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. Author manuscript; available in PMC: 2013 Aug 29.
Published in final edited form as: Curr Opin Rheumatol. 2012 Nov;24(6):642–648. doi: 10.1097/BOR.0b013e328356d9dc

Racial Differences between Blacks and Whites with Systemic Sclerosis

Richard M Silver *, Galina Bogatkevich *, Elena Tourkina *, Paul J Nietert **, Stanley Hoffman *
PMCID: PMC3756312  NIHMSID: NIHMS483065  PMID: 22955018

Abstract

Purpose of review

Racial disparities appear to exist in the susceptibility and severity of systemic sclerosis (SSc, scleroderma) and are responsible for a greater health burden in blacks as compared to whites. Disparities in socioeconomic status and access to health care do not sufficiently explain the observed differences in prevalence and mortality. It is important to determine if there might be a biologic basis for the racial disparities observed in SSc.

Recent findings

We present data to suggest that the increased susceptibility and severity of SSc in blacks may result in part from an imbalance of pro-fibrotic and anti-fibrotic factors. Racial differences in the expression of transforming growth factor-β1 (TGF-β1) and caveolin-1, as well as differences in the expression of hepatocyte growth factor (HGF) and PPAR-γ have been demonstrated in blacks with SSc, as well as in normal black subjects. A genetic predisposition to fibrosis may account for much of the racial disparities between black and white patients with SSc.

Summary

A better understanding of the biologic basis for the racial disparities observed in SSc may lead to improved therapies, along with the recognition that different therapies may need to be adapted for different groups of patients.

Keywords: Systemic Sclerosis, Health Disparities, TGF-β, Caveolin-1, HGF

Introduction

There is considerable evidence that the health burden of systemic sclerosis (SSc, scleroderma) is greater among blacks than whites. In the United States, blacks are more likely to develop SSc than whites and to experience greater morbidity and reduced survival [1-7]. Age of onset is earlier and the more severe diffuse cutaneous form of SSc (dcSSc) is more frequent in blacks than in whites [1,5,8]. The incidence of dcSSc among blacks is approximately 2.5 fold higher than for whites (20 cases per million per year versus 8 cases per million per year) [1]. The most recent study of SSc mortality in the United States reported death rates that peaked a decade earlier in the black population when compared with those in the white population, with age-adjusted mortality significantly higher for blacks than for whites (7.1 vs. 4.4 deaths per million population per year) [7]. For those hospitalized when under the age of 65 years, black patients are more likely to experience in-hospital death than whites (<35 yrs: 4.2 vs. 1.2%; 35-49 yrs: 4.7% vs. 2.7%; 50-64 yrs: 6.9 vs. 6.8%) [9]. Blacks are also more likely to develop severe interstitial lung disease (ILD) or pulmonary hypertension (PH), two pulmonary complications that together account for more than 50% of all SSc-related deaths [8,10,11].

The basis for the racial disparities in prevalence and outcomes remains uncertain and is not fully explained by differences in socioeconomic status or access to health care [9, 12. In this review we present results of recent studies suggesting there may be an underlying genetic predisposition that provides a biological basis for the racial disparities observed in SSc patients.

Serum Auto-Antibody Profiles and Racial Differences

Serum auto-antibodies are strongly associated with specific SSc disease manifestations, and the frequency of these various serum auto-antibodies differs among blacks and whites. Topoisomerase I and U3 RNP auto-antibodies, which tend to be associated with dcSSc and severe ILD, are seen more commonly in black patients than in white patients [4,13-15]. In contrast anti-centromere antibodies, which tend not to be associated with dcSSc nor with severe ILD, are seen with much lower frequency in black patients [16].

Such observations might suggest an immunogenetic and serological basis for the racial disparities observed among SSc patients. However, a recent study by Steen and colleagues suggests that auto-antibody status per se is not a sufficient explanation for the observed racial disparities [17]. Steen and colleagues analyzed consecutive black (n=203) and white (n=2945) SSc patients seen between 1972 and 2007, as part of the Pittsburgh Scleroderma Database. Consistent with prior studies, black patients were found to have certain auto-antibodies with significantly greater frequency than white patients (anti-topoisomerase I: 25% vs. 18%; anti-U1 RNP: 13% vs. 4%; anti-U3 RNP: 16% vs. 2%). On the other hand, certain auto-antibodies were detected with significantly less frequency in blacks than in whites (anti-centromere: 7% vs. 22%, anti-RNA polymerase III: 10% vs. 21%).

