Potential conflict of interest: Nothing to report.
Author names in bold designate shared co‐first authorship.
To the Editor:
We read with interest the report by Sookoian et al.1 Recent studies demonstrate that transmembrane 6 superfamily member 2 (TM6SF2) rs5854292 is a risk factor for nonalcoholic fatty liver disease (NAFLD), steatohepatitis, and confers an increased risk of advanced fibrosis in >2,250 biopsy‐proven NAFLD cases.2 Sookoian et al., studying just 226 NAFLD cases, report a modest association with steatohepatitis only and so suggest that the TM6SF2‐fibrosis association is inconclusive. We believe their study has limitations, making this assertion highly questionable.
Furthermore, we disagree that using genotype frequencies taken directly (not inferred) from 1000 Genomes data2 could explain differences between studies. Considering population structure when replicating associations involving rare variants is important,4 but rs58542926 is not rare (European minor‐allele frequency 0.07—identical to that we confirmed in a separate UK healthy‐control population).2 Therefore, we do not believe the higher rs58542926 frequency we reported in NAFLD reflects population stratification.2
Importantly, our main analysis demonstrating increased risk of NAFLD fibrosis for rs58542926 involved direct comparison of fibrosis stages within a histologically characterized NAFLD cohort without recourse to population controls.2 This eliminated interference from controls with undiagnosed NAFLD, unlike the Sookoian et al. study that defined controls according to ultrasound criteria and was therefore subject to misclassification owing to the well‐recognized insensitivity of ultrasound.5 Failure by Sookoian et al. to see any fibrosis association probably reflects limited statistical power: Only 130 NAFLD cases had disease greater than simple steatosis and the reported fibrosis score in their NASH group was modest (1.4 ± 1.3 [SD]). Their suggestion that another study supports a lack of association with fibrosis is similarly questionable because that, too, was underpowered, involving only 15 cases with advanced fibrosis/cirrhosis (but including four rs58542926 heterozygotes).6
Several possible explanations for association of rs58542926 with fibrosis exist, with a direct effect from intrahepatic triglyceride accumulation not essential. The two‐hit theory for NAFLD7 remains a useful paradigm, but does not exclude the possibility of more‐complex mechanisms.
1. Sookoian S, Castaño GO, Scian R, Mallardi P, Fernández GT, Burgueño AL, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015;61:515‐525.
2. Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non‐alcoholic fatty liver disease. Nat Commun 2014;5:4309.
3. Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506‐514.
4. Lee S, Abecasis GR, Boehnke M, Lin X. Rare‐variant association analysis: study designs and statistical tests. Am J Hum Genet 2014;95:5‐23.
5. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. Utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745‐750.
6. Wong VW, Wong GL, Tse CH, Chan HL. Prevalence of TM6SF2 variant and non‐alcoholic fatty liver disease in Chinese. J Hepatol 2014;61:708‐709.
7. Day CP. Is necroinflammation a prerequisite for fibrogenesis? Hepatogastroenterology 1996;43:104‐120.