Genes that alter risk represent origins of disease causation and are therefore involved in diseasepathogenesis. Many strategies are now available to discover these genes. Candidate gene approaches havegiven way to reverse genetics as the genotyping capacity has very recently undergone a technical scientificrevolution. We identified a convincing linkage at 12q24 in our Hispanic (HI) pedigrees multiplex for systemiclupus erythematosus (lupus or SLE) that we confirmed in our European-American (EA) pedigrees (1) andothers confirmed with additional independent samples (2) (p=0.000000014). We screened the linkagesupport interval with 41 markers in promising candidate genes. Markers in three genes suggestedassociation. Follow up case control studies in HI and EA show association in a transcription factor, with thebest haplotype in this gene producing strong evidence for association, an effect that has been independentlyreplicated (p=0.00002). The association remains significant after correction for all the tests actuallyperformed (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 towardbiological 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 toeliminate artifacts from sample population stratification. We will physically define the genomic intervalcontaining the association effect. We will use sequencing and genotyping to characterize the possiblecontributing variants in the interval. We will construct haplotypes and apply standard regression methods toidentify the primary association as well as any remaining residual independent associations. The candidatepolymorphisms and their surrogates will be evaluated for genomic mechanism(s). Once a genomic model isdeveloped, we will explore gene biology. When successfully completed this P01 project will provide one ormore new genes with mechanistic insights into the mechanisms by which lupus is generated. At the sametime the infrastructure developed through this P01 project will provide the basis from which to evaluate thisand other compelling candidate genes important for lupus in Hispanics (HI). The enlarging sample size fromthe continuing efforts to expand the existing collections in Alabama and Oklahoma is critical to provide thestatistical power with which to winnow the false positive genetic associations from those most likely to betrue genetic associations.
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