Notably, when black and white SSc patients within a specific auto-antibody sub-group were compared, racial differences were found to persist. For example, among SSc patients with anti-topoisomerase I antibodies, blacks tended to be younger (mean age 37 yr vs. 43 yr, p=0.005) and had pulmonary fibrosis with greater frequency (72% vs. 52%, p=0.01) and with greater severity (44% vs. 18%, p=0.001) than whites, despite there being no significant difference in disease duration at presentation. After adjustment for age, gender and disease subset, blacks with anti-topoisomerase I antibodies were 75% more likely to die within five years than whites having the same auto-antibody (hazard ratio 1.75, 95% CI 1.06-2.88, p=0.03). This important study suggests that other genetic and/or environmental influences might explain the disparities observed among black and white SSc patients. In the following sections, we will examine potential biologic pathways that may underlie racial disparities observed in SSc.

Racial Differences in TGF-β Expression

Transforming growth factor-β1 (TGF-β1) is a member of a superfamily of proteins regulating cell growth and differentiation, inflammation and immunity [18]. TGF-β1 is considered to be the master regulator of physiologic fibrogenesis and pathological fibrosis [19]. In both normal and SSc fibroblasts, TGF-β1 induces Smad2/3 activation and collagen gene transcription. In SSc dermal fibroblasts, the expression of receptors for TGF-β1 is elevated [20], and multiple abnormalities in downstream Smad signaling pathways have been identified [19].

TGF-β1 undoubtedly plays an important role in the pathogenesis of SSc. Racial differences in the expression of TGF-β1 are well documented [21], and one might speculate that differences in TGF-β1 could contribute to the greater disease susceptibility and severity observed in black SSc patients. Blacks are known to have an increased prevalence of other diseases, e.g., hypertension, focal glomerulosclerosis, diabetic nephropathy, end stage renal disease, keloids, uterine leiomyomata, sarcoidosis and glaucoma, in which TGF-β has been implicated [22-25]. For example, in blacks hypertension is one and one-half times more common and end stage renal disease is eight times more common than in whites [26]. Blacks with hypertension over-express TGF-β1, and genotyping has revealed a single-nucleotide polymorphism (SNP) at codon 10 occurring with higher frequency in blacks than in whites that is associated with higher levels of TGF-β mRNA and protein expression [27]. The same investigators also showed that peripheral blood TGF-β1 protein levels are high in blacks compared with whites, and the levels are associated with plasma renin activity, systolic and diastolic blood pressure, metabolic syndrome and microalbuminuria in blacks, but not in whites [28].

Racial Differences in Other Fibrogenic Cytokines

Interleukin-6 (IL-6) is a pro-fibrotic cytokine implicated in the pathogenesis of SSc. Although its precise role in SSc is not clear, IL-6 is over-expressed by SSc dermal fibroblasts [29,30]. IL-6 serum concentrations are increased and have been correlated with skin thickness [31,32]. Blockade of the IL-6 receptor with the monoclonal antibody tocilizumab, has been reported recently to be associated with improvement in skin score along with histological thinning of dermal collagen bundles [33].

Variants in cytokine genes, including IL-6, have shown association with SSc. Given the association with IL-6, it is interesting that normal black recipients of renal transplants have been shown to have a significantly higher probability of a particular IL-6 polymorphism (-174 G to C allele), which was shown to be associated with greater synthesis of IL-6 protein [34]. The authors suggest that differences in IL-6 production as a result of this polymorphism in the IL-6 gene may be an important factor in the racial variation in renal transplant outcomes [34].

Other cytokines and cytokine modulators with potential relevance to SSc also show racial variations. When analyzing cytokine expression in bronchoalveolar lavage fluid, we observed differences in the expression between blacks and whites for the following cytokines and cytokine modulators: hepatocyte growth factor (HGF)(vide infra), osteoprotegerin (OPG), thrombopoietin (TPO), insulin-like growth factor binding protein 3 (IGFBP-3), stem cell factor (SCF) and vascular endothelial growth factor (VEGF)[35]. Differences between blacks and whites were observed not only in SSc patients, but also in healthy control subjects (see Figure 1). Among the cytokines of potential relevance to SSc and interstitial lung disease, IGFBP-3 was over-expressed in blacks. Recently it was shown that IGFBP-3 production by lung epithelial cells mediates TGF-β-induced tenascin C production [36].

