New genes associated with kidney function and disease

13 April 2010

Chronic kidney disease is a common disorder, affecting around 1 in 10 adults, resulting in progressive loss of kidney function. The condition is associated with increasing age, and is increasing in prevalence partly due to the ageing population in many countries. Despite this growing global health burden, only a limited number of inherited monogenic kidney disorders (e.g. polycystic kidney disease) have been identified, accounting for a small proportion of chronic kidney disease. Two large research collaborations have recently published studies in Nature Genetics identifying several new common genetic variants associated with kidney function and chronic kidney disease.

The first paper reports a genome-wide association (GWA) study and a replication study to identify genetic loci associated with serum creatinine levels, a common measure of kidney disease [Chambers et al. (2010) Nat Genet 11 April; doi:10.1038/ng.566]. The data from nine individual studies involving almost 24,000 participants of European descent were combined using a meta-analysis and five positions (on chromosomes 2, 4, 6, 17 and 19) were associated with creatinine levels; only the locus on chromosome 4 had been previously reported. The strongest SNP from each of the four novel loci was then analysed in a further 16,500 Europeans. All four SNPs showed association with creatinine levels (but not with other factors known to mimic links to creatinine) and also with one or both of two alternative measures of kidney function and with chronic kidney disease, so they are good candidates for genuine genetic variants linked to kidney function.

The second study also used a two-stage design to identify association with two measures of kidney function and chronic kidney disease [Kottgen et al. (2010) Nat Genet 11 April; doi:10.1038/ng.568]. The first stage involved a GWA meta-analysis of 20 studies involving 67,000 participants of European descendent, which identified 28 loci, only five of them previously reported. The strongest SNP at each of the 23 novel loci were analysed in a further 23,000 individuals of European ancestry; sixteen still showed significant association. A meta-analysis of both stages of the study suggested that a total of twenty of these novel genetic variants showed significant association with kidney function; thirteen are thought to affect renal function and disease, and seven to relate to creatinine metabolism.

Comment: These very large and well-conducted studies involving more than 100,000 people have identified several strong candidate genes likely to be involved in renal development and function. However, the authors estimate that these variants still only account for a small proportion of variation in kidney function. The studies are also wholly within European populations, but kidney failure is more common among those of South Asian and African Caribbean descent. It will be interesting to see whether the genetic architecture underlying this disease is the same is differing populations.

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