There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

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Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

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A haplotype map of the human genome

The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.

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The pathogenesis of rheumatoid arthritis.

Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases. Herein we discuss the current challenges in the field, such as designing selective inhibitors and developing strategies to overcome resistance mutations. This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors.

Targeting cancer with small molecule kinase inhibitors

�Background Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. Methods We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. Results A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1×10 −4 ); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor α gene (IL2RA) were strongly associated with multiple sclerosis (P = 2.96×10 −8 ), as were a nonsynonymous SNP in the interleukin-7 receptor α gene (IL7RA) (P = 2.94×10 −7 ) and multiple SNPs in the HLA-DRA locus (P = 8.94×10 −81 ).

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Risk alleles for multiple sclerosis identified by a genomewide study.

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting ∼1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P =6.6×10 −4 ; replication-study allelic P =5.6×10 −8 ), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in ∼17% of white individuals from the general population and in ∼28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

The importance of B cells in rheumatoid arthritis (RA) pathogenesis has been recently demonstrated in several clinical studies using the anti-CD20 antibody rituximab, which selectively depletes B cells. A recent phase III clinical trial led to the FDA approval of rituximab for a subset of RA patients. Bruton’s tyrosine kinase (Btk), a member of Tec family kinases, is a key component in the B-cell receptor signal pathway (BCR). Upon activation by upstream kinases (for example, Lyn and Syk), Btk phosphorylates and thereby activates phospholipase-Cg (PLCg), leading to several important downstream events including calcium ion transportation, NF-kB activation, and (auto)antibody generation. Previous biological studies (genetic loss of function and siRNA knockdown) strongly suggest that Btk is also a mediator of proinflammatory signals. Taken together, these studies indicate Btk may be a potential target for the treatment of RA. However, despite the previous discovery of LFM-A13 as a selective Btk inhibitor, there is no published study that has demonstrated that inhibition of Btk activity leads to in vivo efficacy in an animal model of rheumatoid arthritis. As ATP binding sites in kinases are highly conserved, it is a formidable task to develop selective ATP competitive kinase inhibitors. Among several approaches, the use of electrophilic inhibitors has been shown as a viable method to achieve selectivity. Considering the relative scarcity of knowledge on “chemical knockdown” of Btk activity, it is crucial to discover a potent and selective tool compound for this kinase. Herein, we describe the discovery of a selective, irreversible Btk inhibitor and its efficacy in a mouse RA model. An initial campaign to scan for scaffolds capable of inhibiting Btk’s kinase activity identified compound 1 as having

Jill M. Spoerke

Papers

A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase