Genes that alter risk represent origins of disease causation and are therefore involved in disease pathogenesis. Many strategies are now available to discover these genes. Candidate gene approaches have given way to reverse genetics as the genotyping capacity has very recently undergone a technical scientific revolution. We identified a convincing linkage at 12q24 in our Hispanic (HI) pedigrees multiplex for systemic lupus erythematosus (lupus or SLE) that we confirmed in our European-American (EA) pedigrees (1) and others confirmed with additional independent samples (2) (p=0.000000014). We screened the linkage support interval with 41 markers in promising candidate genes. Markers in three genes suggested association. Follow up case control studies in HI and EA show association in a transcription factor, with the best haplotype in this gene producing strong evidence for association, an effect that has been independently replicated (p=0.00002). The association remains significant after correction for all the tests actually performed (Bonnferroni) under the overly conservative assumption of marker independence (p=0.003). In Project #2, we will evaluate the genomics of the genetic association and carry these findings toward biological mechanism. We will more than double the sample size studied to date (>6600 HI and EA subjects) to improve power to discriminate the true genetic contributions. We will use currently accepted strategies to eliminate artifacts from sample population stratification. We will physically define the genomic interval containing the association effect. We will use sequencing and genotyping to characterize the possible contributing variants in the interval. We will construct haplotypes and apply standard regression methods to identify the primary association as well as any remaining residual independent associations. The candidate polymorphisms and their surrogates will be evaluated for genomic mechanism(s). Once a genomic model is developed, we will explore gene biology. When successfully completed this P01 project will provide one or more new genes with mechanistic insights into the mechanisms by which lupus is generated. At the same time the infrastructure developed through this P01 project will provide the basis from which to evaluate this and other compelling candidate genes important for lupus in Hispanics (HI). The enlarging sample size from the continuing efforts to expand the existing collections in Alabama and Oklahoma is critical to provide the statistical power with which to winnow the false positive genetic associations from those most likely to be true genetic associations.
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