ArticlePDF Available

Haptoglobin polymorphism and the risk of actinic keratoses and cutaneous squamous cell carcinoma: A case-control study

Authors:
Lieve Brochez at Universitair Ziekenhuis Ghent
Lieve Brochez
Reinhart Speeckaert at Ghent University
Reinhart Speeckaert
Dirk De Bacquer at Ghent University
Dirk De Bacquer
Joris R Delanghe at Ghent University
Joris R Delanghe
Show all 5 authorsHide
Download full-text PDFDownload full-text PDF
Read full-text
Download citation
5c41f83fa6fdccd6b5b6e0
0c.pdf
Content uploaded by Isabelle Hoorens
Author content
All content in this area was uploaded by Isabelle Hoorens on Jan 18, 2019
Content may be subject to copyright.
Brochez_et_al-2019-The_Journal_of_Dermatolo
gy.pdf
Content uploaded by Isabelle Hoorens
Author content
All content in this area was uploaded by Isabelle Hoorens on Jan 18, 2019
Content may be subject to copyright.
RESEARCH NOTE
Haptoglobin polymorphism and the risk of actinic keratoses
and cutaneous squamous cell carcinoma: A case–control
study
Lieve BROCHEZ,
1
Reinhart SPEECKAERT,
1
Dirk DE BACQUER,
2
Joris DELANGHE,
3
Isabelle HOORENS
1
1
Department of Dermatology, University Hospital Ghent,
2
Department of Public Health, Ghent University,
3
Department of Clinical
Biology, University Hospital Ghent, Ghent, Belgium
Little is known about the influence of haptoglobin (Hp)
polymorphism on the development actinic keratoses (AK) and
squamous cell carcinoma (SCC) in healthy patients. Hp acts
protectively against free radicals and is associated with
endothelial function, angiogenesis, iron-driven oxidative stress
and immune response. Hp synthesis is primarily induced in the
liver by cytokines such as interleukin (IL)-1, IL-6 and tumor
necrosis factor. Its main functional property is binding free
hemoglobin. Recent evidence suggest that Hp is also a potent
regulator of Langerhans cell (LC) function in the skin.
1
We
demonstrated previously that the Hp 1-1 phenotype is associ-
ated with the development of SCC and Kaposi sarcoma in
immunocompromised patients.
2,3
This study investigated
whether the Hp phenotype could be linked to the risk of devel-
oping AK and SCC in non-immunocompromised patients.
In total, 93 patients with AK, 68 patients with SCC and 133
healthy controls were enrolled in this case–control study. AK
were assessed clinically (grades I, II and III, and field damage)
and all SCC were biopsy proven. Hp phenotyping was per-
formed using hemoglobin-supplemented starch gel elec-
trophoresis on a serum blood sample as previously described
by Smithies et al.
4
Serum Hp concentrations were determined
immunonephelometrically using a BN II analyzer (Siemens,
Erlangen, Germany). Ferritin concentrations were measured
using an electrochemiluminescence immunoassay (Cobas
8000ce E602; Roche, Mannheim, Germany).
Fifty-two (17.7%) of the studied subjects had the Hp 1-1
phenotype, 151 (51.3%) the Hp 2-1 phenotype and 91 (31.0%)
the Hp 2-2 type. This corresponds to allele frequencies of
0.434 for the Hp1 allele and 0.566 for the Hp2 allele. These
group and allele frequencies are similar to other studies in
European populations, and this distribution is within the
Hardy–Weinberg equilibrium (P=0.43). The age, sex and skin
phototype distributions were similar between the different Hp
phenotype groups and adjusted for as confounding variables in
all logistic regression models. The Hp 1-1/2-1 phenotype fre-
quency was significantly higher in the AK group compared with
the control group and remained significant after adjustment for
confounding variables (odds ratio [OR] =2.77; 95% confidence
interval [CI], 1.18–6.49). However, no association between AK
grade and Hp phenotype could be demonstrated. The
combined risk for AK and SCC in a sun-exposed area for 1-1
individuals was 2.56 (95% CI, 1.21–5.41) and 1.88 (95% CI,
1.06–3.33) for 2-1 individuals compared with Hp 2-2 individu-
als. Patients with the Hp 1-1 phenotype had a significantly
lower age at diagnosis with SCC compared with the combined
group of Hp 2-1 and Hp 2-2 patients (median, 65.0 [54.0–73.2]
vs 75.0 [65.0–80.0]; P=0.01).
