Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration.

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 almost seven times (odds ratio, 6.69; 95% confidence interval, 1.45-30.8; P = .01). Application of the HFE test in primary CVD demonstrated increased specificity and positive predictive values (98% and 86%, respectively), with negligible sensitivity and negative predictive values.

CONCLUSIONS: The overlap of primary CVD and the C282Y mutation consistently increases the risk of developing venous leg ulceration. These data, which have been confirmed in other clinical settings, suggest new strategies for preventing and treating primary CVD.

CLINICAL RELEVANCE: The number of patients affected by primary CVD is so great that the vast majority of ulcers are also related to this common problem. On the other hand, there is not a reliable way for identifying in advance, from the broad base of primary CVD patients (20-40% of the general population), the high risk minority (10% of primary CVD cases) who will develop a venous ulcer. In such cases, a simple C282Y blood genetic test demonstrated an elevated specificity in predicting ulcer development (98%, CI 95%, 92.8-99.7). The genetic test could be applied starting from the C2 class, varicose veins, the most common situation observed in clinical practice. In perspective, the presence of the C282Y mutation would strengthen the indications and priorities for surgical correction of superficial venous insufficiency.