Higher Heme Iron Intake Research Articles

Dietary Interventions for Cancer Prevention: An Update to ACS International Guidelines.

Cancer, the second leading cause of death worldwide, demands the identification of modifiable risk factors to optimize its prevention. Diet has emerged as a pivotal focus in current research efforts. This literature review aims to enhance the ACS guidelines on diet and cancer by integrating the latest findings and addressing unresolved questions. The methodology involved an advanced PubMed search with specific filters relevant to the research topic. Topics covered include time-restricted diet, diet quality, acid load, counseling, exercise and diet combination, Mediterranean diet, vegetarian and pescetarian diets, weight loss, dairy consumption, coffee and tea, iron, carbohydrates, meat, fruits and vegetables, heavy metals, micronutrients, and phytoestrogens. The review highlights the benefits of the Mediterranean diet in reducing cancer risk. Adherence to overnight fasting or carbohydrate consumption may contribute to cancer prevention, but excessive fasting may harm patients' quality of life. A vegetarian/pescetarian diet is associated with lower risks of general and colorectal cancer compared to a carnivorous diet. High heme and total iron intake are linked to increased lung cancer risk, while phytoestrogen intake is associated with reduced risk. Coffee and tea have a neutral impact on cancer risk. Finally, the roles of several preventive micronutrients and carcinogenic heavy metals are discussed.

Ingested nitrate and nitrite and end-stage renal disease in licensed pesticide applicators and spouses in the Agricultural Health Study

BackgroundNitrate and nitrite ingestion has been linked to kidney cancer, possibly via the endogenous formation of carcinogenic N-nitroso compounds. These exposures might also contribute to end-stage renal disease (ESRD).ObjectivesWe investigated associations of drinking water nitrate and dietary nitrate and nitrite intakes (total and by food type) with incident ESRD in the Agricultural Health Study. We also explored modifying effects of vitamin C and heme iron intake, which may affect endogenous nitrosation.MethodsWe performed complete case analyses among private pesticide applicators and their spouses. We obtained water nitrate estimates for participants whose primary drinking water source at enrollment (1993−1997) was public water supplies (PWS) or private wells (N = 59,632). Average nitrate concentrations were computed from historical data for PWS users and predicted from random forest models for private well users. Analysis of dietary nitrate and nitrite was restricted to the 30,177 participants who completed the NCI Dietary History Questionnaire during follow-up (1999−2003). Incident ESRD through 2018 was ascertained through linkage with the U.S. Renal Data System. We estimated adjusted hazard ratios (HRs) and 95%CI for associations of tertiles (T) of exposure with ESRD overall and explored effects in strata of vitamin C and heme iron intake.ResultsWe identified 469 incident ESRD cases (206 for dietary analysis). Water nitrate and total dietary nitrate/nitrite were not associated with ESRD, but increased ESRD was associated with nitrate and nitrite from processed meats. We found apparent associations between nitrite and ESRD only among participants with vitamin C <median (T3 vs. T1 HR: 2.26, 95%CI: 1.05, 4.86) and with heme iron ≥median (T3 vs. T1 HR: 1.73, 95%CI: 0.89, 3.39).SignificanceESRD incidence was associated with dietary nitrate/nitrite from processed meat among all study participants and with total dietary nitrite among participants with lower vitamin C or higher heme iron intake.Impact statementThere are few well-established environmental risk factors for end-stage renal disease (ESRD), a worldwide public health challenge. Ingestion of nitrate and nitrite, which may lead to endogenous formation of carcinogenic N-nitroso compounds, has been linked to some cancers and chronic diseases. We investigated these exposures in relation to ESRD in an agricultural cohort. ESRD incidence was associated with dietary nitrate/nitrite from processed meat and with total dietary nitrite among subgroups with lower vitamin C or higher heme iron intake. This study provides preliminary evidence that points to dietary nitrite and possibly dietary nitrate intake as a potential contributor to ESRD.

Nutritional Aspects of Iron in Health and Disease.

