufficiency, resultant steatorrhoea, Vitamin-D (25-OH) deficiency (13.86 ngm/ml) with Hypocholesterolemia (85mg/dl) in a 30 years old male ß Thal-minor patient (Hemoglobin 11mg/dl with Fetal Hemoglobin 2.10%, Hb A2 4.60% and Hb Adult 84.80% and altered Hemogram) with increased Para thyroid hormone (62 pg/ml) & moderate Serum Ca+2 (9.5mg/ml) indicate towards a cascade of phenotypic pleotropy where the ß Thalassemia mutation ,be it in the 5’ cap site of the mRNA , differential splicing etc in heterozygous state is effecting several metabolic pathways. Compensatory extramedulary hematopoiesis may not coped up well with the stressful life style of the young individual and increased erythropoietic stress with high demand for cholesterol for RBC membrane synthesis may have resulted in Hypocholesterolemia.Oxidative stress and tissue hypoxia may have caused the pancreatic insufficiency, leading to Vitamin D deficiency. This may in turn have caused the secondary hyperparathyroidism to sustain serum Calcium level. Irritability and stress intolerance of the patient was a cumulative effect of the vicious cycle of metabolic compromises. From these findings we propose that the metabolic deficiencies in the ß Thalassemia mutations may be considered as the phenotypic display of the pleotropy to explain the genetic epidemiology. According to the recommendations from the NIH Workshop on Gene-Environment Interplay in Common Complex Diseases: Forging an Integrative Model, study design of observations should be informed by gene-environment hypotheses and results of a study (genetic diseases) should be published to inform future hypotheses. Variety of approaches is needed to capture data on all possible aspects, each of which is likely to contribute to the etiology of disease. Speakers also agreed that there is a need for development of new statistical methods and measurement tools to appraise information that may be missed out by conventional method where large sample size is needed to segregate considerable effect. A meta analytic cohort study in future may bring about significant insight on to the title comment.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1334808Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 6207
 R.Saxena ,I.Panigrahi, "Molecular basis of Thalassemia," In Recent Advances in Hematology 2 , V.P.Choudhury , R.Saxena and H.P.Pati Eds,Jaypee Brothers, pp 58-72, 2006.
 K.T.McDonough,A.W.Nienhuis, "The Thalassemias. In : D.J.Nathan and F.A.Oski (Eds).4th Ed. Hematology of Infancy and Childhood.Philadelphia,PA:Saunders;pp 783-879. 1993.
 O .Shalev, E. Yehezkel, E.A. Rachmilewitz, "Inadequate utilization of routine electronic RBC counts to identify beta thalassemia carriers," Am J Public Health.,78(11):1476-7, Nov 1988.
 C.H. Wang, R.F. Schilling, "Myocardial infarction and thalassemia trait: an example of heterozygote advantage," Am J Hematol. ,49(1):73- 5,1995.
 M.R. Namazi, "Minor thalassemia as a protective factor against cerebrovascular accidents," Med Hypotheses ,59(3):361-2. Sep,2002 .
 M. Hashemi, E. Shirzadi, Z. Talaei, L. Moghadas, I. Shaygannia, M. Yavari, N. Amiri, H. Taheri, H. Montazeri, H. Shamsolkottabi, "Effect of heterozygous beta-thalassaemia trait on coronary atherosclerosis via coronary artery disease risk factors: a preliminary study,"Cardiovasc J Afr. 18(3):165-8,May-Jun 2007.
 M. Karimi, V. E. Marvasti, S. Motazedian and M. Sharifian,"Is Beta- Thalassemia Trait a Protective Factor against Hypertension in Young Adults?" Ann Hematol, Vol. 85, No. 1, pp. 29-31, January 2006.
 M. Gallerani, C. Scapoli, I. Cicognani, A. Ricci, L. Martinelli, R. Cappato, R. Manfredini, G. Dall-Ara, M. Faggioli, P.L. Pareschi, "Thalassemia trait and myocardial infarction: low infarction incidence in male subjects confirmed", J Intern Med,230(2):109-11,1991.
 K.Y. Kok, S.K. Yapp, "Techniques and clinical outcomes of laparoscopic cholecystectomy in adult patients with beta-thalassemias," Surg Laparosc Endosc Percutan Tech ,13(3),168-72 ,Jun 2003 .
