Inflammation is known to play an important role in the pathogenesis of coronary heart disease (CHD) [1,2•]. Mild-to-moderate elevations of plasma levels of C-reactive protein (CRP), a biomarker of inflammation, have been shown to be predictive of future cardiovascular events [3,4,5•], although the specific role of CRP in the pathogenesis of CHD is uncertain [5•,6,7•]. As reviewed below, previous candidate gene studies [7•,8•] have shown associations of single nucleotide polymorphisms (SNPs) in the CRP gene with plasma CRP levels, although these genotypes have not been linked to increased CHD risk. In two recent genome-wide association studies (GWASs) [9••,10••], SNPs in several genes with a wide range of metabolic functions, including that for hepatic nuclear factor (HNF) 1-α, were also found to be strongly associated with plasma CRP levels. We here discuss these findings and their potential for linking inflammatory and metabolic pathways involved in the pathogenesis of CHD.
Inflammation, atherosclerosis, and C-reactive protein
Atherosclerosis is considered to be an inflammatory disease. Every stage in the progression of CHD, from the formation of an initial fatty streak to advanced lesions, plaque formation, and thrombosis, involves inflammatory processes. For detailed reviews of the known molecular mechanisms, see [1,2•,11].
Circulating levels of several markers of inflammation correlate with increased CHD risk, and much attention has been given to CRP as a marker for risk. Several studies [12–16] have provided strong evidence that elevated CRP levels independently predict CHD, and it has been shown that statin treatment can substantially reduce CHD risk in conjunction with lowering CRP levels, although a direct causal connection has not been established [17•].
CRP, the classical acute phase protein, has been extensively studied. During inflammation, infection, or tissue injury, the liver secretes a large amount of CRP into the circulation, in response to cytokines, complementing activation products and hormones. Levels of serum CRP rise so rapidly and dramatically that, in the clinic, blood CRP is frequently monitored to gauge the degree of inflammation in patients . The cytokine IL-6, derived in part from adipose tissue as well as vascular tissue, is a potent regulator of a number of acute phase genes in the liver and is largely responsible for the induction of CRP. Neither the normal function of CRP nor its role in cardiovascular disease is understood. Although there have been suggestions of mechanisms by which CRP may have direct involvement in the pathogenesis of CHD , a more widely held view is that chronically elevated CRP is a marker for a more generalized inflammatory process that contributes to disease risk [7•].
Genetic polymorphisms associated with plasma C-reactive protein
Variation in CRP levels is known to be heritable and several CRP genetic polymorphisms are associated with plasma CRP [20–23,24•]. It has also been shown that common genetic isoforms of APOE are associated with plasma CRP [25,26]. However, these collectively account for only a small portion of the estimated genetic variance of plasma CRP. Recently, two GWAS studies [9••,10••] have reported additional SNP associations with plasma CRP levels. The larger of the two [10••] included 6345 apparently healthy women in the Women's Genome Health study (WGHS) in whom 336 108 genome-wide SNPs were analyzed. The second study [9••] involved a two-stage analysis in a total of 1980 Caucasian men and women from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study. In phase 1, a genome-wide panel of 317 000 SNPs was analyzed in approximately half the study population and in phase 2, 13 680 of these SNPs were genotyped in the remaining participants. The results for the combined PARC group were analyzed using Bayesian factors.
Both confirmed strong associations of CRP concentration with the SNPs in the genes for CRP and APOE. In addition, both studies found associations of plasma levels of CRP with SNPs in the HNF1A (TCF1) gene encoding HNF1-α. These associations were confirmed in a cohort of 4333 European-descended participants in the Cardiovascular Health study (CHS) [9••]. Imputation of untyped SNPs in the HNF1A locus from the HapMap database in the combined PARC/CHS population identified several SNPs within a 5 kb region of HNF1A intron 1 that had the strongest association with plasma CRP levels. Notably, one of these SNPs (rs7310409) was the SNP most strongly associated with plasma CRP in WGHS [10••]. The strengths of the associations of HNF1A met the criteria for genome-wide significance in both reports. Because, as reviewed below, HNF1A appears to be involved in the transcriptional regulation of the CRP gene, it is plausible that these genetic associations may have a functional basis.