Figure 1. Cytokine array analysis of bronchoalveolar lavage (BAL) fluid from Caucasian and African American patients with systemic sclerosis (SSc) and normal controls.

Figure 1

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Positive controls are at positions A1, B1, C1, D1, J8, and K8. Negative controls are at positions E1, F1, and I8. Arrow indicates the postion of hepatocyte growth factor (I6). Insulin-like growth factor binding protein-3, osteoprotegerin, stem cell factor, thrombopoietin, and vascular growth factor are located at positions A7, B8, C4, B5, and C5, respectively. Note that overall BAL fluid samples from Caucasian subjects contains less of the cytokines than do the BAL fluid samples from African American subjects. Reprinted with permission from Arthritis Rheum 2007;56:2432-42 (reference 35).

It remains to be determined if racial variations in IL-6, IGFBP-3 or other cytokines play a role in the susceptibility or severity of SSc. One Italian study found no association between 22 cytokine SNPs and SSc susceptibility or severity, however the numbers of patients and controls were modest [37]. Using a multifactor dimensionality reduction model, the authors concluded there was evidence for gene-gene interaction among cytokine single-nucleotide polymorphisms, including the pro-fibrotic cytokine IL-6, as well as genes for other regulatory cytokines [37].

Racial Differences in Caveolin Expression

Our group and others have shown that a reduced level of caveolin-1 in lung fibroblasts from patients with SSc and from bleomycin-treated mice promotes collagen over-expression and lung fibrosis [38-40]. Caveolin-1 is a protein associated with plasma membrane invaginations known as caveolae and with other cellular membranes. Caveolin-1 binds to and thereby inhibits the function of kinases in several major families including PKC, MAPK, Src, and G protein [41-44]. Of note, caveolin-1 regulates signaling and cell functions induced by the major pro-fibrotic cytokine, TGF-β [45-47]. There are multiple points of intersection between TGF-β and caveolin-1 signaling. For example, TGF-β inhibits caveolin-1 expression in a variety of cell types including fibroblasts (both lung and dermal) and monocytes, suggesting that the TGF-β-rich milieu in the blood and tissues of SSc patients leads to the reduction of caveolin-1 expression and to an altered behavior of cells that promote fibrosis. Caveolin-1 also modulates TGF-β signaling in dermal fibroblasts by inhibiting Smad3 phosphorylation and its translocation to the nucleus [48-50] . Additionally, caveolin-1 regulates TGF-β signaling via its effects on the endocytosis of TGF-β ligand-receptor complexes. TGF-β receptors sort to both caveolin-1-rich lipid rafts and early endosomes [50-52]. Early endosomal internalization increases TGF-β signaling while caveolin-1-dependent internalization in lipid rafts leads to receptor degradation, thereby inhibiting TGF-β signaling [53].

We recently demonstrated that deficiency of caveolin-1 exists not only in SSc lung fibroblasts but also in other cell types, e.g., monocytes and neutrophils, from patients with SSc [54]. Furthermore, with decreased expression of caveolin-1 there was activation of ERK, JNK and p38 [54]. To evaluate the potential role of caveolin-1 in the predisposition of blacks to SSc, we compared caveolin-1 levels in monocytes from SSc patients and normal subjects. We found caveolin-1 expression in normal black subjects to be only 40% of that in normal white subjects, i.e., caveolin-1 in normal black subjects was almost as low as in monocytes from SSc patients (see Figure 2).

Figure 2. Low caveolin-1 expression in healthy African American and SSc monocytes.

Figure 2

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Caveolin-1 levels in monocytes from healthy Caucasians, healthy African Americans (AA), and SSc patients (SSc) were quantified by Western blotting followed by densitometry using GAPDH as a loading control. The level in healthy Caucasians was set to 100 arbitrary units. The data shown represent the average ± s.e.m. from 7 healthy Caucasians, 7 healthy AAs, and 7 SSc patients. Compared to Caucasian, p < 0.01 for both AA and SSc.

