Sex-Specific Genetically Predicted Iron Status in relation to 12 Vascular Diseases: A Mendelian Randomization Study in the UK Biobank

Abstract

Background. Iron overload has been implicated in the pathogenesis of varicose veins (VVs). However, the association of serum iron status with other vascular diseases (VDs) is not well understood, which might be a potential target for VD prevention. This study was aimed at investigating the causal associations between iron status and VDs using the Mendelian randomization (MR) method. Methods. A two-sample MR was designed to investigate whether iron status was associated with VDs, based on iron data from a published genome-wide association study meta-analysis of 48,972 subjects of European descent and VD data obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). We further explored whether there was sex difference in the associations between genetically predicted iron status and VDs. Results. The results demonstrated that iron status had a significant causal effect on VVs of lower extremities ( P < 0.001 ) and a potential effect on coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively), but not on other VDs. Furthermore, higher iron status exerted a detrimental effect on VVs of lower extremities in both genders ( P < 0.05 ) and a protective effect on male patients with coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively). Conclusions. This MR study provides robust evidence that higher iron status increases the risk of VVs of lower extremities, whereas it reduces the incidence of coronary atherosclerosis in the male population, which indicates that iron has divergent effects on vascular pathology.

Exploring the Association between Hemochromatosis and Lower-Limb Venous Disease

“…11,12,[20][21][22] The majority of studies were of moderate or high quality. 9,11,12,18,19,21,22 Results from a meta-analysis with a large number of participants (five studies on venous disease including 1,279 cases and 2,506 controls) did not show any significant association between HFE genotypes and venous disease; 21 however, analysis from two case-control studies (N = 638 and N = 1,227) found a significant relationship between overall risk for CVD (including varicose veins) and the HFE p.C282Y variant. 9,22 One of these studies further concluded that p.H63D was not associated with an increased risk of CVD but an earlier onset of the disease.…”

“…Sample sizes ranged from 99 to 410,166 participants. Three studies investigated a range of gene polymorphisms, 9,17,18 and one evaluated iron status 19 with the endpoints of CVD (including varicose veins) and VLUs. Five studies investigated the specific gene polymorphisms for HFE (p.C282Y and p.H63D) with endpoints of CVD (including varicose veins) and VLUs 11,12,20–22 .…”

“…Five studies investigated the specific gene polymorphisms for HFE (p.C282Y and p.H63D) with endpoints of CVD (including varicose veins) and VLUs 11,12,20–22 . The majority of studies were of moderate or high quality 9,11,12,18,19,21,22 …”

“…9,22 One of these studies further concluded that p.H63D was not associated with an increased risk of CVD but an earlier onset of the disease. 9 Sokolova et al 22 identified a borderline reduced risk of those with p.H63D having VLUs, and Yang et al 19 concluded that iron status had a significant causal effect on the vascular disease of varicose veins in the lower extremities. In one secondary analysis, HFE gene variant carriers had a smaller proportion of healing of VLUs and a longer time to healing, which was impaired by high-strength compression.…”

Potential intervention target of atherosclerosis: Ferroptosis (Review)

“…The imbalance of iron metabolism mediates the occurrence of ferroptosis, and promotes the formation and development of AS. Initially, a toxic iron reaction is associated with an excess of stored iron (25), which can accelerate cerebral tissue oxidation by increasing oxygen radical generation (26). This leads to super-oxidation damage in the inner wall of the cerebral artery, further aggravating the iron overload through the oxidized low-density lipoprotein (ox-LDL)-mediated Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) signaling pathway in macrophages (27).…”