RESUMO
We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.
Assuntos
Variação Genética , Antígenos HLA/genética , Escleroderma Sistêmico/genética , Antígenos HLA/química , Antígenos HLA-DR/química , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Conformação MolecularRESUMO
The dbMHC resource (http://www.ncbi.nlm.nih.gov/mhc/sbt.cgi?cmd=main) at the National Center for Biotechnology Information (NCBI) has developed an online tool for evaluating the allelic composition of sequencing-based typing (SBT) results of cDNA or genomic sequences. Whether the samples are heterozygous, haploid or a combination of the two, they can be compared with two up-to-date databases of all known alleles of several human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) loci. The results of the submission are returned as a table of potential allele hits, along with the respective base changes and an interactive sequence viewer for close examination of the alignment.
