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Cited by 105Iron Metabolism and DisordersDiagnosis and Treatment of Venous DiseasesErythropoietin and Anemia Treatment

Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration

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Zamboni, Paolo, Tognazzo, Silvia, Izzo, Marcello, Pancaldi, Francesca, Scapoli, Gian L., Liboni, Alberto, Gemmati, Donato·2005·Journal of Vascular Surgery
DOI 10.1016/j.jvs.2005.04.003
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Abstract

Objective Chronic venous disease (CVD) is the most common vascular disorder, progressing in approximately 10% of cases toward chronic venous leg ulceration, whereas the hemochromatosis gene (HFE) C282Y mutation is the most common recognized genetic defect in iron metabolism. Because CVD leads to local iron overload in the affected legs, we investigated whether two common HFE mutations could increase the risk of chronic venous leg ulceration. Methods This was a case-control study at the Vascular Diseases Center, University of Ferrara, Italy. From a cohort of 980 consecutive patients affected by severe CVD (CEAP clinical classes C4 to C6) we selected 238 cases with the exclusion of any other comorbidity factor potentially involved in wound etiology (group A). They were subdivided into group B, including 137 patients with ulcer (classes C5 and C6: 98 primary and 39 postthrombotic cases), and group C, including 101 cases with no skin lesions (class C4). They were completely matched for sex, age, and geographic origin with 280 healthy controls (group D). A total of 518 subjects were polymerase chain reaction genotyped for HFE mutations (C282Y and H63D). We assessed the risk of ulceration by comparing the prevalence of ulcer in homogenous cases with and without the HFE variants. Other main outcome measures were the sensitivity, specificity, and predictive values of the genetic test in CVD cases. Results C282Y mutation significantly increases the risk of ulcer in primary CVD by almo…

Integrity signals

Registry

Crossref · 10.1016/j.jvs.2005.04.003

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 20 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The H63D mutation was not associated with an increased risk of ulcer in any group.

    “Furthermore, we did not find any increased risk in any group regarding H63D mutation.”
    • Also stated in: § DISCUSSION · plain
      “In our study, the H63D mutation by itself did not prove to play the same role as the C282Y mutation in facilitating the occurrence of ulcerous lesions.”
    Quote in the paperSubstantial claim
  • Findingown data

    In subjects affected by postthrombotic ulcer, the C282Y mutation did not seem to be associated with a significant risk of ulcer.

    “Consequently, in subjects affected by postthrombotic ulcer (subgroup E), the C282Y mutation did not seem to be associated with a significant risk.”
    • Also stated in: § DISCUSSION · hedged
      “Similarly, neither the C282Y nor the H63D mutation seems to be significantly associated with the appearance of ulcers in patients affected by CVD secondary to postthrombotic syndrome.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In primary chronic venous disease cases, the negative predictive value of the genetic test for ulcer development was 53% (95% CI 45.1%-98.2%).

    “On the contrary, assessment of sensitivity and negative predictive values was certainly less interesting for future clinical application (12%: 95% CI, 6.0%-20%; and 53%: 95% CI, 45.1%-98.2%,respectively).”
    Quote in the paperNot a substantial claim
  • Findingown data

    When primary ulcer patients were compared with primary C4 cases, the prevalence of C282Y was significantly higher (6.6% vs 1.02%; P = .008).

    “Finally, further analysis of prevalence by comparing primary ulcer vs primary C4 cases showed a highly significant difference (6.6% vs 1.02%; P ϭ .008).”
    Quote in the paperSubstantial claim
  • Findingown data

    When group B was compared with C4 patients without skin lesions (group C), the prevalence of C282Y showed a similar, although not significant, difference (5.1% vs 1.5%; P = .063).

    “When we compared group B with C4 patients without skin lesions (group C), the prevalence demonstrated a similar, although not significant, appreciable difference (5.1% vs 1.5%; P ϭ .063).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    The prevalence of double carriers of H63D/C282Y in the primary chronic venous disease group was greater than among healthy controls (3.06% vs 1.07%), but not significantly higher (P = .357).

    “Although the prevalence of double carriers of the variants under study (H63D/C282Y) found in the primary CVD group was greater than among healthy controls (3.06% vs 1.07%, respectively), it was not significantly higher (P ϭ .357).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The healthy blood donor controls were free of chronic venous disease.

