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DeCode-Led Team Tracks Down New Gout Risk Variants

NEW YORK (GenomeWeb News) – An international research team led by investigators at DeCode Genetics has used whole-genome sequence and array data from the Icelandic population to track down new variants associated with gout and with the elevated uric acid levels in the blood that contribute to the inflammatory arthritis condition.

Along with known risk variants, the researchers found two new risk variants: one in an exon of the alcohol dehydrogenase family gene ALDH16A1 on chromosome 19, which appears to increase gout risk by around three times, and another in the centromeric region of chromosome 1. The researchers reported their findings in the early online version of Nature Genetics yesterday.

"This study underscores the importance of whole genome sequencing of well-phenotyped populations," senior author Kari Stefansson, CEO at DeCode and a researcher at the University of Iceland, said in a statement. "We are pleased that the clinical and genetic resource that deCODE has built enables us to make such discoveries."

Drawing from the whole-genome sequence data on 457 Icelandic individuals that the team has used to track down genes involved in ovarian cancer and other diseases in the past, the team looked at nearly 16 million SNPs in their effort to find new gout-associated variants.

From genotypes that were directly genotyped and/or imputed in 41,675 Icelanders, the researchers looked for variants linked to the disease and related traits. Of the Icelandic individuals who were directly genotyped with Illumina arrays, 789 were affected by gout.

By adding in information on 381 more cases with in silico genotypes, the team ratcheted up their effective sample size to 968 cases.

The effective sample size of the participant group for whom serum uric acid measurements were available was 15,506, including more than 11,350 directly genotyped individuals and about 9,400 individuals with in silico genotype data.

Using this information, the team found ties between gout and serum uric acid levels and a missense mutation in the chromosome 19 gene ALDH16A1 — an association they subsequently verified through targeted Sanger sequencing in 1,094 Icelanders with gout and 4,923 Icelanders without gout.

The same mutation turned up in seven individuals when they did targeted Sanger sequencing studies in 532 individuals from Norway, 1,538 individuals from Denmark, 1,024 individuals from the Netherlands, and 854 individuals from the US.

Another variant, found in the centromeric region of chromosome 1, also attracted the team's attention. The SNP, which was associated with uric acid levels in the blood and was also nominally associated with gout itself, fell near a common variant associated with serum uric acid levels in the past.

Although the risk of gout tends to increase with age, the chromosome 19 variant tended to coincide with younger age at the time of diagnosis.

For both the ALDH16A1 and chromosome 1 SNPs, the association with gout and uric acid levels was particularly pronounced in males, the researchers noted. In general, gout is roughly three times as common in men as it is in women.

Along with the previously undetected risk variants, the team also confirmed several associations detected through past association studies of more common variants.

"The current study illustrates how signals that have gone undetected when only imputations based on the HapMap Project were available can now be found through the imputation of variants based on whole-genome sequencing," the researchers wrote.