Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

Azza A. M. H. Swar Aldahab, Abdallah. O. Elkhawad

Abstract


Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G>A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G>A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G>A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G>A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

Full Text:

PDF

References


Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera

R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation:

A systematic review and meta-analysis.

Lancet. 2006 Feb; 367(9508):404–11. DOI: 10.1016/S0140-

(11)61294-4.

Li S, Zou Y, Wang X. Warfarin dosage response related

pharmacogenetics in Chinese population. PLoS One. 2015

Jan16; 10(1). DOI: 10.1371/journal.pone.0116463

Witt DM, Delate T, Clerk NP, Martell C. On behalf of the

Warfarin Association Research Project and other Endeavours

(WARPED) Consortium. Blood. Jul 2009; 114:952-

Kim JH, Song YB, Shun DH. How well does the target INR

level maintain in warfarin–treated patients with non-vulvar

atrial fibrillation? Yonsi Med J. 2009 Feb 28; 50(1):83–8.

DOI: 10.3349/ymj.2009.50.1.83.

Lubetsky A, Srern ED, Chetrit A, et al. Vitamin K intake

and sensitivity to warfarin in patients consuming regular

diets. Thromb Haemost. 1999; 81:396–9.

De Assis MC, Rabelo ER, Avila CW, et al. Vitamin K guided

strategy: A randomized controlled trial. Circulation.

; 120:1115–22. DOI: 10.1161/CIRCULATIONAHA.109.849208.

Johnson JA, Gong L, Wirl-Carrillo M, Gage BF, et al.

Clinical pharmacogenetics implementations Consortium

Guidelines for CYP2C9 and VKORC1 genotypes and warfarin

dosing. Clinical Pharmacology and Therapeutics.

; 90(4):625–9. DOI: 10.1038/clpt.2011.185.

Scone E, Avery P, Wynne H. Vitamin K supplementation

can improve stability of anticoagulation for patients with

unexpected variability in response to warfarin. Blood. 2007

Mar; 109 (6):2419–23.

Perera MA, Cavallari LH, Limdi NA, Gamazon ER,

Konkashbaev A, Daneshjou R, Pluzhnikov A, Crawford

DC, Wang J, Liu N, Tatonetti N, Bourgeois S, Takahashi H,

Bradford Y, Burkley BM, Desnick RJ, Halperin JL, Khalifa

SI, Langaee TY, Lubitz SA, Nutescu EA, Oetjens M, Shahin

MH, Patel SR, Sagreiya H, Tector M, Weck KE, Rieder MJ,

Scott SA, Wu AH, Burmester JK, Wadelius M, Deloukas P,

Wagner MJ, Mushiroda T, Kubo M, Roden DM, Cox NJ,

Altman RB, Klein TE, Nakamura Y, Johnson JA. Genetic

variants associated with warfarin dose in African-American

individuals: A genome-wide association study. Lancet.

Aug 31; 382(9894):790–6. DOI: 10.1016/S0140-

(13)60681-9.

Parra J, Booton MR, Perini JA. Genome wide association

study of warfarin maintenance dose in Brazilians sample.

Pharmacogenomics. 2015 Aug; 16(11):1253–63. DOI:

2217/PGS.15.73.

Syn NL, Lee SC, Brunham LR, Goh BC. Pharmacogenetics

versus clinical dosing of warfarin in individuals of

Chinese and African–Americans ancestry. Pharmacogenet

Genomics. 2015; 25(10):491–500. DOI: 10.1097/

FPC.0000000000000165.

Dobon B, Hassan HY, Laayouni H, Luisi P, Ricano–Ponce

I. The genetics of East African populations: A nilo-saharan

component in the African genetic landscape. Scientific Reports;

DOI: 10.1038/srep09996.

Jonson JA. Clinical pharmacogenetics implementation consortium

guidelines for CYP2C9 and VKORC1 genotypes

and warfarin dosing. Clin Pharmacol Ther. 2011 Sep. DOI:

1038/clpt.2011.

Wadelius M. Warfarin pharmacogenetics: It matters if you

are black or white. Blood. 2014 Oct; 124 (14):2171.

Patillon B, Luis P. Positive selection in the chromosome 16

VKORC1 genomic regoins has contributed to the variability

of anticoagulant response in humans. PlosOne. 2012;

(12). DOI: 10.1371/journal.pone.0053049.

Wadellus M. Warfarin Pharmacogenetics: It matters if

you’re black or white. Blood. 2014 Oct 2; 124(14):2171.

Sominsky S, Korostishevsky M. The VKORC1 variant and

haplotypes diversity in Ashkenazi and Ethiopian populations.

Appl Genet. 2014 May; 55(2):163–71. DOI: 10.1160/

TH12-10-0789.

Gan GG, Ming TA, Lee M. Allele and genotype frequencies

of VKORC1-1639G>A polymorphism in three different

ethnic groups in Malaysia. As Pac J Mol Bio Biotechnol.

; 20(1):19–23.

Mohammed HSH, Larisa H. VKORC1 geographic distribu-

tion and its impact on warfarin dose requirements

in Egyptians. Thrombosis and Homeostasis. 2013 Jun;

(6):1045–50. DOI: 10.1160/TH12-10-0789.