  • May combine two claims.

    Findingown data

    The prevalence of the C282Y polymorphic allele in C4 cases (group C) was 1.5%, less than that in healthy controls (2.1%), but the difference was nonsignificant (P = .778).

    “It is interesting to note that the prevalence of the C282Y polymorphic allele found in C4 cases of group C (1.5%) was less than that in healthy controls (2.1%); however, such a difference is nonsignificant (P ϭ .778),”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The healthy blood donor controls were free of chronic venous disease.

  • May combine two claims.

    Findingown data

    Among primary chronic venous disease cases, more than 85% of C282Y carriers developed an ulcer, whereas ulcer occurred in only 47% of wild types (P = .01).

    “It is noteworthy that more than 85% of C282Y carriers in primary cases developed an ulcer, whereas ulcer occurred in only 47% (P ϭ .01) of the wild types (Table II).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The frequencies of the two mutations in the healthy control population were very similar to those previously reported for the Italian population.

    “Finally, the frequencies of the two mutations registered in the healthy control population seemed very similar to those previously reported for the Italian population.[21][22][23]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21][22][23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: The healthy blood donor controls were free of chronic venous disease.

  • May combine two claims.

    Findingown data

    Neither in the case group without lesions (group C) nor in the subgroup with postthrombotic ulcers were double carriers identified.

    “Very interestingly, neither in the case group (group C) without lesions nor in the subgroup with postthrombotic ulcers were double carriers identified.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Several authors have hypothesized that iron could be released to generate free radicals because of excessive oxidative stress, to activate proteolytic hyperactivity on the part of metalloproteinases, or to downregulate tissue inhibitors of metalloproteinases.

    “Several authors have hypothesized that this iron could be released to generate free radicals because of excessive oxidative stress, to activate a proteolytic hyperactivity on the part of metalloproteinases, or to downregulate tissue inhibitors of metalloproteinases.14,[16][17][18][19][20]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 14,[16][17][18][19][20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Clinical and hemodynamic parameters, including duplex scanning and plethysmographic investigations, fail to predict ulcer appearances and are insufficient for categorizing patients by the clinical severity of the disease.

    “Clinical and hemodynamic parameters, including duplex scanning and plethysmographic investigations, fail to predict ulcer appearances and are insufficient for categorizing patients by the clinical severity of the disease.[5][6][7][8]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5][6][7][8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    To develop iron overload pathologies, other inherited or acquired conditions are necessary, such as environmental factors, concomitant diseases, or both.

    “Therefore, to develop iron overload pathologies, other inherited or acquired conditions are necessary, such as environmental factors, concomitant diseases, or both.1,2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] McCune, 2003, Screening for hereditary haemochromatosis within families and beyond, Lancet source
    • cites [2] Beutler, 2002, Penetrance of C282Y hereditary haemochromatosis mutation in USA, Lancet source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cases and controls were completely matched for sex, age, and geographic origin.

    “They were completely matched for sex, age, and geographic origin with 280 healthy controls (group D).”
    • Also stated in: § Selection of cases and controls. · plain
      “The controls (group D) were 280 healthy subjects selected from among blood donors who were matched for sex, age, and geographic origin with the patients described previously (Table I).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    These genetic defects present lower penetration than previously thought and cannot be advocated alone for the development of hereditary hemochromatosis.

    “It was recently discovered that these genetic defects present lower penetration than previously thought and cannot be advocated alone for the development of HH.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] McCune, 2003, Screening for hereditary haemochromatosis within families and beyond, Lancet source
    • cites [2] Beutler, 2002, Penetrance of C282Y hereditary haemochromatosis mutation in USA, Lancet source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Genotypes were confirmed by regenotyping a random selection of samples for each polymorphism, with no discrepancies between duplicate genotypes.

    “Genotypes were confirmed by regenotyping a random selection of samples (cases and controls) for each polymorphism investigated.There were no discrepancies between genotypes determined in duplicate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Patients with ulcer have a higher concentration of iron and rate of transferrin saturation in the serum from the affected leg than do C4 patients.