 C .Borgna-Pignatti, F. Rigon, L. Merlo, R. Chakrok, R. Micciolo, L. Perseu, R. Galanello, "Thalassemia minor, the Gilbert mutation, and the risk of gallstones," Haematologica,88(10):1106-9, Oct, 2003.
 W.Y. Au, W.C. Cheung, G.C. Chan, S.Y. Ha, P.L. Khong, E.S. Ma, "Risk factors for hyperbilirubinemia and gallstones in Chinese patients with b thalassemia syndrome," Haematologica. 88(2):220-2, Feb 2003.
 M. Maioli , S. Pettinato , G.M. Cherchi , D. Giraudi , A.Pacifico ,G. Pupita , G.B.M. Tidore , "Plasma lipids in beta-thalassemiaminor," Atherosclerosis . Vol 75 ,2-3,245-248, 1989.
 M. Dimitriadou, A. Christoforidis, L. Fidani, M. Economou, V. Perifanis, I. Tsatra, G. Katzos, M .Athanassiou-Metaxa, "Fok-I gene polymorphism of vitamin D receptor in patients with beta-thalassemia major and its effect on vitamin D status," Hematology.;16(1):54-8, Jan 2011.
 M.G. Vogiatzi, E.A. Macklin, F.L. Trachtenberg, E.B. Fung, A.M. Cheung, E. Vichinsky,N. Olivieri, M. Kirby, J.L. Kwiatkowski, M. Cunningham, I.A. Holm, M. Fleisher, R.W. Grady,C.M. Peterson, P.J. Giardina, "Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America," Br J Haematol,146(5):546-56. Epub 2009 Jul 13.
 D .Dal Sacco, A. Parodi, E. Cozzani, G. Biolcati, D. Griso, A. Rebora, "A case of variegate porphyria with coeliac disease and betathalassaemia minor,"Dermatology,209(2):161-2, 2004.
 S. Timon, H.M. O'Flynn, D.E. Tate, T.P. Sculco, "Bilateral pathologic fractures in a patient with beta-thalassemia undergoing total hip arthroplasty," J Arthroplasty,13(2),217-20,Feb ,1998.
 N.G├│mez Rodr├¡guez, J.M. S├ínchez Burs├│n, A .Atanes Sandoval, J .Gra├▒a Gil, J .de Toro Santos, F .Galdo Fern├índez,
[Osteoporosis as the first manifestation of minor betathalassemia].
[Article in Spanish], An Med Interna,9(6):287-90,Jun,1992.
 N. Greep, A.L. Anderson, J.C. Gallagher, "Thalassemia minor: a risk factor for osteoporosis?" Bone Miner,16(1),63-72. Jan ,1992.
 M.G. Vogiatzi, E.A. Macklin, F.L. Trachtenberg, E.B. Fung, A.M. Cheung, E. Vichinsky, N. Olivieri, M. Kirby, J.L. Kwiatkowski, M. Cunningham, I.A. Holm, M. Fleisher, R.W. Grady, C.M. Peterson, P.J. Giardina, "Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America,"Br J Haematol,146(5),546-56. Epub 2009 Jul 13.
 M. Madhar, M. Latifi, S. Aziz, B.Essadki, T. Fikry,
[Aseptic osteonecrosis of the femoral head in thalassemia minor: a case report].
[Article in French]. Rev Chir Orthop Reparatrice Appar Mot.;91(2):170-2. 2005,Apr.
 M. Medrano San Ildefonso, A. Urruticoechea Arana,
[Beta-thalassemia minor and seronegative oligoarthritis].
[Article in Spanish]. An Pediatr (Barc), 59(5):502-3 Nov,2003.
 G.E. Pamuk, O.N. Pamuk, T. Set, O. Harmandar, N. Yesil. , "An increased prevalence of fibromyalgia in iron deficiency anemia and thalassemia minor and associated factors," Clin Rheumatol,27(9):1103- 8. Epub 2008 Apr 11.
 E. Fibach, E. Rachmilewitz, "The role of oxidative stress in hemolytic anemia," ,Curr Mol Med.8(7):609-19, 2008 Nov
 K. G. Wormsley, W. F. W. E. Logan,V. F. Sorrell, G.C. Cole, "Neurofibromatosis with pancreatic duct obstruction and steatorrhoea,"Postgrad Med J ,43: 432-435, 1967.
 S. Engelborghs, B.A. Pickut, P.P. De Deyn, "Recurrent transient ischemic attacks in a 15-year-old boy with beta-thalassemia minor and thrombophilia. Contribution of perfusion SPECT to clinical diagnosis," Acta Neurol Belg,103(2):99-102, 2003 Jun.
 M.Y. Abdalla, M. Fawzi, S.R. Al-Maloul, N .El-Banna, R.F. Tayyem, I.M. Ahmad, "Increased oxidative stress and iron overload in Jordanian _-thalassemic children," Hemoglobin,35(1):67-79, 2011.
 S. Selek, M. Aslan, M. Horoz, M. Gur, O. Erel, "Oxidative status and serum PON1 activity in beta-thalassemia minor," Clin Biochem,40(5- 6):287-91,Epub 2007 Jan 13.
 O. Nevruz, U. Ulas, T. Cetin, Y. Kutukcu, A. Kurekci , "Cognitive dysfunction in betathalassemia minor," Am J Hematol, 82(3):203-7, 2007,Mar.
 M.R. Namazi, "Minor thalassemia may be a risk factor for impulsiveness," Med Hypotheses,60(3):335-6, 2003 Mar.
 A.F.Ghiam, A.Hashemi, S.Taban, M.R.Bordbar, M.Karimi , "Beta Thalassemia Minor as a Risk Factor for Suicide and Violence: A Failure to Replicate,"Psychology, , 1: 17-21,2010.
 V. Arango, M. D. Underwood and J. J. Mann, "Serotonin Brain Circuits Involved in Major Depression and Suicide,"Progress in Brain Research, Vol. 136, pp. 443-453, 2002.
 C. Van Heeringen, "Suicide, Serotonin, and the Brain,"Crisis, Vol. 22, No. 2, pp. 66-70, 2001.
 O. Johnson, J. Becnel and C. D. Nichols, "Serotonin 5-HT(2) and 5- HT(1A)-like Receptors Differentially Modulate Aggressive Behaviors in Drosophila Melanogaster,"Neuroscience, Vol. 158, No. 4, pp. 1292- 1300, 18 February 2009.
 J. H. Meyer, A. A. Wilson, P. Rusjan, M. Clark, S. Houle, S. Woodside, J. Arrowood, K. Martin and M. "Colleton, Serotonin2A Receptor Binding Potential in People with Aggressive and Violent Behaviour," Journal of Psychiatry and Neuroscience, Vol. 33, No. 6, pp.499-508, November 2008.
 M. Karimi, V. E. Marvasti, S. Motazedian and M. Sharifian, "Is Beta- Thalassemia Trait a Protective Factor against Hypertension in Young Adults?" Ann Hematol,Vol. 85, No. 1, pp. 29-31, January 2006.
 T. Dork, et al , "Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens," Hum Genet ,100:365-77, 1997.
 J.E. Mickle, G.R. Cutting, "Genotype-phenotype relationships in cystic fibrosis," Med Clin North Am ,84:597-607, 2000.
 R. Radpour, M.A. Gilani, H. Gourabi, A.V. Dizaj, S. Mollamohamadi, "Molecular analysis of the IVS8-T splice variant 5T and M470V exon 10 missense polymorphism in Iranian males with congenital bilateral absence of the vas deferens," Mol Hum Reprod ,12:469-73, 2006.
 P. Prasun, M. Pradhan, S. Agarwal, "One gene, many phenotypes," J Postgrad Med,53:257-61, 2007.
 T.A. Manolio, et al, " Finding the missing heritability of complex diseases," Nature ,461:747-753, 2009.
 B. Mukherjee, J. Ahn, S.B. Gruber, G. Rennert, V. Moreno, N. Chatterjee, "Tests for gene-environment interaction from case-control data: a novel study of type 1 error, power and designs," Genet Epidemiol 32:615-626. 2009
 B .Ebony et al, "Gene-environment interplay in common complex diseases: forging an integrative modelÔÇörecommendations from an NIH workshop," Genetic Epidemiology,Volume 35, Issue 4, pages 217-225, May.