published primary cell eQTL analyses of negatively selected monocytes from whole blood10 and whole blood RNA from a mixed disease and control cohort14 replicates this strong association between 12q15 and expression of both LYZ and CREB1 (CREB1, p=5.1×10−22 (rs11177644) monocytes10; p=3.2×10−67 (rs2168029) whole blood14). The multi-faceted transcriptional properties of CREB1 in immune cells22 ensure it is a highly plausible candidate to regulate expression of many downstream genes, consistent with recent reports of other transcription factors underlying multiple eQTL to one locus12. Of note, LYZ expression was most strongly correlated to that of CREB1 (r2=0.82, p=5.7×10−107) and CREB1 expression was highly correlated with the majority of trans-associated genes to this locus (Supplementary Table 5). This would support a pathway whereby cis-modulation of LYZ results in differential expression of CREB1, possibly through downstream effects via altered lysozyme secretion, with resultant modulation of a network of trans-associated genes.