    “It has recently been demonstrated that patients with ulcer have a higher concentration of iron and rate of transferrin saturation in the serum from the affected leg than do C4 patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Zamboni, 2005, Serum iron and MMP-9 variations in limbs affected by chronic venous disease and venous leg ulcers, Dermatol Surg source

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Premisecitation

    Patients with ulcer lose the ability to counteract iron export from inside phagocytes, and this inability could be genetically determined.

    “It seems that patients with ulcer lose the ability to counteract the iron export from inside the phagocytes, and it has been hypothesized that this inability could be genetically determined.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Zamboni, 2005, Serum iron and MMP-9 variations in limbs affected by chronic venous disease and venous leg ulcers, Dermatol Surg source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    The investigation was conducted in accordance with consensus statement criteria and a previously described method, allowing separation of primary from postthrombotic cases and identification of peripheral arterial disease.

    “This investigation, conducted in accordance with consensus statement criteria and a method previously described, [5][6][7][8] allowed us to separate primary from postthrombotic cases and to identify patients affected by peripheral arterial disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5][6][7][8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The risk associated with hereditary hemochromatosis is increased by the homozygous condition for C282Y or by coinheritance of both variants.

    “C282Y and H63D mutations of the hemochromatosis (HFE) gene are the most common genetic defects in hereditary hemochromatosis gene (HH) in Caucasian populations, and the associated risk is increased by the homozygous condition for C282Y or by coinheritance of both variants.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] McCune, 2003, Screening for hereditary haemochromatosis within families and beyond, Lancet source
    • cites [2] Beutler, 2002, Penetrance of C282Y hereditary haemochromatosis mutation in USA, Lancet source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C282Y and H63D mutations of the hemochromatosis (HFE) gene are the most common genetic defects in hereditary hemochromatosis in Caucasian populations.

    “C282Y and H63D mutations of the hemochromatosis (HFE) gene are the most common genetic defects in hereditary hemochromatosis gene (HH) in Caucasian populations, and the associated risk is increased by the homozygous condition for C282Y or by coinheritance of both variants.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] McCune, 2003, Screening for hereditary haemochromatosis within families and beyond, Lancet source
    • cites [2] Beutler, 2002, Penetrance of C282Y hereditary haemochromatosis mutation in USA, Lancet source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Adjusted odds ratios were calculated by logistic regression models controlling for sex, age, geographic origin, and the H63D polymorphism.

    “Adjusted ORs for single or combined comparisons were calculated by means of logistic regression models that controlled for sex, age, geographic origin, and the H63D polymorphism.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For patient selection, strict exclusion criteria were applied to exclude any other comorbidity factor potentially involved in wound etiology.

    “For patient selection, we strictly applied the following exclusion criteria to exclude any other comorbidity factor potentially involved in wound etiology:”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    No significant differences were observed in the subgroups considered among the comparisons of computed demographic parameters.

    “No significant differences were observed in the subgroups considered among the comparisons of computed parameters.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several adjunctive factors have been investigated during the past 20 years in an attempt to understand the etiology of venous ulceration, but none of them completely explains the entire process.

    “For such reasons, several adjunctive factors have been investigated during the past 20 years in an attempt to understand the etiology of venous ulceration, but none of them completely explains the entire process.[9][10][11]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9][10][11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The expected frequency of control genotypes was checked by using the Hardy-Weinberg equilibrium test.

    “The expected frequency of control genotypes was checked by using the Hardy-Weinberg equilibrium test.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In 85% of ulcer cases, the disorder was referred to primary chronic venous disease, with a combination of superficial and deep reflux in 32% and a pattern of reflux confined to the superficial venous system in 53%.

    “It has been demonstrated in 85% of ulcer cases that the disorder was referred to primary CVD, but with a combination of superficial and deep reflux in 32% and with a pattern of reflux confined to the superficial venous system in 53%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24][25][26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

22 of 22

  • The paper relies on this without support.

    The healthy blood donor controls were free of chronic venous disease.

    “The controls (group D) were 280 healthy subjects selected from among blood donors who were matched for sex, age, and geographic origin with the patients described previously (Table I).”

  • The paper relies on this without support.

    The exclusion criteria applied to cases eliminated all other comorbidity factors potentially involved in wound etiology.