We also recently demonstrated that the low level of caveolin-1 expression in SSc peripheral blood monocytes (PBM) is associated with enhanced migratory capacity toward CXCL12 (stromal-cell derived factor 1), a chemokine ligand that is highly upregulated in SSc lung tissue [55]. Furthermore, the SSc PBM phenotype characterized by a low level of caveolin-1 and enhanced migratory behavior could be induced in normal monocytes by treatment with TGF-β [55]. Given the causal relationship between low caveolin-1 and enhanced migration toward CXCL12 in SSc monocytes, together with the low caveolin-1 levels in monocytes from normal black subjects, we evaluated the ability of monocytes from normal black subjects to migrate toward CXCL12 (Figure 3). As predicted from the reduced expression of caveolin-1, migration of monocytes from normal blacks toward CXCL12 was enhanced (> 2.5 fold compared to monocytes from normal whites). Altogether, these data suggest that blacks may be predisposed to SSc and interstitial lung disease due to reduced expression of caveolin-1 which may, in turn, arise from over-expression of TGF-β (vide supra).

Figure 3. Hypermigration toward CXCL12 by healthy AA and SSc monocytes.

Figure 3

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Monocyte migration was quantified using microchemotaxis chambers (Neuroprobe) with 100 ng/ml CXCL12 in the lower wells. Human monocytes (50 μl at 1 × 106 cells/ml) were placed in the upper wells in medium supplemented with 5 μM CSD or control peptide. After 3 h at 37°, the filters separating the upper and lower wells were removed, fixed, and stained with DAPI. Cells that had migrated to the lower side of the filter were counted in six high power fields per filter. The data presented are the average ± s.e.m. of experiments performed using cells from 10 healthy Caucasians, 10 healthy AA, and 10 SSc patients. Compared to Caucasian, in the absence of CSD p < 0.0001 for both AA and SSc.

Racial Differences in Expression and Function of HGF, c-MET and PPAR-γ

In addition to racial differences in TGF-β and downstream effects predisposing to fibrosis, there are racial differences in the expression of HGF, a cytokine that inhibits fibrosis. HGF is a multifunctional cytokine involved in regeneration after tissue injury that has been shown to attenuate fibrosis in a bleomycin-induced model of lung injury [56]. HGF has been shown to inhibit apoptosis in lung epithelial cells while at the same time promoting apoptotic events in lung myofibroblasts, thereby inhibiting the progression of lung fibrosis. Recent work by Hoshino et al. suggests that a SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene [57].

As noted above we observed racial differences in the expression of HGF, among other cytokines, in bronchoalveolar lavage fluid from both normal subjects and SSc patients [35] (Figure 1). Black SSc patients do not appear to demonstrate the same increase in HGF concentrations in bronchoalveolar lavage fluid, plasma and fibroblast culture medium as do white SSc patients [35]. We also observed that when HGF is applied to cells in vitro the anti-fibrotic effects of HGF are significantly reduced in fibroblasts from blacks [35]. Our results were consistent across different cell lines of SSc lung fibroblasts and in normal lung fibroblasts stimulated with TGF-β. Whereas HGF consistently inhibited collagen type I and connective tissue growth factor (CTGF) accumulation in lung fibroblasts from white subjects, HGF did not reduce collagen or CTGF expression in lung fibroblasts from blacks.

The biologic effects of HGF are mediated by a membrane-spanning tyrosine kinase receptor encoded by the c-Met proto-oncogene. Following binding of HGF, the c-Met receptor undergoes auto-phosphorylation at tyrosine residues in its cytoplasmic domain and initiates a cascade of signal transduction events leading to the down-regulation of collagen and CTGF expression [58]. We found these anti-fibrotic effects of HGF to be significantly reduced in lung fibroblasts from blacks, an effect that appears to be due to an impairment of c-Met receptor phosphorylation [35]. We are testing the hypothesis that a particular variant of the c-MET gene, which may be more frequent in blacks, modulates disease severity in SSc patients.

