THROMBOCYTOPENIA AND THE GENETICS OF SEVERE LUPUS

Oklahoma Medical Research Foundation, Oklahoma City OK

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Abstract

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complicated autoimmune disease with a definite genetic predisposition. However, the exploration of SLE genetics is in its infancy. SLE is an extremely complicated clinical illness with a wide range of manifestations. Thus, far the genome scans have been performed using a general SLE phenotype. Use of stratification of a disease population has proven very useful in other diseases. For example, the BCR1 gene was found only when early onset breast cancer was considered among families that also had ovarian cancer. We hypothesize (and the preliminary data demonstrate) that the, as yet unexplored clinical phenotypes of SLE, will prove extremely valuable in uncovering the genetics of SLE. Thrombocytopenia predicts severe disease and death in SLE, making the identification of the related genetic risk factors especially important. We selected the 38 pedigrees that had an SLE patient with thrombocytopenia (platelets<100,000 per tile) from a collection of 179 pedigrees multiplex for SLE. Linkages were established at lq22-23 (lod-max)=3.71) in the 38 pedigrees and at 11p13 (lod(max) = 5.72) in the 13 African-American pedigrees. Nephritis, serositis, neuropsychiatric involvement, autoimmune hemolytic anemia, anti-double stranded DNA and antiphospholipid antibody were associated with thrombocytopenia. Other results show that SLE is more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient is considered. . We have now begun to fine map the 11p13 region. This project will continue to explore the genetics of the severe phenotype of SLE defined by thrombocytopenia. In particular, the PI will concentrate on the statistically powerful finding on chromosome 11lp13, the strongest found to date in SLE. In the first specific aim the genetic interval will be fine mapped with DNA microsatellite markers in order to confirm linkage and narrow the interval. In the second specific aim the PI will search for genetic association with SLE by typing at single nucleotide polymorphisms throughout the defined interval supporting linkage. In Specific Aim 3, the genetic polymorphism(s) responsible for the linkage will be sought by sequencing genes within the now narrowly defined linkage interval. Finally, in specific Aim 4 the PI will assemble a new cohort of families multiplex for SLE such that linkages and associations as well as particular polymorphisms can be prospectively confirmed.