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SLCO1B1 Variants and Methotrexate Clearance

ABSTRACT:

Methotrexate plasma concentration is related to its clinical effects. To identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL), we performed a genome-wide analysis (GWAS) of 500,568 germline single-nucleotide polymorphisms (SNPs) in 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1 (rs11045879 (P = 1.7 x 10^-10) and rs4149081 (P = 1.7 x 10^-9) (Trevino et al, PMID: 19901119). To test whether rare variants in SLCO1B1 could alter its function, we genotyped SLCO1B1 exons in a slightly larger group of 699 children with ALL who received methotrexate and identified 93 single nucleotide polymorphisms (SNPs). We found several common and rare non-synonymous (NS) SNPs associated with methotrexate clearance.

NS SNPs predicted to be functionally damaging (common or rare) were more likely to be found among patients with the lowest adjusted methotrexate clearance (lowest 10%) than patients with high clearance (highest 10%). Four SLCO1B1 haplotypes were associated with reduced methotrexate clearance and we verified that these haplotypes have lower function with in vitro transport assays. We were able to quantitatively account for a third of the population variability in clearance of methotrexate with clinical and genetic covariates. This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays, sequencing, and genotyping.

PROVIDER: phs000426 | dbGaP |

SECONDARY ACCESSION(S): PRJNA76039PRJNA76037

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs000426.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000426.MethotrexateClearance.v1.p1.MULTI.pdf	Pdf
	manifest_phs000426.MethotrexateClearance.v1.p1.c1.BRU.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in-silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analysed in-vitro and in-vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, DBP and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2, which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

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SLCO1B1 Variants and Methotrexate Clearance

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