The effect of vitamin D pathway genes and deferasirox pharmacogenetics on liver iron in thalassaemia major patients

Pharmacogenomics Journal

Volumn 19, Issue 5, 2019, Pages 417-427

  Allegra, Sarah ^a   Cusato, Jessica ^a   De Francia, Silvia ^b   Longo, Filomena ^b   Pirro, Elisa ^b   Massano, Davide ^b   Avataneo, Valeria ^a   De Nicolò, Amedeo ^a   Piga, Antonio ^b   D’Avolio, Antonio ^a  

^a UNIVERSITY OF TURIN   (Italy)

^b UNIVERSITY OF TURIN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

DEFERASIROX; FERRITIN; IRON; VITAMIN D; CALCITRIOL RECEPTOR; CYTOCHROME P450 2D6;

AGE; AREA UNDER THE CURVE; ARTICLE; CYP24A1 GENE; CYP27B1 GENE; CYP2D6 GENE; DRUG METABOLISM; DRUG TRANSPORT; FERRITIN BLOOD LEVEL; GENE; GENE LINKAGE DISEQUILIBRIUM; GENOTYPE; HUMAN; IRON OVERLOAD; LIVER LEVEL; LIVER STIFFNESS; MAJOR CLINICAL STUDY; PHARMACOGENETICS; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM; THALASSEMIA MAJOR; TROUGH CONCENTRATION; UGT1A1 GENE; VDBP GENE; VDR GENE; VITAMIN METABOLISM; ADULT; BETA THALASSEMIA; FEMALE; GENETICS; LIVER; MALE; METABOLISM; NUCLEAR MAGNETIC RESONANCE IMAGING;

ADULT; BETA-THALASSEMIA; CYTOCHROME P-450 CYP2D6; DEFERASIROX; FEMALE; HUMANS; IRON; LINKAGE DISEQUILIBRIUM; LIVER; MAGNETIC RESONANCE IMAGING; MALE; PHARMACOGENETICS; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, CALCITRIOL; VITAMIN D;

EID: 85060139641     PISSN: 1470269X     EISSN: 14731150     Source Type: Journal    
DOI: 10.1038/s41397-019-0071-7     Document Type: Article

References (96)

