Fine mapping the TAGAP risk locus in rheumatoid arthritis

A common allele at the TAGAP gene locus demonstrates a suggestive, but not conclusive association with risk of rheumatoid arthritis (RA). To fine map the locus, we conducted comprehensive imputation of CEU HapMap single-nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) of 5500 RA cases and 22 621 controls (all of European ancestry). After controlling for population stratification with principal components analysis, the strongest signal of association was to an imputed SNP, rs212389 (P 3.9 x 10(-8), odds ratio 0.87). This SNP remained highly significant upon conditioning on the previous RA risk variant (rs394581, P = 2.2 x 10(-5)) or on a SNP previously associated with celiac disease and type I diabetes (rs1738074, P = 1.7 x 10(-4)). Our study has refined the TAGAP signal of association to a single haplotype in RA, and in doing so provides conclusive statistical evidence that the TAGAP locus is associated with RA risk. Our study also underscores the utility of comprehensive imputation in large GWAS data sets to fine map disease risk alleles. Genes and Immunity (2011) 12, 314-318; doi:10.1038/gene.2011.8; published online 10 March 2011Pathophysiology and treatment of rheumatic disease

Extracellular 14-3-3 eta: An Early Rheumatoid Arthritis Pathogenic Factor

Pathophysiology and treatment of rheumatic disease

A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate

Atopy is a well-defined immune phenotype that is reported to be a risk factor for asthma. Among the many loci that contribute to a genetic predisposition to asthma, the cysteinyl leukotriene receptor genes and their variants have been important subjects of study because they are functionally and pharmacologically implicated in the atopy phenotype affecting many asthma subjects. Moreover, the product of cysteinyl-leukotriene 1 receptor gene (CysLT1), located at Xq13.2, is targeted by LT receptor antagonists. In our earlier association study, the M201V variant of the cysteinyl-leukotriene 2 receptor gene (CysLT2), located at 13q14, was implicated in atopic asthma. Here we report the screening of the coding region of the CysLT1, gene in the highly asthmatic Tristan da Cunha population. In this population, we discovered a CysLT1 G300S variant that is carried with a significantly higher frequency in atopics and asthmatics from the Tristan da Cunha population. Furthermore, we report the asthma independent association of the CysLT1 G300S variant with atopy. Subsequently, we compared the changes conferred by each SNP on CysLT function. The CysLT1 300S receptor interacts with LTD4 with significantly greater potency. For the 300S variant, a statistically significant decrease in the effector concentration for half-maximum response (EC50) for intracellular Ca flux and total InsP generation is observed. Other aspects of the receptor function and activity, such as desensitization, pharmacologic profile in response to montelukast, and cellular localization, are unchanged. These in vitro analyses provide evidence that the 300S CysLT1 variant, found more commonly in atopics in the Tristan da Cunha population, encodes a functionally more sensitive varian

91% Of Early RA Patients Are Positive For Serum 14-3-3 eta Or Its Auto-Antibodies

Pathophysiology and treatment of rheumatic disease

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Development and application of statistical models for medical scientific researc

GENETIC INTERACTION IN THE SUSCEPTIBILITY OF RHEUMATOID ARTHRITIS

Development and application of statistical models for medical scientific researc

Citrullinated 14-3-3 eta Antibodies Are Specific for Early and Established RA and Are Complementary to ACPA

Pathophysiology and treatment of rheumatic disease