HFE Variants Research Articles

Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants.

The aims of this study were to describe hepcidin levels and to assess their associations with iron status and the main variants in the HFE gene in healthy and full-term newborns during the first year of life, as a longitudinal study conducted on 140 infants. Anthropometric and biochemical parameters, hepcidin, hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), mean corpuscular volume (MCV), and C-reactive protein (CRP), were assessed in 6- and 12-month-olds. Infants were genotyped for the three main HFE variants: C282Y, H63D, and S65C. Hepcidin levels increased from 6 to 12months of age (43.7 ± 1.5 to 52.0 ± 1.5ng/mL; p < 0.001), showing higher levels in infants with better iron status compared to those with iron deficiency (ID) (44.8 ± 1.5 vs 37.9 ± 1.3ng/mL, p < 0.018, and 54.3 ± 1.5 vs 44.0 ± 1.4ng/mL, p < 0.038, in 6- and 12-month-olds, respectively). In multivariate linear regression models, iron status was found to be associated with hepcidin levels in infants with wild-type HFE gene (p = 0.046 and p = 0.048 in 6- and 12-month-olds, respectively). However, this association was not found in HFE-alteration-carrying infants. Hepcidin levels increased in healthy infants during the first year of life and were positively associated with iron levels only in infants with wild-type HFE gene, a situation that requires further investigation.

Wheatgrass Extract (Mugineic Acid): An Inexpensive and Effective Iron Chelator in Patients with Myelodysyplastic Syndromes

Background: Patients with red blood cell (RBC) transfusion-dependent myelodysplastic syndromes (MDS) and congenital anemias are at risk of transfusional hemosiderosis and organ injury from reactive iron species. Available iron chelating drugs in the US are either inconvenient for administration (parenteral deferoxamine) or are costly (oral deferasirox or deferiprone - median cost for these drugs exceeds $13,000-$18,000/month, Master S et al Blood 2016; 128:4858). Additionally, available chelators frequently have adverse effects including gastrointestinal (GI) upset or renal insufficiency. Wheatgrass, a food supplement prepared from the cotyledons of the Triticum aestivum Common Wheat plant, is sold either as a freeze-dried powder or as a juice extracted from the fresh leaves of the plant. Recently wheatgrass was found to contain high concentrations of the hexedentate iron chelator mugineic acid, a phytosiderophore that has comparable efficacy to deferasirox (ICL670) in a murine model of iron overload, and which may be a clinically meaningful iron chelator (Das et al J Biochem 2016; 160:163, Mukhopadhyay S et al JCO 2009; 15S:7012). Methods: Twelve patients with transfusion-dependent MDS (n=11) or congenital dyserythropoietic anemia (n=1) self-administered wheatgrass that they either grew themselves in potting soil or in an agricultural setting (n=3), procured from a juice bar (n=7), or obtained in powder form from a nutritional supplement store (n=2). Three patients also had known HFE variants. Seven patients had previously taken deferasirox and 2 patients had also received deferoxamine, but either did not tolerate these drugs or did not achieve adequate chelation. For patients using wheatgrass in the juice form, approximately 30 mL of juice was obtained from the leaves and stems of ~7 day-old wheatgrass. Serum ferritin was monitored over a period of at least 3 months. Serial hepatic T2* MRI was performed in 2 patients, one of whom also continued to take deferasirox. Results: The serum ferritin of patients at baseline was 2370 ng/mL (range, 1553-6089 ng/mL). The median decrement in serum ferritin in patients taking wheatgrass was 834 ng/mL (range of reduction, 251 to 1774 ng/mL). 3 patients reported worsening in GI upset or diarrhea but only 1 patient discontinued wheatgrass due to these effects; other adverse events were not observed. Two patients who grew their own wheatgrass noted mold outbreaks in the culture and switched to wheatgrass obtained from a juice bar. 1 patient noted a reduction in transfusion needs (of uncertain connection to wheatgrass administration), and the hepatic iron concentration measured by MRI decreased in both patients who were assessed radiographically. Conclusion: Mugineic acid in wheatgrass has iron chelating activity in patients with transfusion-associated iron overload. The annual cost of daily wheatgrass supplement from an urban juice bar (~$1500) is approximately 10% of the monthly cost of deferasirox or deferiprone in the US and less than 1% of the annual cost. Formal trials of wheatgrass or of purified mugineic acid in iron-overloaded patients with MDS or congenital anemias are indicated. Disclosures Steensma: H3 Biosciences: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Equity Ownership; Onconova: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.

Wpływ białka HFE na metabolizm żelaza.