Dietary iron assimilation is critical for health and essential to prevent iron-deficient states and related comorbidities, such as anemia. The bioavailability of iron is generally low, while its absorption and metabolism are tightly controlled to satisfy metabolic needs and prevent toxicity of excessive iron accumulation. Iron entry into the bloodstream is limited by hepcidin, the iron regulatory hormone. Hepcidin deficiency due to loss-of-function mutations in upstream gene regulators causes hereditary hemochromatosis, an endocrine disorder of iron overload characterized by chronic hyperabsorption of dietary iron, with deleterious clinical complications if untreated. The impact of high dietary iron intake and elevated body iron stores in the general population is not well understood. Herein, we summarize epidemiological data suggesting that a high intake of heme iron, which is abundant in meat products, poses a risk factor for metabolic syndrome pathologies, cardiovascular diseases, and some cancers. We discuss the clinical relevance and potential limitations of data from cohort studies, as well as the need to establish causality and elucidate molecular mechanisms.

Dietary iron intake and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of prospective cohort studies.

We aimed to assess the long-term association of total, heme, non-heme, and supplemental iron intake and risk of type 2 diabetes (T2D). PubMed, Scopus, and Web of Science were searched to October 2021. Two researchers extracted data in duplicate and rated the certainty in the estimates using the GRADE approach. Random-effects models were applied to estimate the relative risks (RRs) and 95% CIs. Dose-response associations were modeled by a one-stage weighted mixed-effects meta-analysis. Eleven prospective cohort studies 323,788 participants and 28,837 incident cases of T2D were included. High versus low category meta-analysis indicated that higher heme iron intake was associated with a 20% higher risk of T2D (95% CI 1.07, 1.35; I2 = 77%, n = 11; GRADE = moderate). Dose-response analysis indicated a positive monotonic association, wherein each 1mg/day increment in heme iron intake was related to a 16% higher risk (95% CI 1.03, 1.30). No significant relationship was detected between dietary intakes of total, non-heme, and supplemental iron and risk of T2D (GRADE = very low). In summary, higher heme iron intake was associated with a higher risk of T2D. Our results are in line with existing evidence indicating that adopting a Western-style dietary pattern, rich in dietary sources of heme iron, was associated with a higher risk of T2D. The protocol of this systematic review was registered at PROSPERO (registration number: CRD42021226835).

Correlation Between High Serum Ferritin Level and Gestational Diabetes: A Systematic Review.

Gestational diabetes mellitus (GDM) is a growing pregnancy-related health problem all over the world. It has been noticed that women with high serum ferritin levels have a strong relationship with GDM by increased insulin resistance and increased insulin secretion from the pancreas resulting in pancreatic beta-cell exhaustion. Heme iron is also responsible for increasing the body's iron store and hence causing oxidative injury to pancreatic cells.In this systematic review, we researched the association between high serum ferritin levels and GDM. Three databases were consulted for articles related to GDM and high ferritin. These include Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, and PubMed Central (PMC). Additional articles were retrieved from the institutional database. After filtering, 10 articles were finally selected, and quality was checked using the Joanna Briggs Institute (JBI) Critical Appraisal quality check tool. Serum iron biomarkers including ferritin, iron, and soluble transferrin receptor (sTfR) were measured.Our systematic review indicates that high maternal serum ferritin has a significant role in the development of GDM. We have also noticed the importance of sTfR and serum hepcidin as biomarkers to monitor high ferritin levels. Our study also observed a positive relationship between high heme iron intake and gestational diabetes mellitus. Therefore, more research is required to understand this relationship to identify populations at risk.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

Electronic structure and reactivity of heme bound insulin

Insulin resistance as well as insulin deficiency are said to be principal to the development of type 2 diabetes mellitus (T2Dm). Heme has also been suggested to play an important role in the disease etiology since many of the heme deficiency symptoms constitute the common pathological features of T2Dm. Besides, iron overload, higher heme iron intake and transfusion requiring diseases are associated with a higher risk of T2Dm development. In this study the interaction between these two key components i.e. heme and insulin has been studied spectroscopically under different conditions which include the effect of excess peptide as well as increasing pH. The resultant heme-insulin complexes in their reduced state are found to produce very little partially reduced oxygen species (PROS) on getting oxidized by molecular oxygen. The interaction between insulin and previously reported T2Dm relevant heme-amylin complex were also examined using absorption and resonance Raman spectroscopy. The corresponding data suggest that insulin sequesters heme from heme-amylin to form the much less cytotoxic heme-insulin.

