Does tumor necrosis factor play a role in alcoholic steatohepatitis? The potential pitfalls of a case-controlled allelic association analysis

✍ Scribed by K C Wilhelmsen

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 103 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260132

✦ Synopsis

Grove et al. found that one of the polymorphisms was associated with the development of alcoholic steatohepatitis. The Most patients seek medical attention not for rare condimost tantalizing explanation for this observation is that a tions inherited in a simple Mendelian manner but rather polymorphism in the TNF promoter does, in fact, cause a for disorders resulting from a complex interaction between predisposition to alcoholic steatohepatitis. An alternative, but specific genetic backgrounds and environmental factors. In still intriguing, possibility is that other polymorphisms, identifying the genes responsible for human diseases that nearby on the same chromosome and possibly in the major are transmitted as simple Mendelian traits, well documented histocompatibility locus, may also predispose to alcoholic progress performed by human molecular geneticists may porsteatohepatitis. It is important to remember, however, that tend future developments in understanding the traits progenetic case-control studies are open to a much less interestduced by complex gene-to-gene and gene-to-environment ing explanation for the observed association of a TNF polyinteractions. In the future, a systematic genome-wide analysis morphism with alcoholic steatohepatitis. Specifically, if cases may identify all of the major genetic factors that contribute and controls come from different genetic backgrounds, a to complex traits. 1 Ultimately, it may be more directly possiviolation of the null hypothesis is far more likely to result ble to study how these gene effects interact with each other from this admixture than from association with a particular and with environmental influences to produce disease. Until polymorphism. One would not be intrigued, for example, by then, the focus will be on the study of specific candidate a difference in the allele frequencies between Inuits with genes. In this issue of Hepatology, the report by Grove et al. 2 alcoholic steatohepatitis and Ethiopian alcoholics without on an association of a tumor necrosis factor (TNF) promoter alcoholic steatohepatitis. This gross example of admixture polymorphism and of an alcoholic steatohepatitis is an examwould make statistical analysis absurd. Admixture that is far ple of a candidate-gene based association study.

more subtle can easily confound carefully designed case-Twin studies, family studies, and anecdotal experience control studies, particularly when the effect of the gene is suggest that genetic factors contribute to the susceptibility small. in some of the alcoholic end-organ complications. Still, the Thus, caution is necessary in interpreting the results by genetic dissection of that complex process seems to require Grove et al. It is also important not to overlook clues as to a prior knowledge of the solution. Working from the observathe etiology of complex traits. In essence, keeping a high tion that exposure to TNF produces a liver morphology restandard in identifying disease susceptibility polymorphisms sembling alcoholic steatohepatitis, Grove et al. tested the allows for the avoidance of type-1 errors (false positives) but hypothesis that polymorphisms in this gene cause a predispoalso risks the possibility of overlooking significant contribusition to alcoholic steatohepatitis.

tions and, therefore, committing type-2 errors (false nega-Allelic association analysis has been used to identify distives). The critical question in interpreting the results by ease susceptibililty in genes for many other human disease Grove et al., then, is to estimate the likelihood that these conditions. Even if only in a small subset of affected patients, results stem from a type-1 error. demonstrating that a gene is predisposed to a specific genetic There is no agreement among geneticists as to what criteria condition can provide insight into the pathogenesis of the should be used for this type of analysis. A recent set of disorder. If it can be confirmed that polymorphisms in TNF guidelines to establish a common set of criterion was procause a predisposition to alcoholic steatohepatitis, it can be posed by Lander and Kruglyak; 3 those guidelines met with hypothesized that other elements in the TNF signaling pathsubstantial dissension and letters to the editors. The most way might also be risk factors for the development of this important lesson to be learned from these various opinions is condition.

that the context of the obtained results is critically important. Grove et al. used a case control study design to look at Some statisticians would dismiss the results of Grove et al. two polymorphisms in TNF. They compared the frequency with the argument that if they had not found a positive result of alleles among alcoholics who did or did not have alcoholic with this locus, they would have proceeded to check another steatohepatitis. The null hypothesis is that these populations candidate gene until they found a positive result. The consedo not differ significantly and that the TNF polymorphisms quence of this scenario is that the threshold for convincing evidence has to be higher than for a single discrete analysis.

The crux of the issue, then, is to answer the question as Abbreviation: TNF, tumor necrosis factor.