Hereditary hemochromatosis type 1 is an autosomal recessive disorder caused by HFE gene mutations, which is an iron homeostasis metabolism controlling co-factor. Adults with male predomination present with clinical symptoms derived by iron overload in organs. The phenotype expression is individual with an influence of individual and environmental factors. Despite the fact that HFE variants are widespread, its impact still remains unknown. The article reviews the literature considering the role of HFE gene mutations regarding its impact in children.

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

Different distribution of the common HFE variants between western and eastern Spanish populations evidences an independent haplotype gene flow

IntroductionHereditary hemochromatosis is a disease responsible for excess blood iron. The hemochromatosis gene has two predominant variants, H63D and C282Y single nucleotide polymorphisms. Our study aims to analyze the diagnostic utility of genotyping the 63 and 282 loci, and examine the geographic distribution of these mutations in Spain. Methods and materialsGenotyping was performed on 94 healthy control individuals and 324 patients suspected of hereditary hemochromatosis, and also biochemical test to 313 individuals in the patients group. ResultsThe comparison of allelic frequencies between East and West of Spain, as well as other countries located at a similar longitude, evidenced a west-east distribution gradient of the C282Y allele. In addition, heterogeneous distribution of the H63D mutation in Spain was observed. Patients who carried the 282YY genotype showed significantly higher biochemical parameters (ferritin>300μg/L, Fe>180μg/L, IST>60%, UIBC>355μg/L and CTFH>370μg/dL), which confirmed the correlation between the mutated homozygous genotype and the associated hemochromatosis phenotype. ConclusionOur results strengthen the importance of executing genetic tests to increase the efficiency of hereditary hemochromatosis diagnosis, which reveal an interesting variability among geographical regions.

The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda.

Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT.

Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis.

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc.

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.

Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.

Genome-wide association study of serum iron phenotypes in premenopausal women of European descent

A genome-wide association study was performed on 1130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10−14) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p=4×10−7), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10−8) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10−6). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women.

Identification of Polymorphic Gnpat As a Risk Factor for Porphyria Cutanea Tarda

Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y) that increases iron absorption by reducing hepcidin expression is a risk factor for PCT. These observations suggest that PCT is an iron dependent disease and that factors that affect iron homeostasis influence the risk of developing the PCT. Recently, a polymorphic variant (D519G) of GNPAT was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype [McLaren CE, et al. Hepatology Aug;62(2):429-39 2015]. Available evidence suggests that like HFE C282Y, GNPAT D519G increases iron absorption by reducing expression of hepcidin. Therefore, we investigated the prevalence GNPAT D519G in patients with PCT. The study population consisted of 247 patients with PCT. High-resolution DNA melting analysis and Taqman SNP assays were used to identify HFE (C282Y) and GNPAT (D519G) allelic variants, respectively and mutations in uroporphyrinogen decarboxylase (UROD) were identified by nucleotide sequencing. Patients with mutant UROD were categorized as familial PCT (F-PCT) (n=87, 36.0%) and those with wild-type UROD were categorized as sporadic PCT (S-PCT) (n=155, 64.0%). GNPAT D519G was significantly enriched in the patient population (prevalence 22.1%, p<0.001) compared to the general population (prevalence 13.6%) as was HFE C282Y (prevalence of 19.2% in the study population compared to 1.5% in the general population, p<0.001). The relative risk of GNPAT D519G was significantly increased in patients with F-PCT compared to those with S-PCT (odds ratio 1.81, CI 1.06-3.08) whereas the relative risk of HFE C282Y in the F-PCT was lower than in the S-PCT population (odds ratio 0.82, CI 0.46-1.47). Together, these observations suggest that GNPAT D519G, is more likely to require a cofactor (e. g., mutant UROD) to produce PCT whereas HFE C282Y functions as an independent PCT risk factor. This difference may be a consequence of the relative potency of GNPAT D519G (weak) and HFE C282Y (strong) with respect to effects on iron homeostasis. Our studies have identified a new risk factor (polymorphic GNPAT) for PCT that adds support for the involvement of aberrant iron metabolism in the pathobiology of PCT. DisclosuresNo relevant conflicts of interest to declare.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

IntroductionOlfactory dysfunction has been identified as an early warning sign for Alzheimer's disease, Parkinson's disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone. MethodsOlfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE). ResultsThe average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD=5.7) years. Mean tibia lead was 16.3 (SD=12.0)μg/g bone, mean patella lead was 22.4 (SD=14.4)μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD=7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15μg/g tibia lead: β=−1.57; 95% CI: −2.93, −0.22; p=0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE β=2.26; 95% CI: 0.09, 4.43; p=0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15μg/g tibia lead: β=−1.25; 95% CI: −2.64, 0.14; p=0.08) while the HFE term dropped 15% (β=1.91; 95% CI: −0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene–lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n=149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15μg/g tibia lead β=−1.39; 95% CI: −3.00, 0.22; p=0.09). ConclusionCumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene status may also affect olfactory function.

Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption

BackgroundHFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation.ResultsUsing data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35–54.71 %) but rare in Europeans (5.98 %) and Africans (4.35 %). The T allele at tag SNP rs9366637 (C/T) captured 95.8 % of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22 % higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption.ConclusionsOur results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0223-y) contains supplementary material, which is available to authorized users.

Association of genetic variants with response to iron supplements in pregnancy.

The incidence of iron deficiency anemia in pregnancy is high in India where iron supplementation is a regular practice. The response to oral iron is influenced by several factors such as age, body mass index, gravida, socioeconomic status, food, vitamin deficiency and compliance to supplements. The major challenge is to understand the various modulators of iron status in this high-risk group so that we can improve the diagnosis and the management of these patients. The current study was designed to evaluate the iron status during pregnancy and to identify factors which might be influencing their response to oral iron. We investigated a total of 181 pregnant women with anemia (Hb<11g/dl) and evaluated the impact of probable factors on anemia and their iron status. Assessment of the response was based on hemoglobin and serum ferritin or transferrin saturation level after 8 and 20weeks of iron supplementation. Socioeconomic, clinical, hematological, biochemical and genetic factors were all evaluated. Molecular analysis revealed that HFE variant allele (G) (rs1799945) was significantly associated with an adequate response to iron supplementation. We identified five subjects with a sustained poor response, and targeted re-sequencing of eleven iron-related genes was performed in them. We have identified seven novel variants in them, and in silico analysis suggested that these variants may have an iron regulatory effect. Taken together, our findings underscore the association of genetic variants with response to supplements in pregnancy, and they can be extended to other diseases where anemia and iron deficiency coexist.

Hereditary Hemochromatosis in an Adult Due to H63D Mutation: The Value of Estimating Iron Deposition By MRI T2* and Dissociation Between Serum Ferritin Concentration and Hepatic Iron Overload

Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia.The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia.A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts.The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: < 336 μg/l), serum iron: 37 μmol/l ( normal values <28.6μmol/l), fasting transferrin saturation: 64% (normal < 50%).A random glucose 6.5 and 6.4 mmol/L (normal values 5.5mmol/L ), A1C of 5,4 %, normal creatinine and electrolytes, alanine aminotransferase (ALT) of 66 U/l (normal < 40U/l), mild elevation of bilirubin 39 umol/l (normal <24umol/l), normal U&E Hepatitis B and C antibodies were negative.OGTT revealed impaired glucose tolerance. Thyroid function, morning serum cortisol, LH and FSH and serum total testosterone concentrations were in the normal range.A diagnosis of polycythemia vera was excluded on the basis of WHO Criteria 2008. The polymerase chain restriction assay was negative for the common mutation (C282Y) but positive for H63 D mutation.Family screening confirmed HH in his brother (homozygous), whereas his mother, two brothers and the sister were carriers (heterozygous). His four offspring were carriers. This suggested an autosomal recessive mode of inheritance.Conventional MRI study showed a normal liver size with diffuse fatty changes and focal areas of fatty sparing with some evidence of iron deposition. Whereas, T2-star (T2*) sequences showed a diffuse and significant decrease in liver signal intensity. A LIC liver concentration of 27 mg Fe/g dry wt was found (normalvalues:< 2 mg Fe/g dry wt; severe iron overload: ≥15 mg Fe/g dry wt).No significant iron deposition in the spleen, heart or pancreas was observed.At the age of 41 years the patient complained of tremors in both hands and arms while sitting or standing still (resting tremor) that improved with hands movements. A brain MRI revealed iron deposition in the basal ganglion. It was concluded that basal ganglionicn iron deposition mediated the neurological decline.Currently, the transferrin saturation and serum ferritin levels are within normal.Discussion:This is the first case of HH secondary to H63 D among an Arab family and the first reported case of Parkinsonism tremors secondary to this mutation.The H63D HFE variant is less frequently associated with HH, but its role in the neurodegenerative diseases has received a great attention.An accurate evaluation of iron overload is necessary to establish the diagnosis of HH and to guide iron chelation in HH by determination of liver iron concentration (LIC) by means of T2* MRI.Although serum ferritin concentration was only mildly increased a significant siderosis in the liver was detected by MRI T2* technique occurred. Liver siderosis was associated with mild impairment of liver function (increased serum ALT and bilirubin ).Conclusion:Our data further confirm that serum ferritin levels are not an accurate measure of total body iron stores in HH. Iron deposition in the liver and basal ganglion occurred despite mild elevation of ferritin. changes in basal ganglion may present by parkinsonian like tremors in these patients Use,T2* MRI should be encouraged in patients with HH for better evaluation of Iron overload and avoidance of Complications since serum ferritin can be misleading in these conditions. DisclosuresYassin:Qatar National research fund: Patents & Royalties, Research Funding. Aldewik:Qatar Ntional Research Fund: Patents & Royalties, Research Funding.

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83–2.35), which increased to 2.96 (95% CI=1.29–6.80) in the presence of a particular TFRC genotype for rs3817672 (Pinteraction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05–6.12; Pinteraction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52–2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29–3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.

Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study

BackgroundGenome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained...

Meta-analyses of HFE variants in coronary heart disease

AimHFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. Methods and resultsWe conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. ResultsMeta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01–1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case–control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. ConclusionsOur meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese.

Modification by hemochromatosis gene polymorphisms of the association between traffic-related air pollution and cognition in older men: a cohort study

BackgroundPrevious studies found effect modification of associations between traffic-related air pollution and cardiovascular outcomes by polymorphisms in the hemochromatosis gene (HFE). As traffic-related air pollution may impact cognition through effects on cardiovascular health or through mechanisms which may also influence cardiovascular outcomes, we hypothesized that HFE polymorphisms would also modify a previously observed association between traffic-related air pollution exposure and cognition in older men.MethodsWe considered data from 628 participants of the VA Normative Aging Study. We estimated long term exposure to black carbon (BC), a marker of traffic related air pollution, using a spatio-temporal land use regression model. We assessed cognition using the Mini-Mental State Examination (MMSE), a test of global function, and performance on a battery of other tests, covering a wide range of domains. We investigated whether variants of HFE C282Y and H63D modified the association between BC and having a low MMSE score using logistic models with generalized estimating equations and multiplicative interaction terms. Similarly, we assessed whether HFE variants modified the association between BC and performance on the cognitive battery using linear mixed models with multiplicative interaction terms.ResultsOur results suggest modification of the BC-cognition association by HFE C282Y, although the test of interaction did not achieve statistical significance. In multivariable-adjusted models, participants who lacked a HFE C282Y variant (CC) exhibited an adverse association between BC and total cognition z-score (beta for a doubling in BC concentration: -0.061, 95% CI: -0.115, -0.007), while we did not observe an association in participants with at least one variant genotype (CY or YY) (beta for a doubling in BC concentration: 0.073, 95% CI: -0.081, 0.228; p-value for interaction: 0.11). The pattern of association was similar for analyses considering performance on the Mini-Mental State Examination. There was little evidence to support effect modification of the BC-cognition association by the HFE H63D genotype.ConclusionsOur data suggest that older adults who lack an HFE C282Y variant may be more susceptible to an adverse effect of traffic-related air pollution exposure on cognition. This finding and the proposed biological mechanism require confirmation.

Diagnostic utility of HFE variants in Spanish patients: Association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia

Two single nucleotide polymorphisms (SNPs) in the Human Hemochromatosis (HFE) gene, C282Y and H63D, are the major variants associated to altered iron status and it is well known that these mutations are in linkage disequilibrium with certain Human Leukocyte Antigen (HLA)-A alleles. In addition, the C282Y SNP has been previously suggested to confer susceptibility to acute lymphoblastic leukemia (ALL). We have aimed to assess the diagnosis utility of these polymorphisms in a population of Spanish subjects with suspicion of hereditary iron overload and to evaluate the effect of their associations with HLA-A alleles on the susceptibility to ALL. Both the 63DD [OR=4.31 (1.7–11.2)] and 282YY (p for trend=0.02) genotypes were more frequently found among subjects with suspicion of iron overload than among controls. 282YY carriers displayed significantly higher transferrin saturation index (TSI) values (p<0.001) as well as serum iron (p=0.01) and ferritin (p=0.01) levels. In addition, transferrin levels were lower in these subjects (p=0.01). Likewise, patients who were carriers of the compound heterozygous diplotype (282CY/63HD) showed significantly higher TSI and serum iron and ferritin concentrations. The H63D SNP did not significantly affect the analytical parameters measured. All 282YY carriers and 69.2% of compound heterozygotes showed an altered biochemical index. The frequencies of the HFE SNPs in ALL pediatric patients were lower than those found in controls, whereas the HLA-A*24 allele was significantly overrepresented in the patients group [OR=3.76 (1.9–7.3)]. No HFE-HLA-A associations were found to modulate the ALL risk. These results suggest that it may be useful to test for both HFE H63D and C282Y polymorphisms in patients with iron overload, as opposed to just genotyping for the C282Y SNP, which is customary in some healthcare centers. These HFE variants and their associations with HLA-A alleles were not observed to be relevant for the susceptibility to ALL in our population.