Limits...
Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

View Article: PubMed Central - PubMed

ABSTRACT

Background: Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective of this study was to perform genome-wide association study (GWAS) to identify genetic variants associated with the risk for ATD induced liver toxicity in Ethiopian patients.

Result: Treatment-naïve newly diagnosed tuberculosis patients (n = 646) were enrolled prospectively and treated with rifampicin based short course anti-tuberculosis therapy. Whole genome genotyping was done using Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on 48 DILI cases and 354 ATD tolerants. Replication study was carried out for 50 SNPs with the lowest P-values (top SNPs) using an independent cohort consisting of 27 DILI cases and 217 ATD tolerants. In the combined analysis, the top SNP identified was rs10946737 (P = 4.4 × 10−6, OR = 3.4, 95 % confidence interval = 2.2–5.3) in the intron of FAM65B in chromosome 6. In addition, we identified a cluster of SNPs with suggestive genome-wide significance in the intron of ATP/GTP binding protein-like 4 (AGBL4).

Conclusion: We identified genetic variants that are potentially associated with ATD induced liver toxicity. Further studies with larger sample sizes are essential to confirm the findings.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3078-3) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

−Log10P values of logistic regression across chromosomes in the GWAS
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5037629&req=5

Fig2: −Log10P values of logistic regression across chromosomes in the GWAS

Mentions: The Quantile-quantile (QQ) plot for the observed versus expected P-values, and Manhattan plot for the regression analysis are shown in Figs. 1 and 2, respectively. The top SNP in the GWAS after adjustment for sex, HIV status, CD4 count and HIV viral load was rs10946739 (P = 4.1 × 10−6, odds ratio (OR) = 3.4, 95 % CI = 2.0–5.6) located in the intron region of family with sequence similarity 65 member B (FAM65B), which is also named as chromosome 6 open reading frame 32 (C6ORF32) (Additional file 1: Table S1). The top SNP in the replication study after adjustment for covariates was rs319952 (P = 1.0 × 10−2, OR = 2.3, 95 % CI = 1.2–4.4) located in the intron of ATP/GTP binding protein-like 4 (AGBL4) in chromosome 1 (Additional file 1: Table S2). In the combined analysis, the top SNP after adjustment for covariates was rs10946737 (P = 4.4 × 10−6, OR = 3.4, 95 % CI = 2.2–5.3) located in the intron region of FAM65B (Table 2). In addition, four of the top SNPs (rs320035, rs393994, rs319952 and rs320003) were clustered in the intron of AGBL4.Fig. 1


Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity
−Log10P values of logistic regression across chromosomes in the GWAS
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037629&req=5

Fig2: −Log10P values of logistic regression across chromosomes in the GWAS
Mentions: The Quantile-quantile (QQ) plot for the observed versus expected P-values, and Manhattan plot for the regression analysis are shown in Figs. 1 and 2, respectively. The top SNP in the GWAS after adjustment for sex, HIV status, CD4 count and HIV viral load was rs10946739 (P = 4.1 × 10−6, odds ratio (OR) = 3.4, 95 % CI = 2.0–5.6) located in the intron region of family with sequence similarity 65 member B (FAM65B), which is also named as chromosome 6 open reading frame 32 (C6ORF32) (Additional file 1: Table S1). The top SNP in the replication study after adjustment for covariates was rs319952 (P = 1.0 × 10−2, OR = 2.3, 95 % CI = 1.2–4.4) located in the intron of ATP/GTP binding protein-like 4 (AGBL4) in chromosome 1 (Additional file 1: Table S2). In the combined analysis, the top SNP after adjustment for covariates was rs10946737 (P = 4.4 × 10−6, OR = 3.4, 95 % CI = 2.2–5.3) located in the intron region of FAM65B (Table 2). In addition, four of the top SNPs (rs320035, rs393994, rs319952 and rs320003) were clustered in the intron of AGBL4.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective of this study was to perform genome-wide association study (GWAS) to identify genetic variants associated with the risk for ATD induced liver toxicity in Ethiopian patients.

Result: Treatment-naïve newly diagnosed tuberculosis patients (n = 646) were enrolled prospectively and treated with rifampicin based short course anti-tuberculosis therapy. Whole genome genotyping was done using Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on 48 DILI cases and 354 ATD tolerants. Replication study was carried out for 50 SNPs with the lowest P-values (top SNPs) using an independent cohort consisting of 27 DILI cases and 217 ATD tolerants. In the combined analysis, the top SNP identified was rs10946737 (P = 4.4 × 10−6, OR = 3.4, 95 % confidence interval = 2.2–5.3) in the intron of FAM65B in chromosome 6. In addition, we identified a cluster of SNPs with suggestive genome-wide significance in the intron of ATP/GTP binding protein-like 4 (AGBL4).

Conclusion: We identified genetic variants that are potentially associated with ATD induced liver toxicity. Further studies with larger sample sizes are essential to confirm the findings.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3078-3) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus