Genome-Wide Association Study Identifies Genetic Loci Associated with Iron Deficiency

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10−7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0×10−9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification

10 patients, 10 years - Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A&nbsp;prospective, multicenter case series.

Background and aims: Glut1 Deficiency (Glut1D) is caused by impaired glucose transport into brain. The resulting epileptic encephalopathy and movement disorders can be treated effectively by high-fat carbohydrate-restricted ketogenic diet therapies (KDT) mimicking fasting and providing ketones as an alternative cerebral fuel. Recently 6-24 months follow-ups of epileptic patients reported elevated blood lipids and intima thickening of the carotid artery raising concerns about potential cardiovascular risks by KDT. To clarify potential cardiovascular risks we performed a prospective 10 year follow up of 10 Glut1D patients.Methods: Between August 2001 and January 2016 we enrolled Glut1D patients on KDT at two hospitals in Germany in this prospective, multicenter case series. The minimal follow up was 10 years. Standard deviation scores (SDS) of body mass index (BMI), total cholesterol (TC), HDL-/LDL cholesterol, and triglycerides (TG) before initiation of KDT were compared with respective values at 6 months, 2, 5 years, and 10 years after initiation. After 10 years on KDT cardiovascular risk, assessed by BMI, carotid intima-media thickness (CIMT) measurement, and blood pressure, was compared to a healthy reference population (n = 550).Results: Baseline and 10 year follow-up investigations were available for 10 individuals with Glut1D on KDT. After two years on KDT BMI increased significantly, while total cholesterol, HDL-cholesterol, and LDL-cholesterol decreased. Within 3-5 years on KDT these differences disappeared, and after 10 years blood lipid parameters reflected the situation at initiation of KDT. Prior to KDT one child had dyslipidaemia, but no child after 10 years on KDT. No significant differences were observed with respect to BMI SDS (p = 0.26), CIMT (p = 0.63) or systolic and diastolic blood pressure (SDS p = 0.11 and p = 037, respectively) in Glut1D children treated with KDT for at least 10 years compared to healthy controls.Conclusions: In contrast to previous short-term reports on adverse effects of KDT, 10-year follow-up did not identify cardiovascular risks of dietary treatment for Glut1D. (C) 2017 The Authors. Published by Elsevier Ltd

Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively.

Contains fulltext : 48360.pdf (publisher's version ) (Closed access)BACKGROUND: GLUT1 deficiency syndrome is caused by impaired glucose transport into the brain resulting in an epileptic encephalopathy, developmental delay, and a complex motor disorder. A ketogenic diet provides an alternative fuel to the brain and effectively restores brain energy metabolism. METHODS: Fifteen children with GLUT1 deficiency syndrome were enrolled prospectively for a 2.0 - 5.5-year follow-up of the effectiveness of a 3 : 1 LCT ketogenic diet. Eight patients enrolled were described previously, seven patients were novel. RESULTS: Four novel heterozygous GLUT1 mutations were identified. 10/15 patients remained seizure-free on the ketogenic diet in monotherapy. In 2/15 patients seizures recurred after 2(1/2) years despite adequate ketosis, but were controlled by add-on ethosuximide. In one patient seizures were reduced without complete seizure control. No serious adverse effects occurred and parental satisfaction with the diet was good. 2/15 patients discontinued the diet. CONCLUSION: GLUT1 deficiency syndrome represents a complex childhood encephalopathy that can be treated effectively by means of a ketogenic diet. The response to the diet did not correlate to clinical, biochemical, or genetic features of the disease. In contrast to previous reports, our results indicate that epilepsy is not always completely controlled by a ketogenic diet and can recur in a subset of patients

Association Between Celiac Disease and Iron Deficiency in Caucasians, but not Non-Caucasians

Background &amp; AimsCeliac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease.METHODSWe analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin &gt;100 mg/L in men and &gt;50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency.RESULTSCeliac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 × 10−6). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7–212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype.CONCLUSIONSCeliac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians—even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease

A genome-wide linkage scan for iron phenotype quantitative trait loci: The HEIRS family study

Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) =2.08, p =0.001) and of UIBC (LOD =9.52), TS (LOD =4.78), and SF (LOD =2.75) to the chromosome 6p region containing HFE (each p \u3c 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD =2.63, p =0.0007) and of UIBC to chromosome 5q (LOD =2.12, p =0.002) and to chromosome 17q (LOD =2.19, p =0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC. © 2007 The Authors Journal compilation © 2007 Blackwell Munksgaard