The Effect of Genetic Variation in TMPRSS6 Gene (SNP rs855791) on Oral Iron Absorption: an Iron Stable Isotope Study

Iron deficiency is considered the most common nutritional deficiency worldwide and affects children and women in both non-industrialized as well as industrialized countries. The main regulatory molecule of iron metabolism is hepcidin, a hormone produced in the liver that regulates intestinal iron absorption, placental transport, recycling of iron by macrophages and release from stores. The expression of hepcidin is regulated by many mediators, one of which is Matriptase-2 - a transmembrane protease. Complete loss of function leads to the rare disease iron-refractory iron deficiency anemia (IRIDA). Matriptase-2 is encoded by the gene TMPRSS6 and the single nucleotide polymorphism (SNP) rs855791 causes a non-synonymous substitution (V736A) that reduces the activity of the protease to inhibit hepcidin transcription. Genome wide association studies have identified the TMPRSS6 SNP rs855791 has a strong association with red blood cell and iron parameters in the general population.

The objectives of the study is to measure oral iron absorption and systemic iron utilization into red blood cells (RBC) using oral isotopic labels in subjects homozygotes for common variants of the TMPRSS6 gene with the SNP rs855791 (A736V); AA vs. VV subjects.

The aim is to conduct an iron absorption study in 80 Taiwanese women of reproductive age, non-pregnant, non-anemic, investigating the effect of the genetic variants of the SNP rs855791. The participants will be split in two groups of equal size; wild type AA vs. mutation VV. Iron absorption and systemic utilization will be assessed by two test meals containing stable isotopes of iron.The primary outcome of the trial is the oral iron absorption from a test meal as compared between the two genotypes AA vs. VV. Secondary outcomes are the comparison iron status markers between the two genotypes.

Study Overview

• Status: Completed
• Conditions: Iron Metabolism Disorders
• Intervention / Treatment: Dietary supplement: Testmeal A; Dietary supplement: Testmeal B

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung
    • Kaohsiung City, Kaohsiung, Taiwan, 83301
      • Kaohsiung-Chang Gun Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Subjects homozygotous for the for AA (CC), or VV (TT) variant of the SNP rs855791 of the TMPRSS6 gene.
• Females 20 - 45 years of age (premenopausal status)
• obtained informed consent
• regular menstrual cycle, ± 2 days

Exclusion Criteria:

• Pregnancy or lactating (assessed by pregnancy test and self-declaration, respectively)
• Anemia defined as Hb < 120 g/L
• Plasma ferritin < 30 µg/l, or > 120 µg/l
• C-reactive Protein > 5 mg/l
• Body weight > 65 kg
• Body mass index (BMI) 18.5 - 25
• Diagnosed metabolic or gastrointestinal disorders, eating disorders or food allergy to the ingredients of the test meal.
• Blood transfusion, blood donation or significant blood loss (accident, surgery) over the past 6 months, prior the first study day.
• Subjects who cannot be expected to comply with study protocol (e.g. non-residents).
• Use of long-term medication during the study
• Subjects that will take part of another clinical study at the same time or had within the last 30 days before the first study day
• Intake of mineral/vitamin supplements 2 weeks before the first study day and during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: wild type AA (CC); All participants with the wild type genotype AA (CC) will be allocated to this group	Dietary supplement: Testmeal A; The tesmeal A is is plain rice, with a seaweed sauce, fortified with labelled iron as stable iron isotope as ferrous sulfate; Dietary supplement: Testmeal B; The tesmeal B is plain rice, with a seaweed sauce, fortified with labelled iron as stable iron isotope as ferrous sulfate
Experimental: mutation VV (TT); All participants with the mutation genotype VV (TT) will be allocated to this group	Dietary supplement: Testmeal A; The tesmeal A is is plain rice, with a seaweed sauce, fortified with labelled iron as stable iron isotope as ferrous sulfate; Dietary supplement: Testmeal B; The tesmeal B is plain rice, with a seaweed sauce, fortified with labelled iron as stable iron isotope as ferrous sulfate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in the isotopic ratio of iron in blood at week 2	The change in the isotopic ratio of iron in blood will be measured after the administration of test meal including iron isotopes.	baseline, 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hepcidin	fasting concentrations of plasma hepcidin in AA and VV variants of SNP rs855791	baseline
iron status	The difference in fasting concentrations of serum iron, transferrin saturation, serum ferritin, hemoglobin, erythrocyte volume in AA and VV variants of SNP rs855791	baseline

Collaborators and Investigators

• Sponsor: Swiss Federal Institute of Technology
• Collaborators: Chang Gung Memorial Hospital

Publications and helpful links

General Publications

• Buerkli S, Pei SN, Hsiao SC, Lee CT, Zeder C, Zimmermann MB, Moretti D. The <em>TMPRSS6</em> variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women. Haematologica. 2021 Nov 1;106(11):2897-2905. doi: 10.3324/haematol.2020.264556.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): February 19, 2019
• Study Completion (Actual): February 19, 2019

Study Registration Dates

• First Submitted: October 18, 2017
• First Submitted That Met QC Criteria: October 18, 2017
• First Posted (Actual): October 23, 2017

Study Record Updates

• Last Update Posted (Actual): June 12, 2019
• Last Update Submitted That Met QC Criteria: June 11, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Iron Metabolism Disorders
• Other Study ID Numbers: TMPRSS6_Fe

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No