The major histocompatibility complex (MHC) is the dominant region of association in SLE from European- derived subjects. In initial SLEGEN genome wide analyses, 86 SNPs spanning 6.4 Mb reached genome wide Statistical evidence at p<10-6. Combined with a replication cohort, analyses involving 5,278 samples reaches impressive significance levels (p<10-44). Multiple effects within this large region are strongly suggested by these and other data and will be further characterized. The large multiracial collection assembled by SLEGEN is a particular strength for this project. We will use the obvious population differences in the MHC to separate and isolate individual genomic elements containing causative polymorphisms. We have the following specific Aims:
Aim 1 : Perform a meta-analysis of available high density MHC datasets to more precisely define the locations and extent of genetic effects within the MHC among European-derived populations. Prediction: At least two separate associations in the MHC region will be convincingly established and characterized in.the European-derived sample.
Aim 2 : Define the region and extent of genetic effects across the MHC in populations of non-European origin (i.e. African-Americans, Hispanics and Asians). Prediction: Analysis of additional ethnic groups will facilitate narrowing of associated regions within the MHC due to population substructure differences in MHC haplotypes. Synergies: All of the other Projects will be very important for the success of this Aim.
Aim 3 : Perform association analyses in subgroups defined by specific SLE disease features. We will examine more homogeneous subgroups as a strategy to further separate the genetic effects within the MHC region, including subsets defined by specific autoanfibodies or clinical variables such as nephritis. Prediction;Particular sub-phenotypes will be less genetically heterogeneous and will provide increased statistical power to more precisely define genotype-phenotype correlations and decipher individual effects within the MHC region.
The MHC represents the most important genetic contribution to SLE for European-derived populations, however prior work has not fully defined the specific causal variants. There is a paucity of data for non- European populations in spite of the excess burden of disease among these groups. A thorough delineation of the MHC contribufion to SLE will be crucial to fully understand the role of other causal variants.
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