The median serum Hp concentrations of AK and SCC
patients were not significantly different in the three phenotype
groups (1.38 g/L [1.02–1.65] Hp 1-1 phenotype, 1.37 g/L [1.03–
1.74] Hp 2-1 phenotype and 1.37 g/L [1.00–1.74] Hp 2-2 phe-
notype). Median ferritin concentrations were the highest in the
2-1 phenotype (206.8 lg/L [122.0–308.1]), followed by
184.5 lg/L (106.7–328.2) in the 1-1 phenotype and 145.4 lg/L
(75.7–236.7) in the 2-2 phenotype patients. The serum Hp con-
centration was significantly higher in patients with SCC in sun-
exposed areas (1.54 g/L [1.09–1.85], P=0.03).
In this study, we found an increased risk of the Hp 1-1/2-1
phenotypes for developing AK compared with Hp 2-2
patients. Moreover, patients carrying the Hp 1-1 type devel-
oped SCC at an earlier age, although the overall number of
SCC patients was not different. Additionally, the Hp 1-1 and
to a lesser extent Hp 2-1 seems to increase the risk for AK
and SCC in sun-exposed areas as compared with the Hp 2-2
phenotype (OR range, 1.9–2.8). The involvement of Hp has
also been extensively examined in autoimmune diseases,
infections and malignancies. It has been shown that Hp 2-2
shows a decreased risk for cervical cancer
5
and is associated
with a better prognosis in ovarian cancer because they pre-
sent less stage III tumors and may present a stronger
immune response than patients with 1-1 and 1-2 pheno-
types.
6
Furthermore, these results corroborate our earlier find-
ings in renal transplant and HIV patients.
2,3
To conclude,
these findings point to involvement of Hp phenotypes in the
development of AK. We hypothesize an altered skin immune
surveillance by a decreased LC function in patients express-
ing the a-1 chain.
Correspondence: Isabelle Hoorens, M.D., Ph.D., Department of Dermatology, University Hospital, Corneel Heymanlaan 10, 9000 Ghent, Belgium.
Email: isabelle.hoorens@uzgent.be
Received 8 October 2018; accepted 19 November 2018.
1©2019 Japanese Dermatological Association
doi: 10.1111/1346-8138.14751 Journal of Dermatology 2019; : 1–2
ACKNOWLEDGMENTS: Dr Hoorens was funded by a Ph.D.
Fellowship of the Clinical Research Fund (KOF) University Hospital
Ghent, Belgium. The study was supported by a research grant from the
Leo Foundation.
CONFLICT OF INTEREST: None declared.
REFERENCES
1 Xie Y, Li Y, Zhang Q et al. Haptoglobin is a natural regulator of Langer-
hans cell function in the skin. J Dermatol Sci 2000; 24(1): 25–37.
2 Speeckaert R, Colebunders B, Boelaert JR et al. Association of
haptoglobin phenotypes with the development of Kaposi’s sarcoma
in HIV patients. Arch Dermatol Res 2011; 303(10): 763–769.
3 Speeckaert R, Brochez L, Lambert J et al. The haptoglobin pheno-
type influences the risk of cutaneous squamous cell carcinoma in
kidney transplant patients. J Eur Acad Dermatol Venereol 2012; 26(5):
566–571.
4 Smithies O. Zone electrophoresis in starch gels: group variations in
the serum proteins of normal human adults. Biochem J 1955; 61(4):
629–641.
5 Quaye IK, Agbolosu K, Ibrahim M et al. Haptoglobin phenotypes in
cervical cancer: decreased risk for Hp2-2 individuals. Clin Chim Acta
2009; 403(1–2): 267–268.
6 Mandato VD, Magnani E, Abrate M et al. Haptoglobin phenotype and
epithelial ovarian cancer. Anticancer Res 2012; 32(10): 4353–4358.
2©2019 Japanese Dermatological Association
L. Brochez et al.
... these findings indicate the involvement of Hp polymorphisms in the development of AK. Altered skin immune surveillance by decreased Langerhans cell function in patients expressing the α-1 chain has been postulated [178]. ...