The Association between Maternal Dietary Iron Intake during the First Trimester of Pregnancy with Pregnancy Outcomes and Pregnancy-Related Complications.

In this study, we investigated the associations of maternal dietary iron intake during the first trimester of pregnancy and pregnancy outcomes and related complications in pregnant women of Isfahan, Iran. In this prospective study, 812 healthy first-trimester singleton pregnant women were selected randomly from 20 various health centers across Isfahan city during 2015–2016. The maternal dietary iron classified into 2 groups, including heme and non-heme iron. Factors including pre-eclampsia, gestational hypertension, gestational diabetes mellitus, intrauterine growth restriction (IUGR), and nausea and vomiting in pregnancy considered as the pregnancy-related complications. Infant's birth weight, birth height, and birth head circumference were also determined as the pregnancy-outcomes. There was a significant association between total iron consumption and infant head circumference (p = 0.01). Total maternal iron (the sum of heme and non-heme iron) was negatively associated with both infant's birth height (p = 0.006) and birth weight (p = 0.02). Non-heme iron consumption is positively associated with high-risk of IUGR (p = 0.004). Heme intake was associated with an increased risk of maternal fasting blood sugar (FBS) (p = 0.04). Higher heme, non-heme, and total iron intake were associated with lower risk of pre-eclampsia (heme: crude p = 0.05; non-heme iron: adjusted p = 0.02; total iron: adjusted p = 0.05). Maternal total iron intake was directly associated with infant head circumference, whereas, negatively associated with both birth weight and birth height. High non-heme iron intake may increase the risk of IUGR, and a high intake of heme iron may increase FBS.

Dietary intake of heme iron is associated with ferritin and hemoglobin levels in Dutch blood donors: results from Donor InSight.

Whole blood donors, especially frequently donating donors, have a risk of iron deficiency and low hemoglobin (Hb) levels, which may affect their health and eligibility to donate. Lifestyle behaviors, such as dietary iron intake and physical activity, may influence iron stores and thereby Hb levels. We aimed to investigate whether dietary iron intake and questionnaire-based moderate-to-vigorous physical activity (MVPA) were associated with Hb levels, and whether ferritin levels mediated these associations. In Donor InSight-III, a Dutch cohort study of blood and plasma donors, data on heme and non-heme iron intake (mg/day), MVPA (10 minutes/day), Hb levels (mmol/L) and ferritin levels (mg/L) were available in 2,323 donors (1,074 male). Donors with higher heme iron intakes [regression coefficients (β) in men and women: 0.160 and 0.065 mmol/L higher Hb per 1 mg of heme iron, respectively] and lower nonheme iron intakes (β: -0.014 and -0.017, respectively) had higher Hb levels, adjusted for relevant confounders. Ferritin levels mediated these associations [indirect effect (95% confidence interval) in men and women, respectively: 0.074 (0.045; 0.111) and 0.061 (0.030; 0.096) for heme and -0.003 (-0.008;0.001) and -0.008 (-0.013;-0.003) for non-heme]. MVPA was negatively associated with Hb levels in men only (β: -0.005), but not mediated by ferritin levels. In conclusion, higher heme and lower non-heme iron intake were associated with higher Hb levels in donors, via higher ferritin levels. This indicates that donors with high heme iron intake may be more capable of maintaining iron stores to recover Hb levels after blood donation.

Abstract 1883: Dietary nitrate and nitrite, micronutrients, and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study

