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Scientists at deCODE Genetics and academic collaborators from Iceland, Norway, Denmark, the Netherlands and the USA today report the discovery of low frequency variants in the human genome that associate with risk of gout, a common inflammatory arthritis, and serum uric acid levels. The study was done in collaboration with Illumina Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders, including over 1,200 patients with gout and over 22,000 individuals for whom serum uric acid measurements were available.

The researchers observed a sequence variant in a previously unidentified gout susceptibility gene located on chromosome 19 that has a large effect on serum uric acid levels and gout. The sequence variant is a mis-sense mutation that causes an increase in the level of uric acid by 0.04 mmol/L and a three-fold increase in the risk of gout. Close to 4% of individuals in the overall Icelandic population carry this variant, and ~0.2% of the individuals assessed by academic collaborators in Norway, Denmark, The Netherlands and the United States.

The variant encodes an amino acid change in ALDH16A1, a member of the aldehyde dehydrogenase (ALDH) superfamily, and could motivate further biological studies of this pathway. Other members of the ALDH superfamily have been associated with other clinical phenotypes including alcohol-induced flushing.

Also, at a previously reported locus on chromosome 1, the researchers discovered another novel low frequency variant associating with serum uric acid level and gout. The variant decreases the risk of gout by 50%, and the level of uric acid by 0.05 mmol/L. Approximately 3% of the Icelandic population carry this variant and 1.5% of the European subjects.

For both loci the effect on risk of gout is significantly higher among men than women, but the effect on serum uric acid levels is the same in both sexes.

“This study underscores the importance of whole genome sequencing of well-phenotyped populations. We are pleased that the clinical and genetic resource that deCODE has built enables us to make such discoveries,” said Kari Stefansson, deCODE’s CEO and senior author of the study.

“We are committed to turning discoveries such as this, as well as our recent findings in ovarian cancer and sick sinus syndrome, and our future discoveries, into real benefit for patients,” Dr. Stefansson continued.

Gout is a common inflammatory arthritis caused by urate crystal formation resulting from a high concentration of uric acid in the blood, which is in turn caused by an imbalance in the dietary intake of purines and in the synthesis an excretion of urate. The incidence of gout increases with age and is three times higher in men than in women.

Scientists at deCODE Genetics and academic collaborators from Iceland, The Netherlands, Spain and Finland today report the discovery of variants in the human genome that associate with  increased risk of invasive ovarian cancer, one of the deadliest forms of cancer in women.  The study was done in collaboration with Illumina Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders, including over 600 patients with ovarian cancer.

The researchers observed a rare sequence variant in a gene named BRIP1 that confers more than eightfold increase in the risk of ovarian cancer in the Icelandic population.  BRIP1 plays an important role in maintaining the stability of the genome and interacting directly with the DNA repair protein encoded by the known breast cancer gene BRCA1.  Interestingly, the mutation also associates with increased risk of being diagnosed with cancer in general, and individuals carrying the variant live 3.6 years fewer on average.

The researchers also searched for mutations in the BRIP1 gene in ovarian cancer patients in other populations.  A rare variant in BRIP1 was found in a Spanish cohort of 144 patients and 896 controls; this mutation confers a significantly increased risk of not only ovarian cancer, but also breast cancer.  Finally, examination of  tumors from ovarian cancer patients that carry the mutation showed a loss of the healthy copy of the gene, further supporting the role of BRIP1 as a classical tumor suppressor.

“This study underscores the important contribution that the Icelandic population can make to the discovery of low frequency sequence variants with large effect.  The potential to do this has been clear since the critical role played by Iceland in the discovery of the BRCA2 gene.  Until now, however, the combination of sequencing technology and analytical techniques were insufficient to unleash the flood of discoveries that we and our collaborators are now making,” said Kari Stefansson, deCODE’s CEO and senior author of the study.

“Our objective is to translate our discoveries most rapidly into benefit for patients.  So, we are committed to working with our collaborators, as we did in this case, to identify the spectrum of mutations occuring in other populations.  This allows us to use the Icelandic resource as a unique discovery cohort, and then quickly elucidate the broader utility,” Dr. Stefansson added.

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries.  Five-year relative survival rate is less than 45%, with the stage at diagnosis being the major prognostic factor.  Importantly, only 19% of ovarian cancer cases are diagnosed while the cancer is still localized and chances of cure are over 90%.  Hence, the discovery of genetic variants that increase the risk of ovarian cancer may enable the development of diagnostic tests to identify women at high risk for the disease.  Women at high risk can then be be offered frequent screening for early detection and treatment or preventive intervention.

deCODEme Complete Scan now includes Testicular Cancer

At deCODEme, we believe that when it comes to planning your preventive health efforts, your genetic profile is the place to start. This month we have added two new diseases, both of which are highly curable if caught early.

If you are a deCODEme customer who has bought our Complete Scan, your account now includes a personalized genetic risk assessment for:

Testicular Cancer of males, and Ovarian Cancer of females.

Our scientists have also added more genetic details to the risk assessment for Prostate Cancer, which now includes a total of 25 genetic risk variants for customers of the Complete Scan.

deCODEme DNA test now includes Ovarian Cancer

Ovarian cancer is the eighth most common cancer in women. Based on ovarian cancer statistics in the U.S., it is expected that 1.4% of women born today will be diagnosed with cancer of the ovary at some point during their lifetime. This represents the lifetime risk of ovarian cancer and means that 1 out of every 71 women will be diagnosed with this disease during their lifetime. deCODEme Complete Scan now includes risk calculation for Ovarian Cancer.

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