1. Hoffbrand AV, Taher A, Cappellini MD. How I treat transfusional iron overload. Blood. 2012;120:3657–69.
2. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011;118:3479–88.
3. Bayanzay K, Alzoebie L. Reducing the iron burden and improving survival in transfusion-dependent thalassemia patients: current perspectives. J Blood Med. 2016;7:159–69.
4. Coates TD, Carson S, Wood JC, Berdoukas V. Management of iron overload in hemoglobinopathies: what is the appropriate target iron level? Ann N Y Acad Sci. 2016;1368:95–106.
5. Kwiatkowski JL. Current recommendations for chelation for transfusion-dependent thalassemia. Ann N Y Acad Sci. 2016;1368:107–14.
6. Oikonomidou PR, Casu C, Rivella S. New strategies to target iron metabolism for the treatment of beta thalassemia. Ann N Y Acad Sci. 2016;1368:162–8.
7. Hamidieh AA, Shazad B, Ostovaneh MR, Behfar M, Tayebi S, Malekzadeh R, et al. Noninvasive measurement of liver fibrosis using transient elastography in pediatric patients with major thalassemia who are candidates for hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1912–7.
8. Musallam KM, Motta I, Salvatori M, Fraquelli M, Marcon A, Taher AT, et al. Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with beta-thalassemia intermedia. Blood Cells Mol Dis. 2012;49:136–9.
9. Poustchi H, Eslami M, Ostovaneh MR, Modabbernia A, Saeedian FS, Taslimi S, et al. Transient elastography in hepatitis C virus-infected patients with beta-thalassemia for assessment of fibrosis. Hepatol Res. 2013;43:1276–83.
10. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–62.
11. Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003;361:1597–602.
12. Waldmeier F, Bruin GJ, Glaenzel U, Hazell K, Sechaud R, Warrington S, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos. 2010;38:808–16.
13. Bruin GJ, Faller T, Wiegand H, Schweitzer A, Nick H, Schneider J, et al. Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. Drug Metab Dispos. 2008;36:2523–38.
14. Taher A, Cappellini MD, Vichinsky E, Galanello R, Piga A, Lawniczek T, et al. Efficacy and safety of deferasirox doses of >30 mg/kg per day in patients with transfusion-dependent anaemia and iron overload. Br J Haematol. 2009;147:752–9.
15. EPAR. Exjade (deferasirox) prescribing information. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2007.
16. Nick H, Wong A, Acklin P, Faller B, Jin Y, Lattmann R, et al. ICL670A: preclinical profile. Adv Exp Med Biol. 2002;509:185–203.
17. Nick H, Acklin P, Lattmann R, Buehlmayer P, Hauffe S, Schupp J, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem. 2003;10:1065–76.
18. Chirnomas D, Smith AL, Braunstein J, Finkelstein Y, Pereira L, Bergmann AK, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood. 2009;114:4009–13.
19. Cusato J, Allegra S, Massano D, De Francia S, Piga A, D'Avolio A. Influence of single-nucleotide polymorphisms on deferasirox C trough levels and effectiveness. Pharmacogenomics J. 2014;15:263–71.
20. Allegra S, Cusato J, Francia SD, Massano D, Piga A, D'Avolio A. Role of pharmacogenetic on deferasirox AUC and efficacy. Glasgow: European Society of Human Genetics; 2015.
21. Allegra S, Cusato J, De Francia S, Massano D, Piga A, D'Avolio A. Deferasirox AUC efficacy cut-off and role of pharmacogenetics. Eur J Clin Pharmacol. 2016;72:1155–7.
22. Dimitriadou M, Christoforidis A, Fidani L, Economou M, Vlachaki E, Athanassiou-Metaxa M, et al. A 2-year prospective densitometric study on the influence of Fok-I gene polymorphism in young patients with thalassaemia major. Osteoporos Int. 2016;27:781–8.
23. Moulas A, Challa A, Chaliasos N, Lapatsanis PD. Vitamin D metabolites (25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D) and osteocalcin in beta-thalassaemia. Acta Paediatr. 1997;86:594–9.
24. Napoli N, Carmina E, Bucchieri S, Sferrazza C, Rini GB, Di Fede G. Low serum levels of 25-hydroxy vitamin D in adults affected by thalassemia major or intermedia. Bone. 2006;38:888–92.
25. Wood JC, Claster S, Carson S, Menteer JD, Hofstra T, Khanna R, et al. Vitamin D deficiency, cardiac iron and cardiac function in thalassaemia major. Br J Haematol. 2008;141:891–4.
26. Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ. Vitamin D: metabolism. Rheum Dis Clin North Am. 2012;38:1–11.
27. Weisman Y, Harell A, Edelstein S, David M, Spirer Z, Golander A. 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature. 1979;281:317–9.
28. Gray TK, Lester GE, Lorenc RS. Evidence for extra-renal 1 alpha-hydroxylation of 25-hydroxyvitamin D3 in pregnancy. Science. 1979;204:1311–3.
29. Stoffels K, Overbergh L, Bouillon R, Mathieu C. Immune regulation of 1alpha-hydroxylase in murine peritoneal macrophages: unravelling the IFNgamma pathway. J Steroid Biochem Mol Biol. 2007;103:567–71.
30. Esteban L, Vidal M, Dusso A. 1alpha-Hydroxylase transactivation by gamma-interferon in murine macrophages requires enhanced C/EBPbeta expression and activation. J Steroid Biochem Mol Biol. 2004;89-90:131–7.
