This is a quickie post, based on a small study just published looking at whether the genotype affects phenotype when it comes to liver cysts.
The ‘genotype’ is the genetic abnormality you carry. The ‘phenotype’ is the appearance of the disease as it shows in the individual. So the genes are a recipe for making proteins. When the genes have a faulty code then the recipe comes out wrong.
The two main genotypes in ADPKD are abnormalities in the PKD1 gene or in PKD2 gene. These genes are recipes for (code for) polycystin proteins, respectively called polycystin 1 and polycystin 2. Both proteins are essential in cell function, but loss of polycystin 1 may result in earlier problems than loss of polycystin2.
A genetic abnormality can be simply seen as a string of wrong codes. The wrong codes may be total nonsense and cannot be interpreted in which case no protein will be made at all, or they can be partly wrong so maybe a protein is made but it doesn’t work properly. Where you get no protein then this is called a ‘truncating’ error – no sense can be made of the message at all. In PKD is is thought that truncating errors on the genes result in a more severe disease.
For a while now it has been recognised that PKD1 genetic abnormalities tend to a more severe phenotype disease (earlier onset, larger cysts and kidneys) than PKD2.
The authors of this paper asked the question:
‘ Is the severity of polycystic liver disease also dependent on the specific genetic abnormality?’
If this were the case then one might expect people with PKD1 to also have more severe cystic liver disease, with perhaps PKD2 genotype being less affected.
The research was based on medical records of patients from the Mayo clinic and for a patient to be included there needed to be both genetic analysis and liver imaging available. This was so for 434 patients.
About 51% of these patients had truncating abnormalities of PKD1, 33% had non-truncating PKD1 abnormalities and 16% had PKD2 abnormalities. If the genotype did have an effect on the liver pathology then one would predict larger livers in the truncating PKD1 group and smaller in the PKD2 group. However they found no significant differences between the three groups when it came to height-adjusted liver volume. This was in marked contrast to the kidney volumes, also adjusted for height, which did follow the pattern of larger in the first group.
From this the authors confidently conclude that the phenotype of the liver cysts in PKD is not related to the genotype.
A pattern they did note though, was increase in liver volumes in women when compared with men which is consistent with other studies suggesting PLD tends to be more advanced in women. But reassuringly their results also led to the conclusion that once past the age of 48 almost half of female PLD sufferers had a reduction in their liver volume. This may not be by much, but it does point to a potential hormonal effect on liver size in ADPKD+PLD beyond that which has been previously considered.
So the bottom line for this paper is that although the genotype may determine phenotype for the kidney disease, it is of far less significance for the polycystic liver disease that accompanies PKD. There are clearly other factors involved – which is a good thing because it means there will be alternative approaches to treatment as these other factors are identified.
Fouad T. Chebib, Yeonsoon Jung, Christina M. Heyer, Maria V. Irazabal, Marie C. Hogan, Peter C. Harris, Vicente E. Torres, and Ziad M. El-Zoghby
Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease
Nephrol. Dial. Transplant. first published online February 29, 2016 doi:10.1093/ndt/gfw008