Abstract Background: Ingested nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOCs), potential human carcinogens. Vitamin C inhibits and heme iron enhances NOC formation. To date, interactions between dietary nitrate and nitrite intakes and these micronutrients have not been evaluated in relation to the risk for breast cancer in prospective cohort studies. Methods: We followed 191,926 postmenopausal women in the NIH-AARP Diet and Health Study for incident breast cancer. Dietary intake was assessed using a food frequency questionnaire at baseline (1995). Daily nitrate and nitrite intakes were computed for total, animal, and processed meat sources, and adjusted for energy intake using a density method. We computed multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by quintiles of nitrate and nitrite for all breast cancers, by estrogen/progesterone receptor (ER/PR) status, and by stage (localized, regional/distant) using Cox proportional hazards regression. We stratified analyses by low or high (≤ or &amp;gt; median) heme iron (138 mg/1,000kcal) and total vitamin C (273 mg/d) intakes. Results: We identified 7,508 incident invasive breast cancers (1995-2006). On average, 95% of nitrate and 70% of nitrite intakes were from plant sources. Red processed meat intake was not associated with risk of all breast cancer but was positively associated with risk of localized breast cancer (adjusted HR = 1.35 for Q5, CI = 1.11-1.42, p-trend&amp;lt;0.001). Heme iron intake was positively associated with risk of all breast cancer (HR = 1.12 for Q5, CI = 1.04-1.21, p-trend = 0.004). Total nitrate intake was associated with higher risk of all breast cancer, particularly among women with high heme iron intake (HR = 1.15, CI = 1.01-1.30 for Q5, p-trend = 0.02), but not among women with low heme iron intake (p-trend = 0.63, p-interaction = 0.17); similar associations were observed when evaluating total nitrate intake in relation to hormone receptor positive cancers (p-interaction = 0.09 for total nitrate x heme iron in relation to ER+/PR+ positive cancer). Total nitrite intake was not associated with overall breast cancer risk. Nitrite intake from processed red meats was associated with higher risk of localized (HR = 1.23, 95%CI = 1.09-1.39 for Q5, p-trend&amp;lt;0.001) but not regional/distant breast cancers (p-trend = 0.41). Vitamin C intake did not interact with nitrate or nitrite intake in relation to breast cancer risk. Conclusions: Our findings suggest that high nitrate intake and nitrite intake from processed meats may increase postmenopausal women's risk of breast cancer, especially for those with high heme iron intake. Citation Format: Maki Inoue-Choi, Rashmi Sinha, Gretchen L. Gierach, Mary H. Ward. Dietary nitrate and nitrite, micronutrients, and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1883. doi:10.1158/1538-7445.AM2015-1883

Heme iron intake and acute myocardial infarction: A prospective study of men

BackgroundEpidemiologic studies of heme iron and non-heme iron intake in relation to risk of acute myocardial infarction (AMI) are lacking. Therefore, we examine the associations between heme iron and non-heme iron intake and fatal and nonfatal AMI in men. Moreover, we investigated whether the associations were modified by intake of minerals (calcium, magnesium, and zinc) that decreases iron absorption. MethodsThe population-based prospective cohort of Swedish Men (COSM) included 36882 men, aged 45–79years, who completed a self-administered questionnaire on diet and had no history of coronary heart disease, stroke, diabetes, or cancer at baseline. ResultsDuring an 11.7year follow-up, 678 fatal and 2593 nonfatal AMI events were registered. The hazard ratio (HR) of fatal AMI among men in the highest compared with the lowest quintile of heme iron intake was 1.51 (95%CI: 1.07–2.13, P-trend=0.02). The association was confined to men with a low intake of minerals that can decrease iron absorption. Among men with combined intakes of calcium, magnesium, and zinc below the medians, the HR of fatal AMI was 2.89 (95%CI: 1.43–5.82) for the highest vs. the lowest quintile of heme iron intake. There was no association between heme iron intake and nonfatal AMI, or between non-heme iron intake and fatal or nonfatal AMI. ConclusionsFindings from this prospective study indicate that a high heme iron intake, particularly with simultaneous low intake of minerals that can decrease iron absorption, may increase the risk of fatal AMI.

Is heme iron intake associated with risk of coronary heart disease? A meta-analysis of prospective studies

