Genetic Risk Factors for Common Causes of Advanced Kidney Disease

Israeli and American Research Teams Close in on Genetic Risk Factors for Common Causes of Advanced Kidney Disease

It is estimated that in North America there are approximately forty million individuals with chronic kidney disease at various stages of severity. Among these, approximately half a million individuals have the final or end-stage of kidney disease requiring life-sustaining dialysis or transplantation. The comparable number in Israel is approximately 3,000 individuals. While these therapies are life-sustaining, they are associated with a reduced quality of life and increased mortality.

In regions of the world where dialysis and transplantation are not available, end-stage kidney disease is fatal. Until recently, it was thought that genetic factors make a relatively minor contribution limited to a few rare forms of kidney disease with a clear-cut familial hereditary pattern. However, the now well-documented observation of marked disparities in the prevalence of the most common forms of end-stage kidney disease among different population groups in North America, suggested that genetic factors may play a more important role than previously considered, in almost all forms of kidney disease.

In particular, African-Americans have an approximately 4-fold higher rate and Hispanic-Americans an approximately 2-fold higher rate of end-stage kidney disease requiring dialysis or transplantation, compared to Americans of European ancestry. There is a comparably higher rate of high blood pressure and other manifestations of kidney disease.

The finding that these disparities could not be attributed solely to socio-economic, cultural, dietary, or environmental factors, strongly pointed to a major genetic contribution to common forms of kidney disease. Indeed, genetic mapping studies reported by American groups of researchers during the past two years, identified a specific gene on chromosome 22 (MYH9), and which is expressed in the kidney, as explaining the African ancestry genetic risk.

In the current issue of the prestigious journal "Human Molecular Genetics", an American research team working with the Israel Institute of Technology and Rambam Medical Center in Haifa, together the Hadassah Medical Center in Jerusalem Israel, and in collaboration research colleagues at Tel Aviv University and the National Institutes of Health in the USA, report finding the very strong predictive association of new markers within this gene, with common forms of end-stage kidney disease in different population groups. In the current study, the researchers found a particular suite of markers which designate and allelic variant of the gene, which appears to have originated in Western and South Africa, carries with it a high risk for kidney disease, when present in admixed populations, such as Hispanic Americans.

Thus, while the researchers report an overall genomic African ancestry contribution of approximately 85% in African-Americans and 30% in Hispanic-Americans, the African risk variant of this particular gene confers an increased risk for end-stage kidney disease of between 3 to 5 fold. This is one of the highest ever reported genetically based set of risk markers for a common disease state, and leads to consideration of utilization of the markers for population health screening in the prevention of kidney disease.

Furthermore, the finding of these predictive genetic markers, paves the way for identifying the actual genetic mutation which promotes kidney injury, and will hopefully lead to the development of preventive and therapeutic interventions. In this regard, HIV-associated end-stage kidney disease is the most highly associated form of kidney failure with these newly reported risk markers. The same Technion and Rambam based research teams had already reported four years ago, that in contrast to African-Americans, Ethiopians seem to be completely protected from this form of kidney failure, and therefore may hold the clue that connects the function of this gene with healthy kidneys.