A 129-kb deletion on chromosome 12 confers substantial protection against rheumatoid arthritis, implicating the gene SLC2A3.

We describe a copy-number variant (CNV) for which deletion alleles confer a protective affect against rheumatoid arthritis (RA). This CNV reflects net unit deletions and expansions to a normal two-unit tandem duplication located on human chr12p13.31, a region with conserved synteny to the rat RA susceptibility quantitative trait loci Oia2. Genotyping, using the paralogue ratio test and SNP intensity data, in Swedish samples (2,403 cases, 1,269 controls) showed that the frequency of deletion variants is significantly lower in cases (P = 0.0012, OR = 0.442 [95%CI 0.258-0.755]). Reduced frequencies of deletion variants were also seen in replication materials comprising 9,201 UK samples (1,846 cases, 7,355 controls) and 2,963 US samples (906 controls, 1,967 cases) (Mantel-Haenszel P = 0.036, OR = 0.559 [95%CI 0.323-0.966]). Combining the three datasets produces a Mantel-Haenszel OR of 0.497 (P < 0.0002). The deletion variant lacks 129-kb of DNA containing SLC2A3, NANOGP1, and SLC2A14. SLC2A3 encodes a high-affinity glucose transporter important in the immune response and chondrocyte metabolism, both key aspects of RA pathogenesis. The large effect size of this association, its potential relevance to other diseases in which SLC2A3 is implicated, and the possibility of targeting drugs to inhibit SLC2A3, argue for further examination of the genetics and the biology of this CNV.

Automated design of paralogue ratio test assays for the accurate and rapid typing of copy number variation.

MOTIVATION: Genomic copy number variation (CNV) can influence susceptibility to common diseases. High-throughput measurement of gene copy number on large numbers of samples is a challenging, yet critical, stage in confirming observations from sequencing or array Comparative Genome Hybridization (CGH). The paralogue ratio test (PRT) is a simple, cost-effective method of accurately determining copy number by quantifying the amplification ratio between a target and reference amplicon. PRT has been successfully applied to several studies analyzing common CNV. However, its use has not been widespread because of difficulties in assay design. RESULTS: We present PRTPrimer (www.prtprimer.org) software for automated PRT assay design. In addition to stand-alone software, the web site includes a database of pre-designed assays for the human genome at an average spacing of 6 kb and a web interface for custom assay design. Other reference genomes can also be analyzed through local installation of the software. The usefulness of PRTPrimer was tested within known CNV, and showed reproducible quantification. This software and database provide assays that can rapidly genotype CNV, cost-effectively, on a large number of samples and will enable the widespread adoption of PRT. AVAILABILITY: PRTPrimer is available in two forms: a Perl script (version 5.14 and higher) that can be run from the command line on Linux systems and as a service on the PRTPrimer web site (www.prtprimer.org).

HGV2009 meeting: bigger and better studies provide more answers and more questions.

The 11th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2009: Tallinn, Estonia, 11th-13th September 2009) provided a stimulating workshop environment where diverse academics and industry representatives explored the latest progress, challenges, and opportunities in relating genome variation to evolution, technology, health, and disease. Key themes included Genome-Wide Association Studies (GWAS), progress beyond GWAS, sequencing developments, and bioinformatics approaches to large-scale datasets.