Somila Mateza, Yuki Bradford, Gary Maartens, Simiso Sokhela, Nomathemba C Chandiwana, Willem D F Venter, Frank A Post, Marylyn D Ritchie, David W Haas, Phumla Sinxadi
{"title":"艾滋病毒呈阳性的南部非洲人的替诺福韦肾毒性药物遗传学。","authors":"Somila Mateza, Yuki Bradford, Gary Maartens, Simiso Sokhela, Nomathemba C Chandiwana, Willem D F Venter, Frank A Post, Marylyn D Ritchie, David W Haas, Phumla Sinxadi","doi":"10.1097/FPC.0000000000000491","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans.</p><p><strong>Methods: </strong>Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine β2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations.</p><p><strong>Results: </strong>336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P = 0.022), ABCC10 rs2125739 ( P = 0.07), and ABCC4 rs1059751 ( P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P = 0.0013), rs691857 ( P = 0.00039), and PKD2 rs72659631 ( P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P = 3.4 × 10 -9 ), CDH4 rs66494466 ( P = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P = 6.1 × 10 -7 ).</p><p><strong>Conclusion: </strong>Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"33 5","pages":"91-100"},"PeriodicalIF":1.7000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234323/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans.\",\"authors\":\"Somila Mateza, Yuki Bradford, Gary Maartens, Simiso Sokhela, Nomathemba C Chandiwana, Willem D F Venter, Frank A Post, Marylyn D Ritchie, David W Haas, Phumla Sinxadi\",\"doi\":\"10.1097/FPC.0000000000000491\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans.</p><p><strong>Methods: </strong>Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine β2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations.</p><p><strong>Results: </strong>336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P = 0.022), ABCC10 rs2125739 ( P = 0.07), and ABCC4 rs1059751 ( P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P = 0.0013), rs691857 ( P = 0.00039), and PKD2 rs72659631 ( P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P = 3.4 × 10 -9 ), CDH4 rs66494466 ( P = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P = 6.1 × 10 -7 ).</p><p><strong>Conclusion: </strong>Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. 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Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans.
Objective: Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans.
Methods: Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine β2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations.
Results: 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P = 0.022), ABCC10 rs2125739 ( P = 0.07), and ABCC4 rs1059751 ( P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P = 0.0013), rs691857 ( P = 0.00039), and PKD2 rs72659631 ( P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P = 3.4 × 10 -9 ), CDH4 rs66494466 ( P = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P = 6.1 × 10 -7 ).
Conclusion: Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.
期刊介绍:
Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.