Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles

Abstract

Trans-acting genetic variants play a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B-cells we identify novel, predominantly cell-specific, cis- and trans-eQTL (expression quantitative trait loci). These include multi-locus trans-associations to LYZ in monocytes and to KLF4 in B-cells. Additionally, we observe B-cell specific trans-association of rs11171739 at 12q13.2, a known autoimmune disease locus, to IP6K2 (pB-cell=5.8×10−15), PRIC285 (pB-cell=3.0×10−10) and an upstream region of CDKN1A (pB-cell=2×10−52; pmonocyte=1.8×10−4), suggesting roles for cell cycle regulation and PPARγ signaling in disease pathogenesis. We also find specific HLA alleles forming trans-association with the expression of AOAH and ARHGAP24 in monocytes but not in B-cells. In summary, we demonstrate that mapping gene expression in defined primary cell populations identifies new cell-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

“…Recently lysozyme (LYZ) on chromosome 12q15 has been described as a monocyte-specific master regulator eQTL 20 . In this study, rs10784774 was identified as cis eQTL for LYZ and as trans eQTL for 62 other genes under baseline condition.…”

Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach

“…We have reported genomewide expression quantitative trait (eQTL) analysis in different primary human cell populations [24]. This global analysis included evidence of a local, cis-eQTL involving CIITA that was specific to B cells.…”

Personalized Medicine Toward Multiple Sclerosis;Current Challenges and Future Prospects

“…28 Moreover, several SNPs in human leukocyte antigen (HLA) genes have been found with the susceptibility of protection of development of NAbs responses. 29,30 Considering all the facts, it is still premature to achieve consensus about the limiting role of NAbs against IFN-β therapy in clinics and, therefore, the evaluation of NAbs in practice is not yet completely applicable.…”