The major histocompatibility complex (MHC) class II transactivator gene (MHC2TA) on chromosome 16p13has recently emerged as the single most important transcription factor for regulation of genes required for class II MHC-restricted antigen presentation. This study will test the hypothesis that genetic variation inMHC2TA is associated with susceptibility to SLE and RA, and that this variation may interact with one or more SLE-associated and RA-associated MHC class II alleles to influence disease risk and secondary phenotypes. The broad long-term objectives are to examine the potential role of MHC2TA in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) pathogenesis and secondary phenotypes in conjunction with known human leukocyte antigen (HLA) risk haplotypes. The specific aims are to genotype over thirty well-characterized single nucleotide polymorphisms (SNPs) in the MHC2TA gene region will be genotyped in 1,000 Caucasian RA families and 1,000 Caucasian SLE families to identify specific alleles, genotypes and haplotypes associated with RA and SLE risk. Family-based association tests, conditional linkage disequilibrium approaches and conditional logistic regression modeling will be performed to identify potential genetic interactions and disease risk modifying effects within this genomic region. Due to the strong relationship of lupus nephritis (LN) to SLE morbidity and mortality, LN will be studied as an important secondary outcome in the SLE families. Associations with specific RA phenotypes (rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) positivity, and erosive disease) in the RA families will also be examined. One of the major strengths of this study is the family-based research design, which will reduce the problem of population stratification often present in genetic case-control studies. Lupus and rheumatoid arthritis are chronic, debilitating autoimmune diseases with a tremendous societal and economic burden. The genetic contribution of the MHC class II gene region is known to be substantial. A better understanding of variation within the MHC class II transactivator gene and how it influences risk and/or phenotypic expression may help lead to improved methods of diagnosis, prognosis and treatment. [unreadable] [unreadable] [unreadable]