Genetics and Genomics of Complex Diseases in Hepatology

We are born with predetermined genetic susceptibility and develop most maladies (i.e., complex diseases) as a result of the interaction between this predisposition and the myriad of environmental factors to which we are exposed to throughout our lives.

In 1865, Mendel demonstrated that a transmittable element passes from one generation to the next determining inheritance. This was the earliest conceptual description of the gene as the hereditary unit. Nearly one and a half centuries later, the Human Genome Project provided us with the opportunity to look for the first time at the entire sequence of the human genome. Based on this endeavor, we learned that two nonbiologically related individuals share 99.9% of their genetic material.[1] [2] Yet, this difference of 0.1% contributes to making each human unique in personality, physical features, and susceptibility to illness. We are alike but at the same time different. Last year, the first genetic map of human variation was published.[3] This work will shed light on the genomic polymorphisms that determine predisposition to disease.

We have made momentous progress, and more is ahead. Thus, it is timely that this issue of Seminars in Liver Disease is devoted to the “Genetics and Genomics of Complex Diseases in Hepatology.” With this in mind, we have invited experts who provided excellent reviews on the current status of the genetics and genomics of selected complex liver diseases.

In the first article, Juran and Lazaridis discuss the application of genomics to the study of complex diseases. This review introduces concepts related to “intricacy of human disease,” provides an overview of the field of genomics, and emphasizes the opportunities and challenges we face in the quest of dissecting the genetic susceptibility to disease.

In the second article, Patrick Marcellin and colleagues outline the implications of genomics for a better understanding of the pathogenesis, progression, and treatment of chronic hepatitis C virus (HCV). With nearly 170 million people infected worldwide, every improvement in preventing or treating chronic hepatitis C will have a significant impact on human health. The authors discuss data on liver gene expression profiling and its response to HCV therapy. In one study, several of these genes were interferon sensitive and two were associated with new interferon-regulatory pathways, thus implicating a mechanism for resistance to treatment. In another study, discriminatory genes were noted between HCV groups treated with interferon and interferon-ribavirin. Emerging proteomics approaches have also been applied to assess the proteome changes of HCV-infected hepatocytes. Deciphering the key host factors implicated in HCV pathogenesis will improve the therapy for this infectious disease.

In the third article, David Brenner and associates review the genomics of liver fibrosis and cirrhosis. Fibrosis of the liver is the result of chronic hepatic injury of diverse cause (e.g., viral, metabolic, autoimmune). Nevertheless, cirrhosis develops in merely a minority of patients with fibrosis. Apart from environmental factors that affect the risk of progression to cirrhosis, genetic contributors are also probably in play to determine disease advancement. The authors discuss variations of fibrosis-associated genes in alcoholic liver disease (ALD) (i.e., proinflammatory cytokines), chronic HCV infection (i.e., angiotensinogen, TGF-α1, pro- and anti-inflammatory cytokines), and nonalcoholic fatty liver disease (NAFLD) (i.e., microsomal triglyceride transfer protein). The significance of understanding the genetic predisposition to advanced fibrosis/cirrhosis is apparent. It is anticipated that several of the fibrosis-associated genes are shared among chronic liver diseases. Still, some of these genes or genetic variants are expected to be more exclusively related to a specific disease. Elaborate designs of genotype-phenotype (i.e., cirrhosis) studies are required to expand these observations.

In the fourth article, de Alwis and Day provide an overview regarding the genetics of ALD and NAFLD. ALD and NAFLD are frequent diseases of the liver. However, only a small percentage of individuals with heavy alcohol consumption or obesity ever develop advanced ALD or NAFLD, respectively. Being able to determine the likelihood of this outcome is essential to hepatologists. As suggested by familial studies, genetic elements are as important as environmental factors in contributing to end-stage ALD or NAFLD. Indeed, functional polymorphisms of genes have been reported for the former and are emerging for the latter. However, to make discoveries with the potential of guiding future prevention approaches or therapy of these diseases we will have to conduct large, well-defined human studies given the heterogeneity and complex pathogenesis of ALD and NAFLD.

In the fifth article, Josep Llovet and colleagues discuss the genomics of hepatocellular cancer (HCC). In the past decade, a plethora of work has unveiled several of the genes and signal transduction pathways (i.e., Wnt-β catenin, hedgehog) involved in hepatocellular cancer. Gene expression profiles and somatic genetic alterations for HCC provide a springboard to elucidate the mechanisms of hepatocarcinogenesis. This direction of work not only will lead to improved molecular understanding and classification of the disease but also has the potential to result in better molecular targets for therapy.

In the sixth article, Michael Trauner and associates present data on the implication of MDR3 in chronic cholestatic liver diseases. Historically, defects of MDR3 (phospholipid export pump) were thought to cause progressive familial intrahepatic cholestasis. We now know that MDR3 mutations or genetic variants may contribute to a diverse array of cholestatic syndromes ranging from cholestasis of pregnancy to cholestasis induced by total parenteral nutrition. Understanding the implication of this transporter in chronic cholestasis has therapeutic ramifications because drugs can modulate the cellular expression of MDR3.

In the seventh article, Richard Lambrecht and colleagues discuss the genetics of porphyria cutanea tarda (PCT), the most common of the cutaneous porphyrias. PCT is either acquired (i.e., sporadic) or genetic (i.e., familial). Both clinical entities are characterized by low activity of the uroporphyrinogen decarboxylate (UROD) gene product. Yet, the etiology of the UROD deficiency in the acquired type of the disease is probably multifunctional; in contrast, the genetic form is due to low-penetrance mutations of the UROD gene. Recent development of DNA testing for PCT and more research will help to elucidate the modifier gene or genes of disease expression.

In the final article, Wittenburg and Lammert review the genetic predisposition to gallbladder stones. Cholelithiasis is very common in the western hemisphere. To date, we know a fair amount regarding the biochemical mechanisms of gallbladder stone formation but we lack knowledge of the genomic loci that cause susceptibility to this disease. However, epidemiologic studies indicate that gallbladder stones aggregate in families. Whether these findings reflect only the environmental exposures and lifestyles shared among relatives or extend beyond to the genomic level is unknown. For example, rare genes have been reported to cause formation of gallstones (i.e., ABCB4, ABCB11) in families. Moreover, the search for common “lithogenic genes” is under way.

In the beginning of this century, we have the opportunity to advance our knowledge of the genetic predisposition to complex liver diseases. The challenges are many but the potential for genomic-based discoveries, which could transform the prognosis and therapy of complex liver diseases, is evident. Let's make this promise reality!

REFERENCES

• 1 Lander E S, Linton L M, Birren B et al.. Initial sequencing and analysis of the human genome.  Nature. 2001;  409 860-921
• 2 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
• 3 International HapMap Consortium . A haplotype map of the human genome.  Nature. 2005;  437 1299-1320