31. Lin R, Nagai Y, Sladek R, Bastien Y, Ho J, Petrecca K, et al. Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002;16:1243–56.
32. Wood RJ, Tchack L, Angelo G, Pratt RE, Sonna LA. DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Physiol Genomics. 2004;17:122–9.
33. Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005;19:2685–95.
34. Allegra S, Cusato J, De Francia S, Arduino A, Longo F, Pirro E, et al. Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes. Pharmacogenomics J. 2017;18:506–15.
35. Allegra S, Cusato J, De Francia S, Longo F, Pirro E, Massano D, et al. Effect of pharmacogenetic markers of vitamin D pathway on deferasirox pharmacokinetics in children. Pharmacogenet Genomics. 2017;28:17–22.
36. Brittenham GM, Badman DG. Noninvasive measurement of iron: report of an NIDDK workshop. Blood. 2003;101:15–9.
37. Jensen PD. Evaluation of iron overload. Br J Haematol. 2004;124:697–711.
38. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–13.
39. Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol. 2010;54:650–9.
40. Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica. 2008;93:1385–8.
41. De Francia S, Massano D, Piccione FM, Pirro E, Racca S, Di Carlo F, et al. A new HPLC UV validated method for therapeutic monitoring of deferasirox in thalassaemic patients. J Chromatogr B. 2012;893–4:127–33.
42. Rodriguez S, Gaunt TR, Day IN. Hardy–Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.
43. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, et al. Linkage disequilibrium in the human genome. Nature. 2001;411:199–204.
44. Schwertner HA, Vitek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. 2008;198:1–11.
45. Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, et al. UGT1A1 gene polymorphism: impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J Gastroenterol. 2009;15:5058–66.
46. Argikar UA, Iwuchukwu OF, Nagar S. Update on tools for evaluation of uridine diphosphoglucuronosyltransferase polymorphisms. Expert Opin Drug Metab Toxicol. 2008;4:879–94.
47. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333:1171–5.
48. Mimura Y, Maruo Y, Ohta Y, Sato H, Takeuchi Y. Effect of common exon variant (p.P364L) on drug glucuronidation by the human UDP-glucuronosyltransferase 1 family. Basic Clin Pharmacol Toxicol. 2011;109:486–93.
49. Kang TW, Kim HJ, Ju H, Kim JH, Jeon YJ, Lee HC, et al. Genome-wide association of serum bilirubin levels in Korean population. Hum Mol Genet. 2010;19:3672–8.
50. Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T, et al. Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet. 2009;18:2700–10.
51. Sanna S, Busonero F, Maschio A, McArdle PF, Usala G, Dei M, et al. Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. Hum Mol Genet. 2009;18:2711–8.
52. Cusato J, Allegra S, De Francia S, Massano D, Piga A, D'Avolio A. Role of pharmacogenetics on deferasirox AUC and efficacy. Pharmacogenomics. 2016;17:561–72.
53. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73–87.
54. Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol. 2010;54:887–93.
55. Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour JF, et al. A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C. PLoS One. 2012;7:e40159.
56. Kitanaka S, Isojima T, Takaki M, Numakura C, Hayasaka K, Igarashi T. Association of vitamin D-related gene polymorphisms with manifestation of vitamin D deficiency in children. Endocr J. 2012;59:1007–14.
57. Rukin NJ, Strange RC. What are the frequency, distribution, and functional effects of vitamin D receptor polymorphisms as related to cancer risk? Nutr Rev. 2007;65:S96–101.
58. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–56.
59. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376:180–8.
60. Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010;9:941–55.
61. Bikle DD. Vitamin D regulation of immune function. Vitam Horm. 2011;86:1–21.
62. Poon AH, Gong L, Brasch-Andersen C, Litonjua AA, Raby BA, Hamid Q, et al. Very important pharmacogene summary for VDR. Pharmacogenet Genomics. 2012;22:758–63.
63. Nesic D, Cheng J, Maquat LE. Sequences within the last intron function in RNA 3'-end formation in cultured cells. Mol Cell Biol. 1993;13:3359–69.
64. Cusato J, Allegra S, Boglione L, De Nicolo A, Baietto L, Cariti G, et al. Vitamin D pathway gene variants and HCV-2/3 therapy outcomes. Antivir Ther. 2014;20:335–41.
65. Allegra S, Fatiguso G, Calcagno A, Baietto L, Motta I, Favata F, et al. Role of vitamin D pathway gene polymorphisms on rifampicin plasma and intracellular pharmacokinetics. Pharmacogenomics. 2017;18:865–80.
66. Andraos C, Koorsen G, Knight JC, Bornman L. Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism. Hum Immunol. 2011;72:262–8.
67. Saeki M, Kurose K, Tohkin M, Hasegawa R. Identification of the functional vitamin D response elements in the human MDR1 gene. Biochem Pharmacol. 2008;76:531–42.