Unlocking the link between haptoglobin polymorphism and noninfectious human diseases: insights and implications
Article
  • Nov 2023
  • CRIT REV CL LAB SCI
Haptoglobin (Hp) is a polymorphic protein that was initially described as a hemoglobin (Hb)-binding protein. The major functions of Hp are to scavenge Hb, prevent iron loss, and prevent heme-based oxidation. Hp regulates angiogenesis, nitric oxide homeostasis, immune responses, and prostaglandin synthesis. Genetic polymorphisms in the Hp gene give rise to different phenotypes, including Hp 1-1, Hp 2-1, and Hp 2-2. Extensive research has been conducted to investigate the association between Hp polymorphisms and several medical conditions including cardiovascular disease, inflammatory bowel disease, cancer, transplantation, and hemoglobinopathies. Generally, the Hp 2-2 phenotype is associated with increased disease risk and poor outcomes. Over the years, the Hp 2 allele has spread under genetic pressures. Individuals with the Hp 2-2 phenotype generally exhibit lower levels of CD163 expression in macrophages. The decreased expression of CD163 may be associated with the poor antioxidant capacity in the serum of subjects carrying the Hp 2-2 phenotype. However, the Hp 1-1 phenotype may confer protection in some cases. The Hp1 allele has strong antioxidant, anti-inflammatory, and immunomodulatory properties. It is important to note that the benefits of the Hp1 allele may vary depending on genetic and environmental factors as well as the specific disease or condition under consideration. Therefore, the Hp1 allele may not necessarily confer advantages in all situations, and its effects may be context-dependent. This review highlights the current understanding of the role of Hp polymorphisms in cardiovascular disease, inflammatory bowel disease, cancer, transplantation, hemoglobinopathies, and polyuria.
View
... Although our data suggest that the Hp gene polymorphism has little if any relevance for prostate cancer prognosis, this does not necessarily exclude a role of this polymorphism for other cancers. Previous studies reported associations of the Hp polymorphism with a variety of cancers, such as actinic keratosis, esophageal cancer, cutaneous squamous cell carcinoma, nasopharyngeal carcinoma, cervical neoplasia, and breast cancer [12][13][14][21][22][23] . Interestingly, for some cancers the greater risk was conferred by the Hp1 allele, whereas for others the greater risk was conferred by the Hp2 allele. ...
Haptoglobin polymorphism and prostate cancer mortality
Article
Full-text available
  • Aug 2020
Prostate cancer is a common malignancy in men worldwide and it is known that oxidative stress is a risk factor for cancer development. A common functional haptoglobin (Hp) polymorphism, originating from a duplication of a gene segment spanning over two exons, results in three distinct phenotypes with different anti-oxidative capacities: Hp1-1, Hp1-2, and Hp2-2. The aim of the study was to investigate the relationship between this Hp polymorphism and prostate cancer mortality. The study was performed on 690 patients with histologically confirmed prostate cancer, recruited between January 2004 and January 2007. Hp genotypes were determined by a TaqMan fluorogenic 5′-exonuclease assay. Hp1-1 was present in 76 (11%), Hp1-2 in 314 (45.5%), and Hp2-2 in 300 (43.5%) patients. During a median follow-up of 149 months, 251 (35.3%) patients died. Hp genotypes were not significantly associated with higher overall mortality (HR 1.10; 95% CI 0.91–1.33; p = 0.34). This remained similar in a multivariate analysis including age at diagnosis, androgen deprivation therapy, and risk group based on PSA level, GS, and T stage (HR 1.11; 95% CI 0.91–1.34; p = 0.30). We conclude that the common Hp polymorphism does not seem to be associated with overall mortality in prostate cancer patients.
View
Association of haptoglobin phenotypes with the development of Kaposi’s sarcoma in HIV patients
Article
Full-text available
  • Jul 2011
  • ARCH DERMATOL RES
Kaposi's sarcoma (KS) is a rare cutaneous tumor caused by human herpes virus-8 (HHV-8) infection that preferentially develops in case of severe immunosuppression, such as in HIV/AIDS disease. Haptoglobin (Hp), a polymorphic multifunctional plasma protein, exerts several immunomodulatory effects and is characterized by a genetic polymorphism leading to three major phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). This study investigated the influence of Hp genetic polymorphism on the development of KS in HIV-positive patients. 661 HIV patients were enrolled in the study with a median age of 35 years and a median follow-up time of 57 months. Hp phenotyping was performed using hemoglobin-supplemented starch gel electrophoresis. In case of low Hp concentration high pressure gel permeation chromatography (HPGPC) was used. The Hp 1-1 phenotype was associated with a significant higher risk of KS compared to the combined group of Hp 2-1 and Hp 2-2 patients (p < 0.0005) which remained significant after adjustment for possible confounding variables (age, gender and AIDS status) (p < 0.001). In contrast, the Hp 2-1 phenotype carried the lowest risk. These findings point to the involvement of Hp phenotypes in the pathogenesis of KS, which may be due to a difference in skin immunosurveillance between the Hp phenotypes.