Heme iron may contribute to the development of atherosclerosis by catalyzing production of hydroxyl-free radicals and promoting low-density lipoprotein oxidation. However, epidemiologic findings regarding the association between heme iron intake and risk of coronary heart disease (CHD) are inconsistent. We aimed to investigate the association by carrying out a meta-analysis of prospective studies. Relevant studies were identified by using PubMed and EMBASE databases between January 1966 and April 2013 and also by manually reviewing the reference lists of retrieved publications. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were computed using a random-effects model. Six prospective studies, which contained a total of 131,553 participants and 2,459 CHD cases, met the inclusion criteria. Combined results indicated that participants with higher heme iron intake had a 31% increased risk of CHD, compared with those with lower intake (RR = 1.31, 95% CI 1.04-1.67), with significant heterogeneity (P(heterogeneity) = 0.05, I(2) = 55.0%). Excluding the only study from Japan (limiting to Western studies) yielded a RR of 1.46 (95% CI 1.21-1.76), with no study heterogeneity (P(heterogeneity) = 0.44, I(2) = 0.0%). The dose-response RR of CHD for an increase in heme iron intake of 1 mg/day was 1.27 (95% CI 1.10-1.47), with low heterogeneity (P (heterogeneity) = 0.25, I (2) = 25.8%). We observed no significant publication bias. This meta-analysis suggests that heme iron intake was associated with an increased risk of CHD.

Heme Bound Amylin: Spectroscopic Characterization, Reactivity, and Relevance to Type 2 Diabetes

Deposition of human amylin or islet amyloid polypeptide (hIAPP) within the β-cells of the pancreatic islet of Langerhans is implicated in the etiology of type 2 diabetes mellitus (T2Dm). Accumulating evidences suggest that increased body iron stores, iron overload, and, in particular, higher heme-iron intake is significantly associated with higher risk of Type 2 diabetes mellitus (T2Dm) (PloS One2012, 7, e41641). Some key pathological features of T2Dm, like iron dyshomeostasis, iron accumulation, mitochondrial dysfunction, and oxidative stress are very similar to the cytopathologies of Alzheimer's disease, which have been invoked to be due to heme complexation with amyloid β peptides. The similar etiology and pathogenic features in both Alzheimer's disease (AD) and T2Dm indicate a common underlying mechanism, with heme playing an important role. In this study we show that hIAPP can bind heme. His18 residue of hIAPP binds heme under physiological conditions and results in an axial high-spin active site with a trans-axial water derived ligand. Arg11 is a key residue that is also essential for heme binding. Heme(Fe(2+))-hIAPP complexes are prone to produce partially reduced oxygen species (PROS). The His18 residue identified in this study is absent in rats which do not show T2Dm, implicating the significance of this residue as well as heme in the pathology of T2Dm.

Heme Iron Intake and Risk of Stroke

Intake of iron, especially heme iron, has been associated with several diseases. However, epidemiological studies of heme iron and nonheme iron intake in relation to risk of stroke are lacking. The aim of this study was to examine the associations between heme iron and nonheme iron intake and stroke incidence in men. The population-based prospective Cohort of Swedish Men included 38 859 men, aged 45 to 79 years, who had no history of stroke, coronary heart disease, or cancer at baseline. Hazard ratios and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards regression models. During an 11.7 years follow-up, 3097 incident cases of stroke, including 2482 cerebral infarctions and 450 intracerebral hemorrhages, were registered. The hazard ratios of total stroke and cerebral infarction for the highest compared with the lowest quintiles of heme iron intake were 1.16 (95% CI, 1.03-1.31; P trend=0.037) and 1.15 (95% CI, 1.00-1.31; P trend=0.089), respectively. The incidence rates of total stroke per 10 000 person-years were 72.6 in the lowest quintile and 84.4 in the highest. The association was confined to men with body mass index <25 kg/m(2), the hazard ratios were 1.40 (95% CI, 1.17-1.68; P trend<0.001) for total stroke and 1.38 (95% CI, 1.13-1.70; P trend=0.001) for cerebral infarction; no association was observed among overweight and obese men. There was no association between nonheme iron intake and risk of total stroke and stroke types. Findings from this prospective study indicate that a high heme iron intake, particularly in normal weight individuals, may increase the risk of stroke.

