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Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry.
Asiimwe, Innocent G; Blockman, Marc; Cavallari, Larisa H; Cohen, Karen; Cupido, Clint Shane; Dandara, Collet; Davis, Brittney H; Jacobson, Barry; Johnson, Julie A; Lamorde, Mohammed; Limdi, Nita A; Morgan, Jennie; Mouton, Johannes P; Muyambo, Sarudzai; Nakagaayi, Doreen; Ndadza, Arinao; Okello, Emmy; Perera, Minoli A; Schapkaitz, Elise; Sekaggya-Wiltshire, Christine; Semakula, Jerome Roy; Tatz, Gayle; Waitt, Catriona; Yang, Guang; Zhang, Eunice J; Jorgensen, Andrea L; Pirmohamed, Munir.
Afiliación
  • Asiimwe IG; University of Liverpool, Liverpool, United Kingdom.
  • Blockman M; University of Cape Town, Cape Town, South Africa.
  • Cavallari LH; University of Florida, Gainesville, Florida, United States.
  • Cohen K; University of Cape Town, Cape Town, South Africa.
  • Cupido CS; University of Cape Town, Cape Town, South Africa.
  • Dandara C; Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
  • Davis BH; University of Alabama at Birmingham, Birmingham, Alabama, United States.
  • Jacobson B; University of the Witwatersrand, Johannesburg, South Africa.
  • Johnson JA; Ohio State University, Columbus, Ohio, United States.
  • Lamorde M; Makerere University, Kampala, Uganda.
  • Limdi NA; University of Alabama at Birmingham, Birmingham, Alabama, United States.
  • Morgan J; Western Cape Department of Health and Wellness, Cape Town, South Africa.
  • Mouton JP; University of Cape Town, Cape Town, South Africa.
  • Muyambo S; University of Zimbabwe, Harare, Zimbabwe.
  • Nakagaayi D; Uganda Heart Institute, Kampala, Uganda.
  • Ndadza A; University of Cape Town, Cape Town, South Africa.
  • Okello E; Uganda Heart Institute, Kampala, Uganda.
  • Perera MA; Northwestern University, Chicago, Illinois, United States.
  • Schapkaitz E; University of the Witwatersrand, Johannesburg, South Africa.
  • Sekaggya-Wiltshire C; Infectious Diseases Institute, Makerere University /Mulago national referral hospital, Kampala, Uganda.
  • Semakula JR; Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda., Kampala, Uganda.
  • Tatz G; University of Cape Town, Cape Town, South Africa.
  • Waitt C; University of Liverpool, Liverpool, United Kingdom.
  • Yang G; St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
  • Zhang EJ; University of Liverpool, Liverpool, United Kingdom.
  • Jorgensen AL; University of Liverpool, Liverpool, United Kingdom.
  • Pirmohamed M; The University of Liverpool, Liverpool, United Kingdom.
Blood Adv ; 2024 Aug 20.
Article en En | MEDLINE | ID: mdl-39163621
ABSTRACT
Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in four African cohorts from Uganda, South Africa, and Zimbabwe, totalling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included two African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n=316) and the University of Alabama at Birmingham (n=199). Following the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci (the CYP2C cluster SNP rs12777823 and CYP2C9 in chromosome 10; VKORC1 in chromosome 16). The genome-wide significance threshold was set at P<5×10-8. The meta-analysis, comprising 1,504 participants identified 242 significant SNPs across three genomic loci, with 99.6% of these located within known loci on chromosomes 10 (top SNP rs58800757, P=4.27×10-13) and 16 (top SNP rs9925964, P=9.97×10-16). Adjustment for the VKORC1 SNP -1639G>A revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P=3.64×10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, our meta-analysis of six cohorts of warfarin-treated patients of African ancestry reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements. We also identified a new locus (MALL), that still requires direct evidence of biological plausibility.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Adv Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Adv Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos