Dissection of HLA-C gene region to investigate its association with complex traits

The genomic region of HLA gene cluster (6p21.3) contains several highly polymorphic genes involved in the immune response and therefore, they have been previously associated to several immune and inflammatory disorders. For the present study we investigated more than 3500 known alleles of HLA-C gene (from IPD-IMGT/HLA database, genomic sequences) that are grouped into 14 serogroups (e.g., C*01:02:01:01). All the sequences have been aligned against the human genome reference sequence (both versions; hg19 and hg38). Overall, the HLA-C gene (length ~3000 bp) contains more than 1500 SNPs. We used a clustering approach to understand how the alleles are evolutionarily connected. According to the clustering analysis we observed that sequences of the same serogroup cluster together more often than sequences of other serogroups, even if with several exceptions. This confirms that alleles of the same serogroup share strong identity in their sequence. Interestingly, as general rule, we observed that the main tree presents two branches, containing each a similar structure (relative distance between serogroups). Of note, the sequences of C*07 and C*17 serogroups belonged to one of the two branches only, whereas the sequences of C*06 and C*12 serogroups were observed in the alternative branch of the tree. We are now studying what are the main features that characterize the two branches. Moreover, the study will go on by investigating the association of the HLA-C serogroup SNP-based alleles with kidney related disease (INCIPE study) and Alzheimer’s disease (NIAGADS database) in large cohorts of individuals.