68. Song YH, Naumova AK, Liebhaber SA, Cooke NE. Physical and meiotic mapping of the region of human chromosome 4q11-q13 encompassing the vitamin D binding protein DBP/Gc-globulin and albumin multigene cluster. Genome Res. 1999;9:581–7.
69. Malik S, Fu L, Juras DJ, Karmali M, Wong BY, Gozdzik A, et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci. 2013;50:1–22.
70. Carpenter TO, Zhang JH, Parra E, Ellis BK, Simpson C, Lee WM, et al. Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res. 2013;28:213–21.
71. Wjst M, Altmuller J, Faus-Kessler T, Braig C, Bahnweg M, Andre E. Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res. 2006;7:60.
72. Anderson LN, Cotterchio M, Cole DE, Knight JA. Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol Biomark Prev. 2011;20:1708–17.
73. Kim SU, Choi GH, Han WK, Kim BK, Park JY, Kim DY, et al. What are “true normal” liver stiffness values using FibroScan? A prospective study in healthy living liver and kidney donors in South Korea. Liver Int. 2009;30:268–74.
74. Colombo S, Belloli L, Zaccanelli M, Badia E, Jamoletti C, Buonocore M, et al. Normal liver stiffness and its determinants in healthy blood donors. Dig Liver Dis. 2010;43:231–6.
75. Kim BK, Kim SU, Choi GH, Han WK, Park MS, Kim EH, et al. “Normal” liver stiffness values differ between men and women: a prospective study for healthy living liver and kidney donors in a native Korean population. J Gastroenterol Hepatol. 2011;27:781–8.
76. Ling W, Lu Q, Quan J, Ma L, Luo Y. Assessment of impact factors on shear wave based liver stiffness measurement. Eur J Radiol. 2012;82:335–41.
77. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30–9.
78. Singh S, Kumar V, Vashisht K, Singh P, Banerjee BD, Rautela RS, et al. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides. Toxicol Appl Pharmacol. 2011;257:84–92.
79. Surekha D, Sailaja K, Rao DN, Padma T, Raghunadharao D, Vishnupriya S. Association of a CYP17 gene polymorphism with development of breast cancer in India. Asian Pac J Cancer Prev. 2011;11:1653–7.
80. Glickstein H, El RB, Shvartsman M, Cabantchik ZI. Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood. 2005;106:3242–50.
81. Glickstein H, El RB, Link G, Breuer W, Konijn AM, Hershko C, et al. Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood. 2006;108:3195–203.
82. Bonner F, Janzarik N, Jacoby C, Spieker M, Schnackenburg B, Range F, et al. Myocardial T2 mapping reveals age- and sex-related differences in volunteers. J Cardiovasc Magn Reson. 2014;17:9.
83. Allegra S, Cusato J, De Francia S, Pirro E, Massano D, Piga A, et al. Deferasirox pharmacokinetic evaluation in beta-thalassaemia paediatric patients. J Pharm Pharmacol. 2016;69:525–8.
84. Allegra S, De Francia S, Cusato J, Arduino A, Massano D, Longo F, et al. Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients. Pharmacogenomics. 2017;18:539–54.
85. Allegra S, De Francia S, Cusato J, Pirro E, Massano D, Piga A, et al. Deferasirox pharmacokinetic and toxicity correlation in beta-thalassaemia major treatment. J Pharm Pharmacol. 2016;68:1417–21.
86. Allegra S, De Francia S, Longo F, Massano D, Cusato J, Arduino A, et al. Deferasirox pharmacokinetics evaluation in a woman with hereditary haemochromatosis and heterozygous beta-thalassaemia. Biomed Pharmacother. 2016;84:1510–2.
87. Allegra S, Massano D, De Francia S, Longo F, Piccione F, Pirro E, et al. Clinical relevance of deferasirox trough levels in beta-thalassemia patients. Clin Exp Pharmacol Physiol. 2017;45:213–6.
88. Cancado R, Melo MR, de Moraes Bastos R, Santos PC, Guerra-Shinohara EM, Ballas SK, et al. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-year Phase 2 study. Eur J Haematol. 2015;95:545–50.
89. Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myelodysplasies). Leuk Res. 2010;34:864–70.
90. Neukirchen J, Fox F, Kundgen A, Nachtkamp K, Strupp C, Haas R, et al. Improved survival in MDS patients receiving iron chelation therapy—a matched pair analysis of 188 patients from the Dusseldorf MDS registry. Leuk Res. 2012;36:1067–70.
91. Leitch HA, Chan C, Leger CS, Foltz LM, Ramadan KM, Vickars LM. Improved survival with iron chelation therapy for red blood cell transfusion dependent lower IPSS risk MDS may be more significant in patients with a non-RARS diagnosis. Leuk Res. 2012;36:1380–6.
92. Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD, et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005;106:1460–5.
93. Brittenham GM, Farrell DE, Harris JW, Feldman ES, Danish EH, Muir WA, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med. 1982;307:1671–5.
94. Fischer R, Tiemann CD, Engelhardt R, Nielsen P, Durken M, Gabbe EE, et al. Assessment of iron stores in children with transfusion siderosis by biomagnetic liver susceptometry. Am J Hematol. 1999;60:289–99.
95. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48:835–47.
96. Berzigotti A, Castera L. Update on ultrasound imaging of liver fibrosis. J Hepatol. 2013;59:180–2.