Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/MRP/CFTR)

Saito, Susumu; Iida, Aritoshi; Sekine, Akihiro; Miura, Yohei; Ogawa, Chie; Kawauchi, Saori; Higuchi, Sadaharu; Nakamura, Yusuke

doi:10.1007/s100380200018

Cited by 127 publications

(31 citation statements)

References 27 publications

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“…Clark and colleagues (8, 9) reported 9 indel mutations (all intronic) and 79 SNPs in screening the entire lipoprotein lipase gene in 71 individuals. Saito et al (10) identified 29 noncoding indels and 297 SNPs in screening nine ABC transporter genes. In contrast, we observed 29 indel mutations, of which eight affected the coding region (see Table 4).…”

Section: Resultsmentioning

confidence: 99%

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

Leabman

Huang

DeYoung

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

211

167

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Membrane transporters maintain cellular and organismal homeostasis by importing nutrients and exporting toxic compounds. Transporters also play a crucial role in drug response, serving as drug targets and setting drug levels. As part of a pharmacogenetics project, we screened exons and flanking intronic regions for variation in a set of 24 membrane transporter genes (96 kb; 57% coding) in 247 DNA samples from ethnically diverse populations. We identified 680 single nucleotide polymorphisms (SNPs), of which 175 were synonymous and 155 caused amino acid changes, and 29 small insertions and deletions. Amino acid diversity ( NS) in transmembrane domains (TMDs) was significantly lower than in loop domains, suggesting that TMDs have special functional constraints. This difference was especially striking in the ATP-binding cassette superfamily and did not parallel evolutionary conservation: there was little variation in the TMDs, even in evolutionarily unconserved residues. We used allele frequency distribution to evaluate different scoring systems (Grantham, BLOSUM62, SIFT, and evolutionarily conserved͞evolution-arily unconserved) for their ability to predict which SNPs affect function. Our underlying assumption was that alleles that are functionally deleterious will be selected against and thus under represented at high frequencies and over represented at low frequencies. We found that evolutionary conservation of orthologous sequences, as assessed by evolutionarily conserved͞evolutionarily unconserved and SIFT, was the best predictor of allele frequency distribution and hence of function. European Americans had an excess of high frequency alleles in comparison to African Americans, consistent with a historic bottleneck. In addition, African Americans exhibited a much higher frequency of population specific medium-frequency alleles than did European Americans.

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Section: Resultsmentioning

confidence: 99%

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

Leabman

Huang

DeYoung

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

211

167

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“…While MRP2 efflux pump is not directly involved in renal transport of tenofovir (33), several genetic studies have suggested its association with TDF-mediated renal dysfunction (15, 18, 19, 27, 34). In addition, we included genes encoding enzymes involved in the intracellular metabolic activation of tenofovir ( adenylate kinase 2 , AK2; adenylate kinase 4 , AK4 ) (35, 36) and genes that are associated with Mendelian Fanconi Syndrome ( oculocerebrorenal lowe protein 1 , OCRL; chloride channel 5 , CLCN5) (37, 38).…”

Section: Introductionmentioning

confidence: 99%

A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome

Dahlin¹,

Wittwer²,

Cruz³

et al. 2015

Pharmacogenetics and Genomics

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BACKGROUND Tenofovir disoproxil fumarate (TDF) is a widely used antiretroviral agent with favorable efficacy, safety and tolerability profiles. However, renal adverse events, including rare Fanconi syndrome (FS), may occur in a small subset of HIV-infected treated patients. OBJECTIVES The aim of this study was to identify genetic variants that may associate with TDF-associated FS (TDF-FS). METHODS DNA samples collected from a 19 cases with TDF-FS and 36 matched controls were sequenced and genetic association studies were performed in eight candidate genes: ATP-binding cassette (ABC) transporters ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. Functional effects of a SNP predicted to alter transport of tenofovir were then investigated in cells expressing an identified variant or ABCC4. RESULTS Overall, the case group showed a trend towards a higher proportion of rare alleles. Six SNPs in ABCC2 (3 SNPs), ABCC4 (1 SNP) and OCRL (2 SNPs) were associated with TDF-FS case status, but did not remain significant after correction for multiple testing. Six SNPs, in OCRL (4 SNPs) and ABCC2 (2 SNPs), were significantly associated with increased serum creatinine levels in the cases, and remained significant after multiple test correction (P < 2 × 10−04). One synonymous SNP in ABCC2 (rs8187707; P=2.10 ×10−04; β =−73.3 ml/min/1.73m2)) was also significantly associated with decreased estimated glomerular filtration rate of creatinine in the cases. However, these results were driven by rare SNPs present in a small number of severely affected cases. A previously uncharacterized, non-synonymous SNP, rs11568694, that was predicted to alter MRP4 function, had no significant effect on tenofovir cellular accumulation in vitro. CONCLUSIONS While no single predictive genetic marker for the development of TDF-FS was identified, these findings suggest that multiple rare variants in multiple genes involved in renal handling of tenofovir and/or renal cell homeostasis may be associated with increased susceptibility to TDF-FS.

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“…The MRP (ABCC) gene family is highly polymorphic and MRP4 is among the most polymorphic (8) and over 20 missense genetic variants have been identified in the NCBI database (http:www.ncbi.nlm.nuh.gov/SNP) and the Pharmacogenetics Research Network (http:www.PharmGKB.org). Because patients who are not TPMT-deficient experience severe thiopurine-induced myelosuppression, including many Japanese patients (3), we hypothesized that MRP4 may provide an explanation for this unexplained thiopurine sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity

et al. 2008

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Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGNs) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase (TPMT) deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that Mrp4 is abundant in myeloid progenitors and tested the role of the multidrug-resistance protein 4 (Mrp4), an ATP binding cassette (ATP) transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage–dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP.

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Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/MRP/CFTR)

Cited by 127 publications

References 27 publications

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome

Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity

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