It is also of interest that in addition to confirming associations of plasma CRP with APOE genetic variants, the WGHS identified significant associations with three other gene loci: the leptin receptor (LEPR), the interleukin 6 receptor (IL6R), and glucokinase regulatory protein (GCKR), as well as a locus in a gene desert on chromosome 12 [10••]. Of these, associations of nominal significance were found for IL6R and GCKR, but not for LEPR, in PARC [9••]. The association with GCKR is of particular interest because variants in this gene, like those in HNF1A, as described below, are associated with maturity-onset diabetes of the young and are also associated with plasma triglyceride levels [27••].
Hepatic nuclear factor 1-α
HNF1-α, also known as transcription factor 1 (TCF1), is a homeodomain-containing transcription factor that is important for diverse metabolic functions in the liver, pancreatic islets, kidneys, and intestines . A large number of genes have been shown to be either direct or indirect targets of HNF1-α in humans and rodent models (Table 1) [29–47]. In humans, rare mutations in HNF1A cause MODY3, one type of maturity-onset diabetes of the young, which is characterized by severe insulin secretory defects [48,49].
Two Hnf1a-knockout mice strains have been created [50,51]. The first, created using a standard method for creating knockouts, resulted in animals that are born normally but fail to thrive and most die postnatally around the weaning period after a progressive wasting syndrome . These HNF1-α-deficient mice have profound hyperphenylalaninemia, exhibit hepatic enlargement and dysfunction, and suffer from severe renal Fanconi syndrome characterized by severe glucose, phosphate, and amino acid urinary wasting . A second strain, created using the Cre-loxP recombination method, exhibited no severe renal effects and animals lived a normal lifespan; however, they were dwarfed, diabetic, and were infertile . These animals had enlarged livers and exhibited progressive liver damage . This strain of knockout mice has been used in subsequent studies to understand the role of HNF1-α in the pancreas and in the liver.
While HNF1-α is known to regulate the expression of a number of liver genes, one important category of proteins whose genes are transcriptionally activated via interaction with HNF1-α are the acute phase proteins, CRP among them. In addition to CRP, HNF1-α has been shown to activate albumin, fibrinogen, a-1-antitrypsin, angiotensin, and insulin-like growth factor 1 [29–34]. Multiple studies [43,45–47] have identified HNF1-α-binding sites in the individual promoters, and several high-throughput and in-silico experiments to determine regulatory targets of HNF1A have provided further evidence for the regulation of CRP and other acute phase reactant genes by HNF1-α. Microarray data also show that Hnf1a knockout results in the downregulation of many acute phase response genes (CRP, albumin, transthyretin, fibrinogen, plasminogen, insulin-like growth factor 1, and serum amyloid P-component) .
Toniatti et al. showed that the human CRP promoter contained two functional HNF1A-binding sites. They demonstrated that HNF1A was necessary but not sufficient for CRP's induction. Recently, it has been shown that HNF1-α is required for cytokine-driven CRP expression and that this involves formation of a complex with two other transcription factors STAT3 and c-Fos [52•].
Hepatic nuclear factor 1-α and cholesterol and bile acid metabolism
There is strong evidence that HNF1-α plays an important role in bile acid and cholesterol homeostasis. It was shown in both knockout mice strains described above that the loss of Hnf1a results in hypercholesterolemia [50,51]. To understand this hypercholesterolemic phenotype, Shih et al. carried out oligonucleotide microchip expression analysis comparing Hnf1a null mice and their wildtype littermates. Key genes involved in bile acid synthesis and transport [e.g., Oatp1/2, Ntcp, farnesoid X-receptor (Fxr), small heterodimer partner (Shp), and Cyp7a1] as well as those involved in cholesterol synthesis (Hmgcr, Fdft1) were differentially expressed [43,53]. Additionally, genes involved in lipid and glucose metabolism were affected, as were genes involved in detoxification; finally, a number of secreted proteins, including CRP, were differentially expressed .
Na+/taurocholate cotransporter protein (NTCP) and organic anion transporter proteins (OATPs) are the primary transporters of bile acids across the basolateral membrane of hepatocytes; after absorption of fatty acids into the intestine, bile acids are reclaimed into the ileum by the apical Na+ dependent bile salt transporter (ASBT); expression of the genes for these important transporters of bile acids was severely downregulated in the Hnf1a−/− mice . Functional-binding sites for HNF1A in the human and mouse OATPC (Oatp4) gene have been identified [35,36] and Jung and Kullak-Ublick  demonstrated that bile acids repress HNF1-α via HNF4-α, which leads to the downregulation of the OATP genes [54,55]. HNF1-α appears to be critical for basal expression of these OATP genes. Although NTCP in the rat has an HNF1-α-binding site in its promoter, human NTCP does not appear to have a binding site for HNF1-α. The human gene does, however, have a binding site for HNF4-α  and its regulation appears to be influenced by HNF4-α [57•]. Based on evidence for regulatory interactions of HNF4-α and HNF1-α , a role for HNF1-α in humans remains a possibility. Finally, the ASBT gene has functional HNF1-α-binding sites and sterol regulatory element binding protein 2 (SREBP2) and HNF1-α act synergistically to transactivate ASBT gene expression .