View
Haptoglobin Phenotype and Epithelial Ovarian Cancer
Article
  • Oct 2012
  • ANTICANCER RES
Haptoglobin (H) is a glycoprotein that regulates the immune response. Serum haptoglobin levels are significantly higher in patients with advanced epithelial ovarian cancer (EOC) with poor survival. Different isoforms of haptoglobin have been found in the serum of patients with EOC. We studied the genetic susceptibility and outcome of patients with EOC correlated to H phenotypes. Analyses of the H phenotypes were performed on sera from patients stored at -70°C. A modified method based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of sera was used, followed by western blotting. Seventy-nine consecutive patients with EOC and 63 healthy women were enrolled. Their mean (±S.D.) age was 58.9±12.46 years. Overall survival was 66 months (95% confidence interval=37.7-94.2). Similar distribution of haptoglobin phenotypes was observed in EOC and in healthy women. No significant correlation was found between haptoglobin phenotype, overall survival and time-to-progression. Fewer G3 tumors were found in patients with H2-2 compared with those with H1-2 (84.2% and 90.6%, respectively, p<0.04). No significant correlation was found between H phenotype and tumor markers or number of relapses. Although ours is a preliminary study based on a small population with scant significant findings, we hypothesize that patients with EOC with haptoglobin 2-2, might have a better prognosis because they present fewer G3 tumors and they may present a stronger immune response than patients with 1-1 and 1-2 phenotypes. Larger studies should be performed to assess the predictive value of haptoglobin phenotype in patients with EOC.
View
The haptoglobin phenotype influences the risk of cutaneous squamous cell carcinoma in kidney transplant patients
Article
  • May 2011
  • J EUR ACAD DERMATOL
Cutaneous squamous cell carcinoma (SCC) is the most frequent skin cancer after organ transplantation. Currently, the pre-identification of transplant patients at increased risk for non-melanoma skin cancer remains difficult. To investigate the Hp polymorphism as a marker for the identification of a subset of patients with an increased susceptibility to develop SCC/Bowen's disease. Haptoglobin phenotyping was performed with haemoglobin-supplemented starch gel electrophoresis in 300 kidney transplant patients. High-performance gel permeation chromatography was used in case of low serum haptoglobin concentration. Cox regression analysis (adjusted for age, gender and Mediterranean origin) showed a significant association of the Hp 1-1 phenotype with a higher risk of SCC/Bowen's disease (P = 0.035) and multiple primary SCCs (P = 0.002). No significant difference between the Hp phenotypes was found for the development of Bowen's disease and SCCs in the first 10 years following renal transplantation. However, after a follow-up of >10 years, a significant association between the Hp 1-1 phenotype and the occurrence of Bowen's disease and SCC was reported (P = 0.002 and P = 0.001 respectively). This study shows an increased risk for the development of (multiple) SCCs in kidney transplant patients with the Hp 1-1 phenotype. This finding points to the role of Hp 1-1 phenotype as an important predictor in identifying a subset of patients with an increased need for preventive measures and is in agreement with the decreased anti-inflammatory capacity of this phenotype.
View
View
Haptaglobin Is a Natural Regulator of Langerhan Cell Function in the Skin
Article
  • Oct 2000
  • J DERMATOL SCI
Langerhans cells (LC), the best-understood antigen presenting cells (APC) of the skin, are functionally plastic. Freshly obtained LC readily activate allogeneic T cells, but are incapable of activating autologous, naive T cells. When placed in culture in the presence of GM-CSF, LC up-regulate surface expression of class I and II MHC molecules along with co-stimulatory molecules, such as B7, CD40 and IL-12. This functional transformation enables the cells to activate naive, autologous T cells in vitro. It is paradoxical that intracutaneous administration of exogenous GM-CSF fails to induce intraepidermal LC to undergo functional transformation in situ. It has been reported that serum contains a factor that prevents fresh LC from undergoing functional transformation in culture, and the relevant serum factor has now been identified as haptoglobin (Hp), based on the following experimental results: (a) SDS-PAGE, amino acid sequencing, and mass spectrometric analyses of the inhibitory factor purified by high performance liquid chromatography (HPLC) from normal human serum revealed molecules completely homologous to Hp alpha-1 chain; (b) pure human Hp, but not serum depleted of Hp, inhibited fresh LC from acquiring the capacity to activate autologous T cells in vitro; (c) abundant Hp was detected in cytoplasmic compartments of fresh, but not cultured, LC. It was concluded that Hp, an acute phase protein, is a systemically-derived factor that prevents epidermal LC from spontaneously undergoing functional maturation in the skin. This novel property of Hp may be important in ameliorating or preventing certain T cell-dependent inflammatory skin diseases.
View
View