Association of NR1I2 gene polymorphisms and time of progression to AIDS

Medeiros, Rúbia Marília de; Menti, Carolina Fialho; Benelli, Jéssica Louise; Matte, Maria Cristina Cotta; Melo, Marineide; Almeida, Sabrina Esteves de Matos; Fiegenbaum, Marilu

doi:10.1590/0074-02760160382

Cited by 2 publications

(3 citation statements)

References 27 publications

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“…16 Additionally, variants in NR1I2 have been associated with the more rapid progression to AIDS in a cohort of adults living with HIV-1 in Brazil. 17 UGT1A1 is responsible for the glucuronidation of unconjugated bilirubin to conjugated bilirubin and is involved with numerous drug-drug interactions and the metabolism of several integrase strand transfer inhibitors. 18 Although the current study is limited to a small sample, children with UGT1A1 genotypes associated with poor metabolizer status had the highest concentrations of dolutegravir.…”

Section: Discussionmentioning

confidence: 99%

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Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

Spector,

Brummel,

Chang

et al. 2024

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677) and UGT1A1 (rs5839491) on dolutegravir PK was examined. Methods: Children defined by age and administered dolutegravir formulation had AUC24 at steady state, Cmax and C24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. Results: The 59 children studied had a median age of 4.6 years, log10 plasma HIV RNA of 4.79 (copies/mm3) and CD4+ lymphocyte count 1,041 cells/mm3; 51% were female. For ABCG2, participants with >1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex, (-15.7, 95% CI: [-32.0, 0.6], p = 0.06) and log10Cmax adjusted mean difference (-0.15 (95% CI: [-0.25, -0.05], p = 0.003). Participants with >1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1, 25.0], p = 0.07). For UGT1A1, poor metabolizers had non-significant higher concentrations (adjusted log10Cmax mean difference 11.8; 95% CI: [-12.3, 36.0], p = 0.34) and lower mean log10 adjusted oral clearance -0.13 L/hr (95% CI: [-0.3, 0.06], p = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA or CD4+ cell counts. Conclusions: Dolutegravir AUC24 for genetic variants in ABCG2, NR1l2 and UGT1A1 varied from -25% to +33%.These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.

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Section: Discussionmentioning

confidence: 99%

“…16 Additionally, variants in NR1I2 have been associated with the more rapid progression to AIDS in a cohort of adults living with HIV-1 in Brazil. 17…”

Section: Discussionmentioning

confidence: 99%

Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

Spector,

Brummel,

Chang

et al. 2024

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Regardless of the inconsistency of research results it is plausible that genetic variations within NR1/2 that influence protein expression or activity, have significant clinical effects of diverse character 38 . SNPs within coding sequence of NR1/2 gene have correlated with risk of overall cancer 44 , progression of AIDS 45 , were the potential risk factor of drug resistance in epilepsy 46 as well as of hematological toxicity induced by irinotecan in colorectal cancer patients 47 . Genetic variants in the 3′UTR region of NR1/2 affect transport, localization and the stability of NR1/2 mRNA 14,40 .…”

Section: Discussionmentioning

confidence: 99%

Genetic 3′UTR variations and clinical factors significantly contribute to survival prediction and clinical response in breast cancer patients

Pamuła‐Piłat

Tęcza

Kalinowska-Herok

et al. 2020

Sci Rep

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The study describes a relationship between the 3′UTR variants, clinicopathological parameters and response to chemotherapy. We analyzed 33 germline polymorphisms in 3′UTRs of ADME genes in 305 breast cancer women treated with FAC regime. Clinical endpoints of this study were: overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS) and overall response defined as treatment failure-free survival (TFFS). The shortened OS was connected with the presence of NR1/2 rs3732359 AA, SLC22A16 rs7756222 CC, as well as SLC22A16 rs9487402 allele G and clinical factors belonging to TNM classification: tumor size >1 cm, nodal involvement and presence of metastases. PFS was related to two polymorphisms PGR rs1824125 GG, PGR rs12224560 CC and SLC22A16 rs7756222 CC as well as preexisting metastases. The RFS was shortened due to the DPYD rs291593 CC, AKR1C3 rs3209896 AG and negative expression of PGR. The presence of ALDH5A1 rs1054899 allele A, lack of pre-chemotherapy surgery and negative status of PGR correlated with worse treatment response. The germline variants commonly present in the population are important factors determining the response to treatment. We observed the effect of the accumulation of genetic and clinical factors on poor survival prognosis and overall treatment response. Breast cancer usually affects women in postmenopausal period, although it is diagnosed increasingly in younger patients often in advanced clinical stages 1. The 5-year survival is around 80% in developed countries 2. Therapeutic strategies for breast cancer include targeted therapy, hormone therapy, radiotherapy, surgery and chemotherapy 1,3. Toxicity and resistance to chemotherapeutic drugs are common problems observed in patients during and after treatment. Lack of sensitivity to chemotherapy is most often associated with dysfunction of protein transporters that remove chemotherapeutic agents from the cells or DNA repair processes 4. The response to systemic treatment is different in patients with the same type of cancer, similar stage of disease and treated with the same medications. Lack of chemotherapy response is observed as cancer-related mortality, disease progression or recurrence 5,6. Metabolism, absorption, distribution and excretion (ADME processes) of drugs are regulated by genes and proteins responsible for biotransformation and metabolic elimination of drugs (enzymes cytochrome P450). Also, proteins belonging to ATP binding cassette (ABC) and solute carrier (SLC) control influx or efflux of toxin and medicines and their cellular distribution 7,8. The expression of ADME genes is regulated at the transcriptional and translational levels. In addition, they undergo posttranslational modifications. ADME dysfunction may lead to reduced drug efficacy or to an adverse drug reaction in pharmacotherapy 9,10. Genetic and epigenetic transformations of ADME genes can modulate the activity and therapeutic effects of chemotherapy and underline interpatient differences in response to therapy 5,11-13 .

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Association of NR1I2 gene polymorphisms and time of progression to AIDS

Cited by 2 publications

References 27 publications

Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

Genetic 3′UTR variations and clinical factors significantly contribute to survival prediction and clinical response in breast cancer patients

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