Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level

Abstract

To investigate whether functional polymorphisms exist in the C-reactive protein (CRP) gene, i.e., ones that contribute directly to differences in baseline CRP among individuals, we sequenced a 1,156-nucleotide-long stretch of the CRP gene promoter in 287 ostensibly healthy people. We identified two single-nucleotide polymorphisms (SNPs), a bi-allelic one at nucleotide -409 (G-->A), and a tri-allelic one at -390 (C-->T-->A), both resident within the hexameric core of transcription factor binding E-box elements. Electrophoretic mobility shift assays confirmed that the SNP within the sequence (-412)CACGTG(-407) (E-box 1) modulates transcription factor binding, and that the one within (-394)CACTTG(-389) (E-box 2) supports transcription factor binding only when the -390 T allele is present. The commonest of four E-box 1/E-box 2 haplotypes (-409G/-390T) identified in the population supported highest promoter activity in luciferase reporter assays, and the rarest one (-409A/-390T) supported the least. Importantly, serum CRP in people with these haplotypes reproduced this rank order, i.e., people with the -409G/-390T haplotype had the highest baseline serum CRP (mean +/- SEM 10.9 +/- 2.25 microg/ml) and people with the -409A/-390T haplotype had the lowest (5.01 +/- 1.56 microg/ml). Furthermore, haplotype-associated differences in baseline CRP were not due to differences in age, sex, or race, and were still apparent in people with no history of smoking. At least two other SNPs in the CRP promoter lie within E-box elements (-198 C-->T, E-box 4, and -861 T-->C, E-box 3), indicating that not only is the quality of E-box sites in CRP a major determinant of baseline CRP level, but also that the number of E-boxes may be important. These data confirm that the CRP promoter does encode functional polymorphisms, which should be considered when baseline CRP is being used as an indicator of clinical outcome. Ultimately, development of genetic tests to screen for CRP expression variants could allow categorization of healthy people into groups at high versus low future risk of inflammatory disease.

C-Reactive Protein Gene Polymorphisms in Disease Susceptibility and Clinical Manifestations of Korean Systemic Lupus Erythematosus

“…We also examined whether these polymorphisms had any effect on serum CRP levels, and found that basal levels of CRP were significantly higher in individuals who had minor allele in -390 C>A or T and 2043 A>G polymorphisms than in those who had the major homozygous genotype, even after conservative Bonferroni adjustment for multiple comparisons (p = 0.03, 0.024, respectively). These results are comparable with the previous reports in Caucasians 16,17,[20][21][22] . Further, we extended this finding to basal CRP level according to haplotype, and found that the basal level of CRP was lower in haplotype ht1[TACGCA] containing major alleles of CRP -390 and 2043, while it was higher in haplotype ht4 [TATGTG] containing minor alleles of CRP -390 and 2043, although the significance disappeared with Bonferroni adjustment.…”

Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: The Cardiovascular Health Study

“…Twin and family studies observe substantial heritability (20-40 percent) for CRP levels 5,6 . Common and functional polymorphisms in the CRP gene have consistently been associated with inter-individual differences in plasma CRP levels 7,8 . Recently, Lange, et al reported that, among persons at risk for a first MI or stroke, several common variants in the CRP gene were associated with increased relative risk of cardiovascular events in the Cardiovascular Health Study (CHS), a longitudinal cohort study of adults over the age of 65 9 .…”

C - reactive protein: An inflammatory marker with specific role in physiology, pathology, and diagnosis

“…33 Within the promoter, several polymorphisms were discovered in transcription factor binding E-box sites, all of which Autologous ligands include native and modified plasma lipoproteins, damaged cell membranes, different phospholipids and related compounds, small nuclear ribonucleoprotein particles, and apoptotic cells. 34,35,36 Extrinsic ligands include many glycan, phospholipid, and other constituents of microorganisms, such as capsular and somatic components of bacteria, fungi, and parasites, as well as plant products.…”