Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver condition that, on a societal level, results in substantial health-care costs, economic losses and reduced health-related quality of life (HRQoL) [1][2][3][4][5][6][7][8] . A biologically and clinically heterogeneous disease, NAFLD covers a broad spectrum of histological conditions that increase both hepatic and non-hepatic morbidity and mortality. The majority of people living with NAFLD have isolated steatosis (non-alcoholic fatty liver, NAFL) and a smaller proportion develop non-alcoholic steatohepatitis (NASH), with increasing hepatic fibrosis leading eventually to cirrhosis, liver cancer, end-stage liver disease and death 9,10 . NASH is a leading cause of progression to cirrhosis and hepatocellular carcinoma 11,12 , and an increasingly common indication for liver transplantation 13,14 . Liver cancer is now the second leading cause of years of life lost among all cancers globally 15 .NAFLD is part of a multisystem disease and is considered the hepatic manifestation of metabolic syndrome [16][17][18] . Although strongly associated with obesity, NAFLD also occurs in individuals with normal weight, especially in Asian populations 19,20 . The causes of death in people living with NAFLD vary depending on disease state. Patients with cirrhosis predominantly have liver-related events, whereas those without cirrhosis have vascular events and non-hepatic cancer 21 . Overall, cardiovascular disease (CVD) is the leading cause of death in patients with NAFLD; other common causes include extrahepatic

Avian influenza viruses of the H9N2 subtype have seriously affected the poultry industry of the Far andMiddle East since the mid-1990s and are considered one of the most likely candidates to cause a new influenza pandemic in humans. To understand the genesis and epidemiology of these viruses, we investigated the spatial and evolutionary dynamics of complete genome sequences of H9N2 viruses circulating in nine Middle Eastern and Central Asian countries from 1998 to 2010. We identified four distinct and cocirculating groups (A, B, C, and D), each of which has undergone widespread inter-and intrasubtype reassortments, leading to the generation of viruses with unknown biological properties. Our analysis also suggested that eastern Asia served as the major source for H9N2 gene segments in the Middle East and Central Asia and that in this geographic region within-country evolution played a more important role in shaping viral genetic diversity than migration between countries. The genetic variability identified among the H9N2 viruses was associated with specific amino acid substitutions that are believed to result in increased transmissibility in mammals, as well as resistance to antiviral drugs. Our study highlights the need to constantly monitor the evolution of H9N2 viruses in poultry to better understand the potential risk to human health posed by these viruses.

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