Reply.

Abstract

Potential conflict of interest: Dr. Stickel advises for and received grants from Gilead. He advises for Biotest and received grants from MSD, Novartis, and Janssen. Author names in bold designate shared co‐first authorship We thank Liu and Que for their remarks on our article reporting an impact of the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant on steatosis, necroinflammation, and fibrosis in patients with chronic hepatitis C.1 We agree that the robustness of the association of the E167K variant with severe fibrosis in the validation cohort, though it was independent of age and sex, is somewhat lessened by the younger age of carriers of the genetic mutation, as well as the lack of adjustment for adiposity. As correctly noted, the uneven age distribution may have even underestimated the contribution of the E167K variant to fibrosis progression. Indeed, E167K carriers had reached F2‐F4 fibrosis at a younger age (52 ± 9 [n = 68] vs. 55 ± 12 years [n = 341]; P = 0.02). However, we would also like to point out that we had already shown an association of the E167K variant with steatosis, necroinflammation, and nearly with fibrosis stage, as well as a significant association with cirrhosis in a larger Italian discovery cohort (n = 815). This was independent of demographic, genetic, anthropometric, and viral features. Furthermore, the effect size of the E167K variant was similar to that detected in the validation cohort. By excluding individuals of the validation cohort at the extremes of age distribution (<25/>75 yrs), the E167K variant was no more associated with age (51 ± 10 [n = 94] vs. 52 ± 11 years [n = 522]; P = not significant) and sex, but, at logistic regression analysis, conferred a similar risk of fibrosis (unadjusted odds ratio [OR]: 1.66; 95% confidence interval [CI]: 0.36‐0.96; P = 0.03; adjusted OR: 1.88; 95% CI: 0.32‐0.88; P = 0.01). In addition, even if we could not correct for body mass, the E167K variant does not impact on adiposity.1 Last, the E167K variant predisposes to hepatic fat accumulation in patients with nonviral liver disease,2 and this translates into increased inflammation and risk of advanced fibrosis in nonalcoholic fatty liver.3 Therefore, we believe that the conclusion that the TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis was supported by the results and is mechanistically plausible. Further studies will certainly contribute to better define the impact of the TM6SF2 variant on hepatic fibrosis progression, as well as the interaction with age, adiposity‐insulin resistance, and alcohol intake.