Alimentary Pharmacology and Therapeutics Letters to the Editors

Letter: PNPLA3 and alcoholic liver disease – an alert to methodological limitations. Authors’ reply A.-J. Chamorro*, J.-L. Torres*, J.-A. Mir on-Canelo†, ‡ R. Gonzalez-Sarmiento , F.-J. Laso* & M. Marcos* *Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. † Department of Epidemiology, University of Salamanca-IBSAL, Salamanca, Spain. ‡ Molecular Medicine Unit-IBSAL, University of Salamanca-SACYLCSIC, Salamanca, Spain. E-mail: [email protected]

our results. Besides, additional data were kindly provided by Dr Falleti et al.,13 as we had already stated in the methodology of our paper. Therefore, this concern is overcome. In summary, it seems clear that our meta-analysis does not need extensive remastering. Of course, further research in this field will be greatly welcome.

ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES

doi:10.1111/apt.13084

SIRS, We read with interest the letter by Dr Sand,1 which raises some methodological concerns about our metaanalysis.2 The main concern refers to the lack of strand information in some primary publications, which could lead to allele misassignment. First, all studies performed in Caucasians included in our meta-analysis reported G as the minor allele, which is also the minor allele for the forward strand in the dbSNP database and in other reports.3 The comparison of observed allele frequencies with public databases is a common approach when transversion polymorphisms are analysed and strand information is uncertain,4, 5 and works particularly well when minor allele frequency is below 0.40, as happens with rs738409 polymorphism. Therefore, data consistency regarding minor allele frequencies between studies, and with other reports, makes the risk of allele misassignment very low. Second, several publications report to have analysed this polymorphism on the forward strand,6–8 and no study, to the best of our knowledge, specifically reports to have analysed it on the reverse strand. Finally, our results are consistent with several other meta-analyses that showed the G allele in the forward strand of this polymorphism as a risk factor for advanced liver disease.3, 9, 10 Although we agree that allele assignment is a theoretical concern when transversions are analysed, this does not invalidate previous meta-analyses on this field. Regarding potential differences in genotype counts between primary studies and our work, the study by Dr Way et al. has been presented so far as abstracts and we referenced one of them11 although detailed genotype counts were available in the other.12 We apologise for this potential source of confusion, which does not affect 594

1. Sand PG. Letter: PNPLA3 and alcoholic liver disease: an alert to methodological limitations. Aliment Pharmacol Ther 2015; 41: 593. 2. Chamorro AJ, Torres JL, Miron-Canelo JA, Gonzalez-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharmacol Ther 2014; 40: 571–81. 3. Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109: 325–34. 4. de Bakker PI, Ferreira MA, Jia X, Neale BM, Raychaudhuri S, Voight BF. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 2008; 17: R122–8. 5. Lill CM, Schjeide BM, Roehr JT, et al. Correspondence to Sand et Al. “Critical reappraisal of a catechol-o-methyltransferase transversion variant in schizophrenia”. Biol Psychiatry 2010; 67: e45–8. 6. Rosendahl J, Tonjes A, Schleinitz D, et al. A common variant of PNPLA3 (p. I148M) is not associated with alcoholic chronic pancreatitis. PLoS ONE 2012; 7: e29433. 7. Stickel F, Buch S, Lau K, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology 2011; 53: 86–95. 8. Trepo E, Gustot T, Degre D, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatology 2011; 55: 906–12. 9. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011; 53: 1883–94. 10. Trepo E, Nahon P, Bontempi G, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 2014; 59: 2170–7. 11. Way MJ, Morgan M. The Pnpla3 I148m mutation significantly increases the risk of developing alcohol-related cirrhosis in alcohol dependent individuals. Alcohol Alcohol 2013; 48: 36–7. 12. Way MJ, McQuillin A, Gurling HMD, Morgan MY. The Pnpla3 I148M Mutation Significantly Increases the Risk of Developing Alcohol-Related Cirrhosis in Alcohol Dependent Individuals. J Hepatology 2013; 58: S563–4. 13. Falleti E, Fabris C, Cmet S, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liv Int 2011; 31: 1137–43.

Aliment Pharmacol Ther 2015; 41: 593–601 ª 2015 John Wiley & Sons Ltd

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Letter: PNPLA3 and alcoholic liver disease--an alert to methodological limitations. Authors' reply.

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