Progress in hepatology
Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: A narrative reviewFactores genéticos asociados con la presencia y progresión de la enfermedad hepática no alcohólica: Una revisión narrativa

https://doi.org/10.1016/j.gastrohep.2011.08.002Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge.

Resumen

La enfermedad hepática no alcohólica (EHNA) es la enfermedad crónica del hígado más común en el mundo. Si bien se considera que la resistencia a la insulina y la obesidad son factores de riesgo importantes para el desarrollo y progresión de la misma, sus bases genéticas no están claras. Antes de 2008, los estudios sobre genes candidatos basados en conocimientos previos de la fisiopatología de la esteatosis hepática produjeron resultados contradictorios. En 2008, Romeo et al. publicaron el primer estudio de asociación amplia del genoma que presentaba indicios genéticos sólidos de la presencia de esteatosis hepática (PNPLA3, dominio de la fosfolipasa-patatina 3; rs738409). Desde entonces, se han publicado dos estudios adicionales de asociación amplia del genoma en los que se identificaron otras nueve variantes genéticas. Si bien estos resultados arrojan luz sobre la genética de la EHNA, la mayoría de las asociaciones no se han replicado en muestras independientes y, por tanto, la importancia de estos hallazgos continúa siendo incierta. Esta revisión pretende resumir los conocimientos actuales sobre la epidemiología genética de la EHNA y destaca las áreas de incertidumbre.

Section snippets

Nonalcoholic fatty liver disease is common and has a genetic basis

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease,1 represents a wide spectrum of disease characterized by the presence hepatic steatosis in the absence of significant alcohol consumption or other causes of liver disease.2, 3 The pathogenic processes leading to steatosis, steatohepatitis (NASH) and fibrosis are multifactorial and involve both environmental and genetic factors.4, 5 Obesity and type 2 diabetes/insulin resistance are the most common risk factors for

Study designs and methodological problems in genetic epidemiology of NAFLD

NAFLD is considered a complex disease because it does have a genetic component but with no simple Mendelian pattern of single-gene inheritance such as Wilson disease. In NAFLD, multiple genes, polygenes, environmental factors, age effects, and their interactions, may be involved.26

Genetic epidemiology studies can be divided into two broad categories: (a) according to the relatedness amongst participants (family-based versus non-related or population-based); and (b) according to the knowledge of

Steatosis: a protective mechanism surrounded by multiple insults

The key pathological finding in fatty liver disease is the accumulation of triglycerides in the hepatocytes. This deposit is due to an imbalance between triglycerides acquisition and removal.28, 29 Triglycerides are neutral lipids consisting of a glycerol backbone and three long-chain fatty acids. The major routes of free fatty acids (FFAs) are (a) dietary intake; (b) lipolysis from fat reservoirs, and (c) de novo lipogenesis. Animal studies and human inherited diseases have shown increased

Genetic epidemiology of NAFLD: a systematic approach

To identify most of the available published literature in genetics of NAFLD, the author performed a systematic search using PUBMED by applying the following search engine: (polymorphism OR SNP) AND (“steatosis” OR “steatohepatitis” OR NAFLD OR NASH) without language restriction and until July 26th, 2011. The search yielded 224 references; of which 60 corresponded to candidate gene studies and are summarized in Table 1 and three genome wide association studies in Table 2. This search engine is

Future directions: candidate-genes are needed

The typical statement “more research is needed” is clearly shown by the examination of both tables. To better understand the genetic determinants of NAFLD, it is key to replicate prior studies. Whereas GWAS are expensive, require thousands of individuals and strong statistical and population genetics knowledge, the use of candidate gene studies in NAFLD is easy to implement and straightforward. The major caveat for these studies is the lack of power. For instance, assuming a genetic risk ratio

Conflict of interest

The author declare no conflict of interest.

Acknowledgement

The author has been supported by the American Diabetes Association Mentor-Based Program (7-07-MN-08, PI: Dr. Frederick L. Brancati).

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