Abstract
The HLA complex is the most gene dense and polymorphic part of the genome which also contains the strongest trans-eQTLs in the genome. We noted the presence of multiple trans-eQTLs for the DNA repair gene XRCC6 ( P −9 ) across the HLA region from 29.5 MB to 32.5 MB (chromosome 6) despite the absence of any cis-eQTL for XRCC6 in its vicinity in chromosome 22. Other than the HLA-linked ones, there is no trans-eQTL for XRCC6 in the genome. Having observed highly significant (P40) mapped to 26 genes including two uncharacterized and four non-coding RNA (ncRNA) genes (HCG9 & 22, lincRNA243 & 1149) in the HLA region. Many also act as cis-eQTLs for local genes, and most of the strongest ( P ; −8 ) cis-eQTLs map to HLA-region ncRNA genes. Their local target genes include an uncharacterized intergenic region 5′ upstream of HLA-B ( n = 6), the ncRNA gene HCG22 ( n = 4) and HLA-C ( n = 1). Examination of the ImmunoChip results on IHWG cell lines did not suggest a common lineage or linkage to an HLA haplotype for these SNPs. Screening of GWAS catalog and dbGAP for associations of the 42 trans-eQTLs with cancer risk revealed existing associations with lung (rs3117582, rs2395185), breast (rs3130544) and liver (rs9275572) cancer, Hodgkin (rs2395185) and non-Hodgkin (rs2647012; rs6457327) lymphoma, and another SNP (rs2596503) has a reported association with glioblastoma. The examination of the Microarray Innovations in Leukemia (MILE) data revealed highly significant inverse correlations between HCG22 and XRCC6 expression levels both in normal bone marrow ( P = 0.0001, r = -0.43, n = 74) and leukemia samples ( P r = −0.27, n = 2022). HCG22 levels also showed an equally strong inverse correlation with TP53 expression. It appears that HLA region genetic variation correlates with expression of HCG22, which in turn inversely correlates with XRCC6 and TP53 levels. The overall observations suggest a non-immunological mechanism for the involvement of HLA region genetic variation in inherited cancer susceptibility, and implicate an ncRNA-mediated mechanism for trans-eQTL effect on XRCC6.
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