Abstract 2632: Genetic variants of iron-dependent metabolism genes and risk of upper gastrointestinal cancers

Abstract Objectives: Both iron overload and iron deficiency cause oxidative stress and DNA damage, which increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. In animal models, iron overload causes forestomach tumors, and in epidemiologic studies, high heme iron intake is associated with some upper GI cancers. Hemochromatosis, which results in excessive iron absorption in the GI tract, is also associated with GI cancer. The mechanism of increased cancer risk may involve the impairment of iron-dependent metabolic functions related to genome protection and maintenance. Genetic variants of genes with iron-dependent metabolic functions may confer differential GI cancer risk. Therefore, we comprehensively examined the genetic variants of these genes and risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a high-risk population in China. Methods: We genotyped 249 tag single nucleotide polymorphisms (SNPs) in 23 genes with known iron-dependent metabolic function in 1027 ESCC cases and 752 GCA cases plus 1452 controls from two epidemiologic studies in a high-risk region in China. For all genes as a single pathway and each gene individually, we calculated summary p-values using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: In pathway-based tests, the iron pathway was not associated with either ESCC (p=0.320) or GCA (p=0.550). However, in gene-based tests, HMOX2 (heme oxygenase 2, p=0.018) and BMP2 (bone morphogenetic protein 2, p=0.032) were associated with ESCC risk, and IREB2 (iron-responsive element binding protein 2, p=0.033) was associated with GCA risk. In SNP-based tests, RS235756 (OR=0.78, CI=0.66-0.91) and RS910141 (OR=0.76, CI=0.63-0.93) tagged to BMP2 (linkage disequilibrium of pairwise r2=0.55) were associated with ESCC risk. RS6500609 (OR=1.30, CI=1.08-1.57) tagged to HMOX2 was also associated with ESCC risk. RS12910090 (OR=0.83, CI=0.72-0.94) and RS2568500 (OR=0.83, CI=0.73-0.95) tagged to IREB2 (r2=0.90) were associated with GCA risk. RS11630228 (OR=1.21, CI=1.06-1.38) also tagged to IREB2 (r2&amp;lt;0.38 with two previous SNPs) was associated with GCA risk. Conclusions: The potential link between iron status and differential UGI cancer risk may involve the impairment of iron-dependent metabolic functions, which leads to oxidative stress and DNA damage. The association of SNPs in HMOX2 and BMP2 with ESCC risk and IREB2 with GCA risk suggests that genetic variants of genes with iron-dependent metabolic functions may differentially confer risk of upper GI cancer. Further research is warranted to replicate these findings and elucidate the functional effects of the SNPs in the context of upper GI carcinogenesis to better understand the role of iron overload or iron deficiency in cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2632. doi:1538-7445.AM2012-2632

Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study

Even though recent studies suggest that a high intake of heme iron is associated with several types of cancer, epidemiological studies in relation to gastric cancer (GC) are lacking. Our previous results show a positive association between red and processed meat and non cardia gastric cancer, especially in Helicobacter pylori infected subjects. The aim of the study is to investigate the association between heme iron intake and GC risk in the European prospective investigation into cancer and nutrition (EURGAST-EPIC). Dietary intake was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat intake, derived from the literature. Antibodies of H. pylori infection and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control study within the cohort. The study included 481,419 individuals and 444 incident cases of GC that occurred during an average of 8.7 years of followup. We observed a statistically significant association between heme iron intake and GC risk (HR 1.13 95% CI: 1.01-1.26 for a doubling of intake) adjusted by sex, age, BMI, education level, tobacco smoking and energy intake. The positive association between heme iron and the risk of GC was statistically significant in subjects with plasma vitamin C <39 mmol/l only (log2 HR 1.54 95% CI (1.01-2.35). We found a positive association between heme iron intake and gastric cancer risk.

Body Iron Stores and Dietary Iron Intake in Relation to Diabetes in Adults in North China

To evaluate the association between body iron stores, dietary iron intake, and risk of diabetes in northern China. The data of a cross-sectional household survey in 2002 in Liaoning Province in northern China was used. The final sample in our study contained 2,997 subjects aged >or=18 years. Fasting plasma glucose and serum ferritin were measured. Dietary information was collected by 3-day food records. Serum ferritin was associated with elevated risk of diabetes even adjusted for age, sex, nondietary factors, and dietary factors. No association among total iron intake, nonheme iron intake, and diabetes risk was found. However, higher heme iron intake was significantly associated with elevated risk of diabetes after adjusting for known factors. In Chinese, associations among higher serum ferritin level, higher heme iron intake, and elevated risk of diabetes were found.