HGF expression is induced by peroxisome proliferator-activated receptor-gamma (PPAR-γ). Wei et al. recently reported that PPAR-γ is diminished in skin and lung tissues from patients with SSc, as well as in fibroblasts explanted from lesional skin [59]. These investigators postulated that excessive TGF-β activity in SSc accounts for impaired PPAR-γ function which, in turn, contributes to unchecked fibroblast activation and progressive fibrosis [59]. Our recent studies support this observation and also suggest there may be racial differences in PPAR-γ expression, with reduced expression of PPAR-γ in lung fibroblasts from black SSc patients as compared with white SSc patients [60].

Recently, Li et al. demonstrated that PPAR-γ binds to the peroxisome proliferator response element in the HGF promoter region of renal mesangial cells, thereby inducing HGF mRNA expression and protein secretion [61]. We have demonstrated that treatment with a PPAR-γ agonist, rosiglitazone, results in increased HGF protein and phosphorylation of the c-Met receptor tyrosine kinase in lung fibroblasts from white SSc patients, which was accompanied by an increase in expression of MMP-1 and a decrease in expression of collagen type I [60]. Treatment of fibroblasts from black SSc patients with rosiglitazone, however, did not affect c-Met phosphorylation [60]. Blocking the c-Met receptor with neutralizing anti-c-Met antibody abolished the effects of rosiglitazone on collagen in lung fibroblasts derived from white SSc patients, while augmenting the expression of the c-Met receptor in lung fibroblasts from black SSc patients restored the anti-fibrotic effects of rosiglitazone [60].

Conclusion

For many years it has been recognized that SSc occurs more frequently in blacks than in whites, and that blacks with SSc tend to have earlier disease onset and worse outcomes than whites. These racial disparities cannot be explained completely by socioeconomic factors, access to healthcare, or by differences in auto-antibody status. Recent studies support the notion that blacks may have a genetic predisposition to diseases that are marked by fibrosis, including SSc. We provide evidence to suggest that the biological basis predisposing to fibrosis may involve both an over-expression of pro-fibrotic factors, e.g., TGF-β and IL-6, and an under-expression of anti-fibrotic factors, e.g., caveolin-1, HGF and PPAR-γ. These differences in gene expression between whites and blacks are likely to be due, at least partially, to genetic differences between these ethnicities. A large whole exome sequencing study in black SSc patients planned to begin soon promises to identify the genetic basis for these, as well as other new disease susceptibility and severity genes. In addition to genetic variation, it will also be important to understand the role of epigenetic and environmental risk factors in contributing to disease. A better understanding of the factors underpinning the imbalance of pro-fibrotic and anti-fibrotic factors will hopefully lead to improved therapies for SSc, along with the recognition that different therapies may need to be adapted for different groups of patients.

Key points.

  • The health burden for systemic sclerosis (SSc, scleroderma) is greater among blacks than whites.

  • SSc in blacks is characterized by earlier age of onset, higher likelihood of diffuse SSc with severe interstitial lung disease and greater mortality.

  • Differences in auto-antibody profiles, e.g., increased prevalence of anti-topoisomerase and decreased prevalence of anti-centromere antibodies, do not account for the greater severity of SSc and increased mortality in blacks.

  • Racial differences in the expression levels of various pro-fibrotic and anti-fibrotic factors might predispose blacks to fibrosing diseases such as SSc.

  • A genetic predisposition to higher expression levels of TGF-β1 and lower expression levels of caveolin-1, PPAR-γ and HGF in blacks compared with whites may contribute to the racial disparities observed in SSc.

Acknowledgments

The authors gratefully acknowledge Dr. Paula Ramos for review of the manuscript and the following sponsors of our research: Scleroderma Foundation, National Center For Research Resources (UL1RR029882), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant R03 AR056767, NIAMS K01 AR054143, NIAMS P60 AR049459-05, NIAMS K01 AR051052-05, USARMY/USAMRAA grant W81XWH-11-1-0508, National Heart, Lung and Blood Institute grant R01 HL73718, and National Center for Complementary and Alternative Medicine grant R21 AT004450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Funding Support: This work was supported by grants from the Scleroderma Foundation, the National Center For Research Resources (UL1RR029882), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant R03 AR056767, NIAMS K01 AR054143, NIAMS P60 AR049459-05, NIAMS K01 AR051052-05, USARMY/USAMRAA grant W81XWH-11-1-0508, National Heart, Lung and Blood Institute grant R01 HL73718, and National Center for Complementary and Alternative Medicine grant R21 AT004450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

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