Identification of an Inflammatory Monocyte Transcriptional Profile and Potential Novel Role for Lactotransferrin in Human Hypertension
Authors: Alexander Matthew , Norlander Allison , Galindo Cristi , Elijovich Fernando , Laffer Cheryl , Gnecco Juan , Madhur Meenakshi 
Published: June 2021

Hypertension affects approximately 50% of all individuals in the United States and is the leading risk factor for global morbidity and mortality. Despite current therapies, blood pressure remains inadequately controlled in almost half of all patients, and even with adequate control, hypertension is associated with a residual cardiovascular risk. Emerging evidence suggests an important role for inflammatory cells such as monocytes in the pathogenesis of hypertension, though the mechanisms by which monocytes promote hypertension are unclear. We set out to determine, in an unbiased fashion, whether patients with hypertension exhibit altered gene expression profiles in peripheral monocytes compared to healthy controls, and whether differentially expressed genes may play a pathogenic role in human hypertension. Using next generation RNA sequencing of peripheral monocytes, we found 60 differentially expressed transcripts in patients with hypertension compared to controls, with significant over‐representation of transcripts related to “Inflammatory Response” by gene ontology analysis. In addition, of the differentially expressed genes, expression of four transcripts significantly correlated with mean arterial pressure in hypertensive and/or control patients by univariate and multivariate stepwise regression. In a separate validation cohort, three of these genes, lactotransferrin (LTF), peptidoglycan recognition protein 1 (PGLYRP1), and interleukin‐18 receptor accessory protein (IL18RAP), remained significantly elevated in patients with hypertension. To provide evidence for functional roles of these genes in hypertension, single nucleotide polymorphisms (SNPs) were identified in LTF and IL18RAP that alter protein function and/or protein levels. An initial phenome‐wide association study of nearly 30,000 individuals revealed a nonsignificant trend for over‐representation of hypertension ICD9 codes in patients with the minor allele of a missense SNP in LTF (rs1126478) that is associated with increased protein levels and decreased antimicrobial function. We then tested whether rs1126478 alleles were differentially present in patients with hypertension relative to controls in a retrospective case‐control study. Indeed, the presence of homozygous minor alleles of rs1126478 was significantly increased in frequency in patients with hypertension relative to controls (odds ratio 1.16; p=0.005). In addition, minor allele homozygosity significantly increased odds of hypertension in a logistic regression analysis controlling for age, gender, body mass index, and presence of coronary artery disease (p=0.018). Taken together, these data demonstrate that monocytes exhibit enhanced pro‐inflammatory gene expression in hypertensive patients. In addition, results identify LTF, an iron‐binding glycoprotein with antimicrobial and pro‐inflammatory function, as a potential novel mediator of human hypertension.Support or Funding Information5K08HL121671‐05 and 1DP2HL137166‐01 to M. Madhur and 5T32HL007411‐37 to M. Alexander.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.