Iron Intake and the Risk of Type 2 Diabetes in Women

Epidemiological studies suggest that high body iron stores are associated with insulin resistance and type 2 diabetes. The aim of this study was to evaluate the association between dietary intake of iron and the risk of type 2 diabetes. We conducted a prospective cohort study within the Nurses' Health Study. We followed 85,031 healthy women aged 34-59 years from 1980 to 2000. Dietary data were collected every 4 years, and data on medical history and lifestyle factors were updated biennially. During the 20 years of follow-up, we documented 4,599 incident cases of type 2 diabetes. We found no association between total, dietary, supplemental, or nonheme iron and the risk of type 2 diabetes. However, heme iron intake (derived from animal products) was positively associated with risk; relative risks (RRs) across increasing quintiles of cumulative intake were 1.00, 1.08 (95% CI 0.97-1.19), 1.20 (1.09-1.33), 1.27 (1.14-1.41), and 1.28 (1.14-1.45) (P(trend) < 0.0001) after controlling for age, BMI, and other nondietary and dietary risk factors. In addition, when we modeled heme iron in seven categories, the multivariate RR comparing women who consumed > or =2.25 mg/day and those with intake <0.75 mg/day was 1.52 (1.22-1.88). The association between heme iron and the risk of diabetes was significant in both overweight and lean women. This large cohort study suggests that higher heme iron intake is associated with a significantly increased risk of type 2 diabetes.

HFE genotypes and dietary heme iron: No evidence of strong gene–nutrient interaction on serum ferritin concentrations in middle-aged women

Background and aim Hereditary hemochromatosis (HH) is a disorder characterized by inappropriately high intestinal iron absorption. In populations of Northern European descent, HH is most commonly caused by mutations (C282Y/H63D) in the HFE gene. Methods and results We investigated the effects of dietary heme iron intake and HFE mutations on serum ferritin concentrations in a population-based random sample of 1611 women aged >50 years using analysis of covariance (ANCOVA). Higher heme iron intake was associated with significantly higher serum ferritin concentrations ( P trend < 0.001). Also, women with the compound or C282Y homozygous genotype had significantly higher serum ferritin concentrations (geometric mean 115.2 μg/L (95% CI 81.4–162.9 μg/L) than women carrying normal alleles (geometric mean 76.6 μg/L (95% CI 72.5–80.9 μg/L). We observed the highest serum ferritin concentrations among postmenopausal women who are compound heterozygous or C282Y homozygous, and who consume relatively high amounts of heme iron (geometric mean 183.9 μg/L (95% CI 97.2–347.8 μg/L). Conclusions Even when there are currently no clinical signs, women with the compound or C282Y homozygous genotype may still be at risk for developing iron overload sometime after menopause.

Interaction Among Heme Iron, Zinc, and Supplemental Vitamin C Intake on the Risk of Lung Cancer: Iowa Women's Health Study

: Redox-active iron present at physiological levels in the pulmonary epithelial lining fluid may lead to damage of lung tissue under some circumstances. For example, factors that increase potential for oxidative stress, such as higher intake of heme iron or higher intake of vitamin C in the presence of high intake of iron, might increase the risk of lung cancer, whereas higher intake of the antioxidant zinc might decrease that risk. During 16 yr of follow-up, 34,708 postmenopausal women, aged 55-69 yr at baseline who completed a food-frequency questionnaire for the Iowa Women's Health Study, were followed for 700 incident lung cancers. When subjects were stratified by intake of vitamin C supplements, among women who took vitamin C supplements of >500 mg/day, after adjusting for age, total energy intake, cigarette smoking, alcohol consumption, and dietary zinc or dietary heme iron intake, relative risks across categories of dietary heme iron intake were 1.0, 0.85, 0.93, 1.32, 1.70, and 3.77 (P for trend = 0.05; P for interaction = 0.08), whereas corresponding figures for dietary zinc intake were 1.0, 1.15, 0.71, 0.84, 0.61, and 0.11 (P for trend = 0.12; P for interaction = 0.04). The strength of the associations of heme iron and zinc intake with lung cancer appeared to be stronger with increasing levels of vitamin C supplement intake. Our results suggest that high dietary heme iron intake may increase the risk of lung cancer, whereas high dietary zinc may decrease the risk of lung cancer among postmenopausal women who consume high-dose vitamin C supplements. This finding may be of particular importance to smokers, for whom vitamin C supplementation is a common recommendation.