Furthermore, Fxr, a bile acid feedback regulator, was decreased in expression in Hnf1a−/− mice, as was its downstream target, Shp1. There is an HNF1-α-binding site in the mouse Fxr promoter and recently a functional HNF1-α-binding site has been identified in the promoter of the human FXR gene .
Finally, HNF1-α is involved in regulating the basal expression of genes encoding the two main hepatic enzymes responsible for cholesterol oxidation – CYP7A1 (cholesterol 7α-hydroxylase)  and CYP27A (sterol 27-hydroxylase, mitochondrial) . HNF1-α also appears to be critical for the regulation of these genes, as well as bile acid transporters, in response to inflammation, and cholestasis [57•,61–65]. Inflammation induced by endotoxin and sepsis leads to decreased binding of HNF1-α (and other nuclear receptors) to bile acid transporters, which results in a decrease in bile acid flux [57•].
Hepatic nuclear factor 1-α and lipoprotein metabolism
In the Hnf1a−/− mice described above , the hypercholesterolemic phenotype involved downregulation of hepatic cholesterol oxidation and this was accompanied by increased expression of genes involved in lipid synthesis regulated by SREBP2, including 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, the rate-limiting enzyme for cholesterol synthesis and acyl-CoA cholesterol transferase 2, which is critical for intrahepatic cholesterol esterification and secretion. There is also evidence (Table 1) for a role of HNF1-α in regulating a number of genes involved in glucose and fatty acid metabolism, including SREBP1c, a transcription factor regulating gene involved in fatty acid and phospholipid synthesis.
Although there is limited information regarding changes in plasma lipoprotein metabolism in the Hnf1a−/− model, there was evidence for the formation of abnormal lipoprotein particles with characteristics of large buoyant HDL . Further investigation into the cause of this effect indicated that apolipoprotein (apo)M may be involved . ApoM is important for formation of prebeta HDL and reverse cholesterol transport, a property of HDL that is felt to be involved in its antiatherogenic effects . The apoM promoter has HNF1-α-binding sites  and is also controlled by HNF3 (FOXA2) .
There is also evidence that a number of other genes involved in plasma lipoprotein metabolism are direct or indirect targets of HNF1-α (Table 1). These include the genes encoding apo A1, A2, C3, and B, as well as those for lipoprotein lipase and hepatic lipase, which are critically involved in catabolism of plasma lipoprotein lipids. Although as noted above, isoforms of APOE have been associated with variation in CRP levels, it is not clear how or whether there is direct interaction between these genes. Finally, it is of interest that an HNF1A SNP (rs 2650000) has recently been reported in a large GWAS to be associated with plasma LDL cholesterol [27••]. This SNP, however, is in weak linkage disequilibrium with the SNPs associated with plasma CRP.
The finding of significant associations of polymorphisms in the HNF1A gene with plasma CRP levels exemplifies the complex interplay between pathways regulating lipid and glucose metabolism with those involved in inflammatory responses. The potential for such interactions is further suggested by reports of the association of CRP levels with SNPs in other genes (APOE, GCKR, LEPR) with multiple metabolic functions. In this regard, it is well recognized that elevations of CRP, as well as other inflammatory markers, are commonly found in individuals with metabolic syndrome , although this relationship has been ascribed primarily to underlying insulin resistance  as well as adiposity. The genetic findings, which involve pathways not directly connected with either of these traits, support the possibility of other deep connections of metabolic and inflammatory networks that may be of both pathophysiological and clinical importance.
Although it is not known to what extent CRP has specific or direct involvement or both in the pathogenesis of CHD, it is certainly a major component of an inflammatory milieu that is critically involved in this disease process. The recent finding that statin treatment substantially reduces CHD risk in conjunction with reductions in both CRP and LDL cholesterol [17•] provides a further incentive for the search for common determinants of these CHD risk markers.
R.M.K. is funded by grant U01HL0169757 from the National Institutes of Health; A.D.A. is funded by U01HL0169757 Suppl from the National Heart, Lung, and Blood Institute of the National Institutes of Health.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 136–137).
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