    “For patient selection, we strictly applied the following exclusion criteria to exclude any other comorbidity factor potentially involved in wound etiology:”

  • The authors state this as an assumption.

    The mutated macrophages increase the possibility of generating free iron and free radicals, possibly leading to matrix breakdown and skin lesions.

    “These already-known effects of the C282Y mutation on human macrophages, if speculatively related to our findings, can lead us to assume that the mutated macrophages increase the possibility of generating free iron and free radicals, possibly leading to matrix breakdown and skin lesions.14,16,18,19,29”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Common hemochromatosis gene mutations such as the C282Y mutation significantly increase the risk of ulcer in chronic venous disease by almost seven times.

    “Studies have shown that common hemochromatosis gene mutations such as the C282Y mutation significantly increase the risk of ulcer in CVD by almost seven times (Zamboni et al., 2005).”

    From The role of iron in the skin and cutaneous wound healing (2014) · cites this paper as Zamboni et al., 2005

    The Assessment of risk of ulceration section reports nearly sevenfold higher odds of ulceration with C282Y in primary CVD (OR 6.69; P = .01). The claim omits the primary-CVD restriction: the result was not statistically significant across all CVD cases, and the paper found no increased risk for the other common mutation, H63D. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • The origin of increased leg iron stores is extravasation of red blood cells in conditions of significant venous stasis.

    “The origin of increased leg iron stores is extravasation of red blood cells (erythrocytes) in conditions of significant venous stasis.”

    From The Big Idea: Iron-Dependent Inflammation in Venous Disease and Proposed Parallels in Multiple Sclerosis (2006) · cites this paper as [6]

  • Over time, with increasing overload of iron, the structure of ferritin changes to haemosiderin.

    “Over time, with increasing overload of iron, the structure of ferritin changes to haemosiderin.4-9”

    From The Big Idea: Iron-Dependent Inflammation in Venous Disease and Proposed Parallels in Multiple Sclerosis (2006) · cites this paper as [6]

  • Erythrocytes are degraded by interstitial macrophages, with the released iron incorporated into ferritin.

    “Erythrocytes are degraded by the interstitial macrophages, with the released iron incorporated into ferritin.”

    From The Big Idea: Iron-Dependent Inflammation in Venous Disease and Proposed Parallels in Multiple Sclerosis (2006) · cites this paper as [6]

  • Recent studies demonstrate a pivotal role for tissue iron accumulation in inducing and maintaining inflammation in chronic venous disease.

    “Recent studies demonstrate a pivotal role for tissue iron accumulation in inducing and maintaining inflammation in CVD.4-9”

    From The Big Idea: Iron-Dependent Inflammation in Venous Disease and Proposed Parallels in Multiple Sclerosis (2006) · cites this paper as [6]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Overall mean age does not match the two patient groups

    Minor

    Groups B and C together make up group A. Weighting their reported mean ages by their sample sizes gives about 61.30 years, not the 61.03 years reported for group A; the gap is larger than the displayed rounding permits.

1 of 1

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Authors
Zamboni, P., Tognazzo, S., Izzo, M., Pancaldi, F., Scapoli, G. L., Liboni, A., & Gemmati, D.
Affiliations
University of Ferrara (IT)
Corresponding author
Zamboni, Paolo
ORCID
Venue
Journal of Vascular Surgery
Publisher
Elsevier BV
Published
2005-08
Volume
42
Issue
2
Pages
309-314
ISSN
0741-5214 (ISSN-L)
DOI
10.1016/j.jvs.2005.04.003
OpenAlex
W2003764905
Cited by
105
References
39
Citations by year
2026: 5 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 6 · 2016: 5 · 2015: 3 · 2014: 7 · 2013: 3 · 2012: 7
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Vascular Surgery (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
  • Zenodo (CERN European Organization for Nuclear Research) (other-oa)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Surgery › Diagnosis and Treatment of Venous Diseases
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
hemochromatosis, HFE C282Y mutation, H63D mutation, chronic venous disease, iron overload, genetic risk factors, CEAP classification, iron metabolism disorders
MeSH terms
Adult, Aged, Aged, 80 and over, Female, Hemochromatosis, Humans, Male

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