Genetic and metabolic components in the regulation of serum urate levels in humans

Uric acid is the final breakdown product of purine metabolism in
humans and present in the blood as urate. Elevated serum urate
levels can cause gout, a painful inflammatory arthritis, and are
implicated in a number of common diseases such as cardiovascular
disease, metabolic syndrome, and type 2 diabetes. The regulation of
serum urate levels is assumed to result from a complex interplay
between genetic, environmental, and lifestyle factors. The
underlying functional biological processes are still not completely
understood. The present thesis aimed to identify genetic and
metabolic factors in the regulation of serum urate levels.
Therefore, two different hypothesis-free approaches were applied.
First, two genome-wide association studies were performed in order
to identify genetic loci that are involved in the regulation of
serum urate levels within the framework of two huge international
consortia. The impact of identified genetic loci was compared
between different ancestries. Second, a metabolic network analysis
within a population-based study was performed aiming to describe
the metabolic vicinity of serum urate. By combining data of
approximately 28,000 individuals in a genome-wide association
study, nine genetic loci were identified to be involved in the
regulation of serum urate levels. The increase of the sample size
to a total of approximately 140,000 individuals within a world-wide
consortium, combined with a systematic protein-protein interaction
network approach, raised the number of detected genetic loci to 28.
Although serum urate shows distinct sex differences, an
investigation of the X chromosome did not provide additional
findings. Whereas the first identified genes were predominantly
involved in urate transport, none of the later identified genes are
obviously involved in its transport but underline the importance of
the metabolic control of its production and excretion. A comparison
between results from different ancestries showed that several of
the loci found in Europeans do also play a role in non-Europeans.
However, results from one ancestry cannot directly be transferred
to other ancestries as the genetic architecture at certain loci can
vary between ancestries. In the metabolite network analysis, serum
urate was not only connected to the well-known purine metabolism,
but also to a group of essential amino acids and a group of several
steroids. Furthermore, association with uricostatic medication
intake was not only connected to purine metabolism but seen for
nine metabolites within the network. The findings highlight
pathways that are important in the regulation of serum urate and
suggest that amino acids as well as steroid hormones play a role in
its regulation. The results of both approaches help to better
understand the complexity of serum urate regulation in humans, and
may help to advance drug development for the treatment and
prevention of hyperuricemia and gout.