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Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease.

Zain SM, Mohamed Z, Pirmohamed M, Tan HL, Alshawsh MA, Mahadeva S, Chan WK, Mustapha NR, Mohamed R - Sci Rep (2015)

Bottom Line: CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003).Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05).In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.

View Article: PubMed Central - PubMed

Affiliation: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

ABSTRACT
A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05). Serum XPO4 levels progressively declined (P = 0.043) from controls (24.6 ng/mL) to simple steatosis (20.8 ng/mL) to NASH (13.8 ng/mL). In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.

No MeSH data available.


Related in: MedlinePlus

Association analysis between CNV gain and NAFLD.Estimations of odds ratios (OR) and 95% confidence intervals (CI) in each study are displayed as closed squares and horizontal lines, respectively. The size of the black squares reflects the weight of the study in the meta-analysis. The diamond represents the combined OR, calculated using a fixed effect model, with its 95% CI. NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis.
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f1: Association analysis between CNV gain and NAFLD.Estimations of odds ratios (OR) and 95% confidence intervals (CI) in each study are displayed as closed squares and horizontal lines, respectively. The size of the black squares reflects the weight of the study in the meta-analysis. The diamond represents the combined OR, calculated using a fixed effect model, with its 95% CI. NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis.

Mentions: In order to further investigate the effect of the CNV gain, we first validated the 67 (68%) available samples from the 98 discovery samples9 using qPCR. The frequency of CNV gain (20.7%) in the control discovery samples was relatively similar to that of the controls from the replication samples (18.5). Results from the discovery samples indicated that CNV gain at 13q12.11 was associated with risk of NAFLD (OR 5.88, 95% CI 1.94–17.82, P = 0.002) and NASH (OR 5.11, 95% CI 1.67–15.67, P = 0.004), but not with simple steatosis. Then, we performed a meta-analysis including both discovery and replication studies (Fig. 1), which confirmed the significant association with NAFLD (OR 2.68, 95% CI 1.79–4.02, P < 0.0001) and NASH (OR 2.64, 95% CI 1.75–4.00, P < 0.0001).


Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease.

Zain SM, Mohamed Z, Pirmohamed M, Tan HL, Alshawsh MA, Mahadeva S, Chan WK, Mustapha NR, Mohamed R - Sci Rep (2015)

Association analysis between CNV gain and NAFLD.Estimations of odds ratios (OR) and 95% confidence intervals (CI) in each study are displayed as closed squares and horizontal lines, respectively. The size of the black squares reflects the weight of the study in the meta-analysis. The diamond represents the combined OR, calculated using a fixed effect model, with its 95% CI. NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543956&req=5

f1: Association analysis between CNV gain and NAFLD.Estimations of odds ratios (OR) and 95% confidence intervals (CI) in each study are displayed as closed squares and horizontal lines, respectively. The size of the black squares reflects the weight of the study in the meta-analysis. The diamond represents the combined OR, calculated using a fixed effect model, with its 95% CI. NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis.
Mentions: In order to further investigate the effect of the CNV gain, we first validated the 67 (68%) available samples from the 98 discovery samples9 using qPCR. The frequency of CNV gain (20.7%) in the control discovery samples was relatively similar to that of the controls from the replication samples (18.5). Results from the discovery samples indicated that CNV gain at 13q12.11 was associated with risk of NAFLD (OR 5.88, 95% CI 1.94–17.82, P = 0.002) and NASH (OR 5.11, 95% CI 1.67–15.67, P = 0.004), but not with simple steatosis. Then, we performed a meta-analysis including both discovery and replication studies (Fig. 1), which confirmed the significant association with NAFLD (OR 2.68, 95% CI 1.79–4.02, P < 0.0001) and NASH (OR 2.64, 95% CI 1.75–4.00, P < 0.0001).

Bottom Line: CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003).Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05).In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.

View Article: PubMed Central - PubMed

Affiliation: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

ABSTRACT
A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05). Serum XPO4 levels progressively declined (P = 0.043) from controls (24.6 ng/mL) to simple steatosis (20.8 ng/mL) to NASH (13.8 ng/mL). In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.

No MeSH data available.


Related in: MedlinePlus