Investigation of Genetic Epidemiology of
Metabolic Compromises in ß Thalassemia Minor
Mutation: Phenotypic Pleiotropy
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.
[1] 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.
[2] 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.
[3] 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.
[4] C.H. Wang, R.F. Schilling, "Myocardial infarction and thalassemia trait:
an example of heterozygote advantage," Am J Hematol. ,49(1):73-
5,1995.
[5] M.R. Namazi, "Minor thalassemia as a protective factor against
cerebrovascular accidents," Med Hypotheses ,59(3):361-2. Sep,2002 .
[6] 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.
[7] 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.
[8] 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.
[9] 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 .
[10] 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.
[11] 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.
[12] 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.
[13] 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.
[14] 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.
[15] 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.
[16] 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.
[17] N.Gómez Rodríguez, J.M. Sánchez Bursón, A .Atanes Sandoval, J
.Graña Gil, J .de Toro Santos, F .Galdo Fernández, [Osteoporosis as the
first manifestation of minor betathalassemia].[Article in Spanish], An
Med Interna,9(6):287-90,Jun,1992.
[18] N. Greep, A.L. Anderson, J.C. Gallagher, "Thalassemia minor: a risk
factor for osteoporosis?" Bone Miner,16(1),63-72. Jan ,1992.
[19] 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.
[20] 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.
[21] 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.
[22] 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.
[23] E. Fibach, E. Rachmilewitz, "The role of oxidative stress in hemolytic
anemia," ,Curr Mol Med.8(7):609-19, 2008 Nov
[24] 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.
[25] 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.
[26] 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.
[27] 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.
[28] O. Nevruz, U. Ulas, T. Cetin, Y. Kutukcu, A. Kurekci , "Cognitive
dysfunction in betathalassemia minor," Am J Hematol, 82(3):203-7,
2007,Mar.
[29] M.R. Namazi, "Minor thalassemia may be a risk factor for
impulsiveness," Med Hypotheses,60(3):335-6, 2003 Mar.
[30] 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.
[31] 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.
[32] C. Van Heeringen, "Suicide, Serotonin, and the Brain,"Crisis, Vol. 22,
No. 2, pp. 66-70, 2001.
[33] 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.
[34] 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.
[35] 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.
[36] T. Dork, et al , "Distinct spectrum of CFTR gene mutations in congenital
absence of vas deferens," Hum Genet ,100:365-77, 1997.
[37] J.E. Mickle, G.R. Cutting, "Genotype-phenotype relationships in cystic
fibrosis," Med Clin North Am ,84:597-607, 2000.
[38] 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.
[39] P. Prasun, M. Pradhan, S. Agarwal, "One gene, many phenotypes," J
Postgrad Med,53:257-61, 2007.
[40] T.A. Manolio, et al, " Finding the missing heritability of complex
diseases," Nature ,461:747-753, 2009.
[41] 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
[42] 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.
[1] 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.
[2] 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.
[3] 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.
[4] C.H. Wang, R.F. Schilling, "Myocardial infarction and thalassemia trait:
an example of heterozygote advantage," Am J Hematol. ,49(1):73-
5,1995.
[5] M.R. Namazi, "Minor thalassemia as a protective factor against
cerebrovascular accidents," Med Hypotheses ,59(3):361-2. Sep,2002 .
[6] 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.
[7] 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.
[8] 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.
[9] 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 .
[10] 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.
[11] 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.
[12] 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.
[13] 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.
[14] 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.
[15] 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.
[16] 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.
[17] N.Gómez Rodríguez, J.M. Sánchez Bursón, A .Atanes Sandoval, J
.Graña Gil, J .de Toro Santos, F .Galdo Fernández, [Osteoporosis as the
first manifestation of minor betathalassemia].[Article in Spanish], An
Med Interna,9(6):287-90,Jun,1992.
[18] N. Greep, A.L. Anderson, J.C. Gallagher, "Thalassemia minor: a risk
factor for osteoporosis?" Bone Miner,16(1),63-72. Jan ,1992.
[19] 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.
[20] 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.
[21] 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.
[22] 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.
[23] E. Fibach, E. Rachmilewitz, "The role of oxidative stress in hemolytic
anemia," ,Curr Mol Med.8(7):609-19, 2008 Nov
[24] 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.
[25] 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.
[26] 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.
[27] 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.
[28] O. Nevruz, U. Ulas, T. Cetin, Y. Kutukcu, A. Kurekci , "Cognitive
dysfunction in betathalassemia minor," Am J Hematol, 82(3):203-7,
2007,Mar.
[29] M.R. Namazi, "Minor thalassemia may be a risk factor for
impulsiveness," Med Hypotheses,60(3):335-6, 2003 Mar.
[30] 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.
[31] 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.
[32] C. Van Heeringen, "Suicide, Serotonin, and the Brain,"Crisis, Vol. 22,
No. 2, pp. 66-70, 2001.
[33] 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.
[34] 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.
[35] 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.
[36] T. Dork, et al , "Distinct spectrum of CFTR gene mutations in congenital
absence of vas deferens," Hum Genet ,100:365-77, 1997.
[37] J.E. Mickle, G.R. Cutting, "Genotype-phenotype relationships in cystic
fibrosis," Med Clin North Am ,84:597-607, 2000.
[38] 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.
[39] P. Prasun, M. Pradhan, S. Agarwal, "One gene, many phenotypes," J
Postgrad Med,53:257-61, 2007.
[40] T.A. Manolio, et al, " Finding the missing heritability of complex
diseases," Nature ,461:747-753, 2009.
[41] 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
[42] 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.
@article{"International Journal of Medical, Medicine and Health Sciences:61204", author = "Surajit Debnath and Soma Addya", title = "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.", keywords = "Genetic disease, Genetic epidemiology,
Heterozygous, Phenotype, Pleotropy, ß Thalassemia minor,
Metabolic compromises.", volume = "6", number = "6", pages = "250-5", }