Yang L, Ge W, Yu F. Impact of vitamin KORC1 gene polymorphism

on inter-individual and interethnic warfarin

dosage requirement. A systemic review and meta-analysis.

Thrombosis and Haemostasis. 2010; 125(4):159–66. DOI:

1016/j.thromres.2009.10.017.

Fung E, Nicholas A, Stern M. Effect of genetic variants

spe- cially CYP2C9 and VKORC1 on the pharmacology of

warfarin. Thromb Hemost. 2012 Nov; 38(8):893–904. DOI:

1055/s-0032-1328891.

Warfarin resistance. Genetics Home Reference. US National

Library of Medicine; 2016 Jun.

Hossam AM, Shahin, Cavallan LH. Vkorc1 geographical

distribution and its impact on warfarin dose requirements

in Egyptians. Thrombosis and Haemostasis. 2016 Mar;

(6):1045-50. DOI: 10.1160/TH12-10-0789.

Vol 8 (4) | 2016 | www.informaticsjournals.org/index.php/ajprhc Asian Journal of Pharmaceutical Research and Health Care 111

Azza A. M. H. Swar Aldahab and Abdallah. O. Elkhawad

Rieder MJ, Reiner AP, Gage BF. Effect of VORC1 haplotypes

on transcriptional regulation and warfarin dose. N

Engl J Med. 2005; 352:2285–93.

Gil AK, Khan NM, Grover S. Genetic epidemiology of

pharmacogenetics variation in CYP2C9, CYP4F2 and

VKORC- 1genes with warfarin dosage in Indian population.

Pharmacogenomics. 2014; 15(10):1337–54. DOI:

2217/pgs.14.88.

Yu Z, Ding YL, Lu. Warfarin dosage adjustment strategy

in Chinese population. Int J Clin Exp Med. 2015 Jun15;

(6):9904–10.

Tanira MO, AL-Mukhaini MK, Alhinai AT. Frequency of

CYP2C9 among Omani patients receiving warfarin and

its correlation with warfarin dose. Community Genetics.

; 10(1):32–7.

Kealey C, Chen Z, Christy J, et al. Warfarin and CYP2C9

genotype; possible ethnic variation in warfarin sensitivity.

Pharmacogenomics. 2007; 8(3):217–25.

Shrif NE, Won H-H, Lee ST, Park JH, Kim KK, Kim MJ,

Kim S, Lee SY, Ki CS, Osman IM, Rhman EA, Ali IA, Idris

MN, Kim JW. Evaluation of the effects of VKORC1 and CYP2C9

genotype and clinical factors on warfarin response in

Sudanese patients. Eue Clin Pharmacol. 2011; 67(11):1119–

DOI: 10.1007/s00228-011-1060-1.

Nita A, Limidi MA, Wadellias, Cavallari L. Warfarin

pharmacogenetics: A single VKORC1 polymorphism is

predictive of dose across 3 racial groups. Blood. 2010;

(18):3827–34. 10.1182/blood-2009-12-255992.

Garcia DD, Regan S, Growther M, et al. Warfarin maintenance

dosing patterns in clinical practice implications for

safer anticoagulation in elderly population. Chest. 2005;

:2049–56.

Zuinali P, Souza GC, de Assis MCS. Dietary vitamin K

intake and stability of anticoagulation with coumarins:

Evidence derived from a clinical trial. Neutr Hosp. 2012;

(60):1987–92. DOI: 10.3305/nh.2012.27.6.6068.

Wieloch M, Alander ASJ, Fryknan V. Anticoagulation control

in Sweden: Reports of time in therapeutic range, major

bleeding and thromboembolic complications from national

quality registry Auricul A Eur Heart J. 2011; 32(18):2282–9.

DOI: 10.1093/eurheartj/ehr134.

Tomiha H, Kadokami T, Momii H, Kawamura M. Patient

factors against stable control of warfarin therapy for Japanese

non-valvular atrial fibrillation patients. Thromb

Res. 2013 Nov; 132(5):537–42. DOI: 10.1016/j.thromres.2013.09.003.

Maria H. Age and gender differences during long term warfarin

therapy monitored with Fiix-prothrombin time in patients

with AF. Skemman . 2015 May. Available from: http//

hdl.handle. net/1949/21520

Seliverstov I. Practical management approaches to anticoagulation

non-compliance, health literacy and limited

English proficiency in outpatient clinic setting. J Thromb

Thrombolysis. 2011Apr; 31(3):321–5. DOI: 10.1007/

s11239-011-0560-2.

Platt A, Alec B. Risk factors for non-adherence to warfarin:

Results from the IN-RANGE study. Pharmacoepidemiology

and Drug Safety. 2008; 17(9):853–60. DOI: 10.1002/

pds.1556.

Befikadu L, Nuredin S. Drug-drug interactions and risk of

bleeding among patients on warfarin therapy: A prospective

observational study. Thrombosis Journal. 2014; 12:20.

DOI: 10.1186/1477-9560-12-20.


Refbacks

  • There are currently no refbacks.


Bookmark and Share


 

 Creative Commons

https://creativecommons.org/licenses/by-nc-sa/4.0/ 

Listed as Green Publisher