Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells

To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.     

Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding

Interactions of CD4 with the class II major histocompatibility complex (MHC) are crucial during thymic ontogeny and subsequently for helper and cytotoxic functions of CD4+CD8- T lymphocytes. CD4 is the receptor for the T-lymphotropic human immunodeficiency virus and binds its envelope glycoprotein, gp120. The residues involved in gp120 binding have been localized to a region within the immunoglobulin-like domain I of CD4, which corresponds to CDR2 of an immunoglobulin variable region, but the CD4 residues important in MHC class II interaction have not been characterized. Here, using a cell-binding assay dependent specifically on the CD4-MHC class II association, we analyse the effects of mutations in CD4 on class II versus gp120 binding. Mutations in CDR2 that destroy gp120 binding affect CD4-MHC class II binding similarly. In addition, binding of soluble gp120 to CD4-transfected cells abrogates their ability to interact with class II-bearing B lymphocytes. In contrast, other mutations within domains I or II that have no effect on gp120 binding eliminate or substantially decrease class II interaction. Thus, the CD4 binding site for class II MHC is more complex than the gp120 binding site, possibly reflecting a broader area of contact with the former ligand and a requirement for appropriate juxtaposition of the two N-terminal domains. The ability of gp120 to inhibit the binding of class II MHC to CD4 could be important in disrupting normal T-cell physiology, acting both to inhibit immune responses and to prevent differentiation of CD4+CD8+ thymocytes into CD4+CD8- T lymphocytes.     

A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region

In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A --> G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 x 10(-10).     

Methods for increasing sensitivity in immunoelectrophoresis

Résumé On décrit 2 modifications apportées à la méthode d'immunoélectrophorèse. L'une d'elles comprend l'électrophorèse dans 2 sens, aux pH divers, en milieu gélifié suivie par l'analyse immunologique, permettant une définition plus avantageuse. L'autre comprend l'électrophorèse sur un fil de rayonne ou d'acétate de cellulose suivie par l'analyse immunologique en milieu gélifié, permettant l'analyse des quantités d'antigène à partir de 3 µg.     

Haplotype tagging for the identification of common disease genes

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.