Don’t forget to ask how mum and dad are doing

Abstract

In this issue of Liver International, Michelle Long and colleagues ex‐ amined the consequences of having parents affected by hepatic ste‐ atosis on the disease risk in offspring from the Framingham study.1 Among a total of 785 offspring where liver fat content was mea‐ sured by tomography, 23% had one parent and 1% had two parents affected by hepatic steatosis. Having one or two parents affected conferred a two‐fold increased risk and more than six‐fold increased risk to develop hepatic steatosis respectively. The strength of the association was generally attenuated by adjustment in a multivariate model for BMI, while the inclusion of a genetic risk score in this anal‐ ysis resulted in no changes in the risk. The novelty of this study re‐ sides in describing the impact of parental hepatic steatosis on the risk to develop this condition in offspring without apparent liver disease. Family history has been used for centuries by physicians to es‐ timate the a priori risk of an individual to be affected by a disease. The basis for investigating family history resides in two aspects, one inborn and the other acquired during life. By examining similar studies on other metabolic diseases, we observe strikingly similar results. Indeed, offspring of individuals with claudicatio intermittens had a 1.8 increased risk to develop this disease when one parent was affected.2 Moreover, a two‐fold in‐ creased risk of having hypertension in the offspring was observed when one parent had early‐onset hypertension. Interestingly, in this study, no risk was conferred by late‐onset hypertension, indicating that the risk is conferred by factors early acquired in life which are likely to be related to genes.3 Overall, these data suggest that com‐ mon mechanisms are responsible for the transgenerational effect on the risk of developing metabolic diseases. When authors included in the multivariate analyses a genetic risk score composed by sequence variations in the PNPLA3, NCAN, LYPLAL1, GCKR and PPP1R3B genes, they found no changes in the risk of developing hepatic steatosis. This result suggests the presence of other common or rare sequence variations contributing to the suscep‐ tibility of hepatic steatosis. A caveat of this analysis that may explain their negative findings is that the genetic risk score included only two loci robustly associated with NAFLD namely the PNPLA34,5 and GCKR,6,7 while the other sequence variants were either proxy (NCAN) or involved in other metabolic liver disease.8,9 It would have been interesting to include in the genetic score sequence variant of the TM6SF210,11 and MBOAT7 loci12,13 which may have strengthened the analysis. Another component contributing to the heritability observed in this study may be epigenetic changes in DNA methylation, in his‐ tone proteins and in non‐coding RNAs which are known to modulate the phenotypic variation of hepatic steatosis.15 Interestingly, the strength of the association conferred by hav‐ ing one affected parent in this study was attenuated when, in the multivariate analyses, BMI was added as a covariate. This finding is not surprising because excess in body weight, unlike in other met‐ abolic diseases, is an important driver of the deleterious effect of genes increasing the susceptibility of hepatic steatosis.16,17 Finally, it is fair to say that lifestyle and dietary habits are also acquired by the offspring through imitational behaviour. In this respect, sed‐ entary lifestyle and excess in calories, both risk factors for hepatic steatosis, are usually seen among members of the same family and this component cannot be dissected by investigating family history. In conclusion, this study shows in an elegant way that simple in‐ vestigation on family history provides a powerful tool to assess the patient risk of hepatic steatosis.