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November 25, 2021

PNPLA3 as a genetic determinant of non-alcoholic fatty liver disease

Although it is normal for the liver to contain some fat, Non-alcoholic fatty liver disease is the build-up of extra fat in liver cells that is not caused by alcohol. If more than 10% of the liver’s weight is fat, it is referred to as fatty liver (or steatosis).

By GlobalData Healthcare

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease across many parts of the world. According to the American Liver Foundation, NAFLD affects up to 25% of people in the US. Although it is normal for the liver to contain some fat, NAFLD is the build-up of extra fat in liver cells that is not caused by alcohol. If more than 10% of the liver’s weight is fat, it is referred to as fatty liver (or steatosis). NAFLD is often nicknamed the ‘silent liver disease’ as it can occur without any symptoms, which leads to many undiagnosed cases. When a build-up of fat causes inflammation or damage, it is known as non-alcoholic steatohepatitis (NASH), which is an advanced form of NAFLD. Scientists have long investigated the heritable genetic factors that predispose individuals to develop NAFLD in later life. The genetic variant Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been mentioned specifically as one of the strongest risk factors. Investigating this link will allow scientists to understand the interaction between genetic factors and the development of NAFLD in later life.

The leading risk factor of NAFLD is obesity; therefore the rising disease burden from NAFLD is associated with increased rates of obesity and its wider metabolic consequences. Due to NAFLD remaining the most common cause of chronic liver disease, combined with rising rates of obesity in the world, GlobalData experts project that there will be an increase in the total number of prevalent cases of NAFLD across the seven major pharmaceutical markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan). If left untreated, NAFLD can lead to serious liver damage. The National Health Service states that an estimated one in three people in the UK have early stages of NAFLD. This highlights the need for more prompt interventions to strategically detect NAFLD in its early stages. NAFLD has increased rapidly over the past decade. GlobalData epidemiologists forecast that the total prevalent cases of NAFLD are expected to reach just over 193 million in the 7MM by the end of 2021. However, in the same year, the estimated number of diagnosed cases of NAFLD will be under 71 million, which equates to a low diagnosis rate of 36%.

Although rising disease burdens from NAFLD may reflect increased rates of obesity, it is widely known that genetic factors determine how individuals respond to excess caloric intake. Furthermore, a recent study conducted by Gao and colleagues in Clinical and Translational Gastroenterology mentioned that, due to familial clustering of NAFLD, the disease can be strongly influenced by heritable genetic factors in which PNPLA3 is most predominantly investigated.

The study included a total of 1,070 individuals with biopsy-confirmed NAFLD recruited in the Eastern Asia Region (China and South Korea). The study was conducted using a cross-sectional method involving two cohorts of adults, and developed a genetic risk factor-based nomogram that allows non-invasive screening to identify NAFLD. In the primary Chinese cohort (n = 538), patients were randomly assembled into a “training set” (n = 402) and a “validation set” (n = 136). Study findings demonstrated that in the training set cohort containing 231 NAFLD participants and that the genotype of the PNPLA3 (C/C, C/G, and G/G) was detected in 83, 105, and 43 participants, respectively. Research has shown that PNPLA3 G/G subjects have a 3.9-fold higher risk of having NAFLD compared with C/C subjects. Furthermore, PNPLA3 C/G subjects also have a 1.75-fold increased risk of having NAFLD versus C/C individuals, according to research by Mazo and colleagues published in Annals of Hepatology.

The study confirmed that PNPLA3 rs738409 was the most robustly associated genetic variant associated with NAFLD as well, confirming that the interaction of genetic and metabolic risk factors plays an important role in the development of the disease.

The correct identification of patients at increased risk of NASH is a major focus of drug development worldwide. The challenge facing healthcare systems is how to accurately identify patients with NAFLD, especially through non-invasive methods, who will then benefit from early lifestyle interventions and future treatment. Future research should focus on understanding more about the role of PNPLA3 and potentially implementing screening for this genetic marker.

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