Relationship Between TMPRSS6 Polymorphisms and Serum Iron Status in the Treatment of Iron Deficiency Anemia in Subclinical Hypothyroidism: A Pilot Study

Year 2025, Volume: 7 Issue: 2, 78 - 84, 21.07.2025

Nurten Bahtiyar , Birsen Aydemir , Deniz Ahmet Cinemre , Güneş Cihan Cinemre , Cengiz Karacaer , Leyla Sevinç Afşar , Fatma Behice Serinkan

https://doi.org/10.38175/phnx.1656193

Abstract

Objective: This study aims to investigate the impact of three SNPs (rs4820268, rs2235321, rs855791) in the TMPRSS6 gene on iron metabolism in patients with subclinical hypothyroidism and iron deficiency anemia (IDA), as well as to evaluate the effects of iron-only and iron-thyroxine combination treatments on individuals with heterozygous and mutant genotypes.
Material and Method: Ninety-five patients with subclinical hypothyroidism and IDA, alongside 30 healthy controls, participated in the study. Participants were grouped as follows: Control (N=30), Hypothyroidism (N=30), Hypothyroidism IDA (N=30), and Hypothyroidism IDA+Thyroxine (N=35). TMPRSS6 rs4820268 and rs855791 polymorphisms were analyzed using TaqMan SNP Genotyping Assays and qPCR, while rs2235321 was genotyped using Allele-Specific PCR (ASPCR). Complete blood count, iron levels, and total iron-binding capacity (TIBC) were measured with an automated analyzer, while ferritin levels were analyzed using immunoassay.
Results: No significant differences were found in the genotype and allele distributions of TMPRSS6 polymorphisms (rs4820268, rs2235321, rs855791) between patients and controls. For rs4820268 and rs855791 heterozygous and mutant genotypes, ferritin levels were lower in the Hypothyroidism and Hypothyroidism IDA groups compared to controls, while TIBC was higher in the Hypothyroidism group. Ferritin was elevated and TIBC decreased in the Hypothyroidism IDA+Thyroxine group compared to Hypothyroidism and Hypothyroidism IDA groups. In terms of the rs2235321 polymorphism, iron and ferritin levels were higher in the Hypothyroidism+IDA+Thyroxine group than in the other hypothyroidism groups, but TIBC was lower.
Conclusion: No significant variation was observed in the genotype and allele frequencies of TMPRSS6 polymorphisms between healthy individuals and those with hypothyroidism. Nevertheless, considering the relationship between hypothyroidism, iron metabolism, and treatment response, particularly in patients receiving combined therapy, treatment-related changes in TIBC and ferritin levels were observed.

Keywords

Subclinical Hypothyroidism , Iron Deficiency Anemia , TMPRSS6 Gene , SNP

Subklinik Hipotiroidizmde Demir Eksikliği Anemisinin Tedavisinde TMPRSS6 Polimorfizmleri ile Serum Demir Durumu Arasındaki İlişki: Pilot Çalışma

Abstract

Amaç: Bu çalışma, TMPRSS6 genindeki üç tek nükleotid polimorfizminin (SNP) (rs4820268, rs2235321, rs855791) subklinik hipotiroidizm ve demir eksikliği anemisi (DEA) olan hastalarda demir metabolizması üzerindeki etkilerini incelemeyi ve heterozigot ve mutant genotiplere sahip bireylerde yalnızca demir ve demir-tiroksin kombinasyon tedavilerinin etkilerini değerlendirmeyi amaçlamaktadır.
Gereç ve Yöntem: Çalışmaya subklinik hipotiroidizm ve DEA tanılı 95 hasta ile 30 sağlıklı kontrol dahil edilmiştir. Katılımcılar şu gruplara ayrılmıştır: Kontrol (N=30), Hipotiroidizm (N=30), Hipotiroidizm+DEA (N=30) ve Hipotiroidizm+DEA+Tiroksin (N=35). TMPRSS6 rs4820268 ve rs855791 polimorfizmleri TaqMan SNP Genotipleme Analizleri ve qPCR ile, rs2235321 polimorfizmi ise Alel-Spesifik PCR (ASPCR) yöntemi ile genotiplendirilmiştir. Tam kan sayımı, demir seviyeleri ve total demir bağlama kapasitesi (TDBK) otomatik analizör ile ölçülürken, ferritin seviyeleri immünoassay yöntemi ile analiz edilmiştir.
Bulgular: TMPRSS6 polimorfizmlerinin (rs4820268, rs2235321, rs855791) genotip ve alel dağılımlarında hasta ve kontrol grupları arasında anlamlı bir fark saptanmamıştır. Rs4820268 ve rs855791 heterozigot ve mutant genotipleri açısından incelendiğinde, Hipotiroidizm ve Hipotiroidizm+DEA gruplarında ferritin seviyeleri kontrol grubuna göre daha düşük, TDBK ise Hipotiroidizm grubunda daha yüksek bulunmuştur. Hipotiroidizm+DEA+Tiroksin grubunda ise ferritin seviyeleri artarken, TDBK düşmüştür. rs2235321 polimorfizmi açısından, Hipotiroidizm+DEA+Tiroksin grubunda demir ve ferritin seviyeleri diğer hipotiroidi gruplarına göre daha yüksekti, ancak TDBK daha düşüktü.
Sonuç: TMPRSS6 polimorfizmlerinin genotip ve alel frekanslarında sağlıklı bireyler ile hipotiroidi hastaları arasında anlamlı bir farklılık gözlenmemiştir. Bununla birlikte, hipotiroidizm, demir metabolizması ve tedavi yanıtı arasındaki ilişki dikkate alındığında, özellikle kombine tedavi alan hastalarda TDBK ve ferritin seviyelerinde tedaviye bağlı değişiklikler gözlemlenmiştir.

Keywords

Subklinik Hipotiroidizm , Demir Eksikliği Anemisi , TMPRSS6 Geni , SNP

References

• Yen PM. Physiological and molecular basis of thyroid hormone action. Physiological reviews 2001; 81: 1097-1142.
• Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. The journal of clinical endocrinology & metabolism 2005; 90: 581-585.
• Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. The Journal of Clinical Endocrinology & Metabolism 2009; 94: 151-156.
• Mehmet E, Aybike K, Ganidagli S, Mustafa K. Characteristics of anemia in subclinical and overt hypothyroid patients. Endocrine journal 2012; 59: 213-220.
• Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Jama 2004; 291: 228-238.
• Cooper DS. Subclinical hypothyroidism. New England Journal of Medicine 2001; 345: 260-265.
• Ganesh SK, Zakai NA, Van Rooij FJ, Soranzo N, Smith AV, Nalls MA, et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nature genetics 2009; 41: 1191-1198.
• Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, Hoggart C, Bayele H, McCarthy MI, Peltonen L. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nature genetics 2009; 41: 1170-1172.
• Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A, Teumer A, et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nature genetics 2009; 41: 1182-1190.
• Pelusi S, Girelli D, Rametta R, Campostrini N, Alfieri C, Traglia M, et al. The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis. BMC nephrology 2013; 14: 1-9.
• Kato A, Tsuji T, Luo J, Sakao Y, Yasuda H, Hishida A. Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. American Journal of Nephrology 2007; 28: 115-121.
• Mohd Atan FNE, Wan Mohd Saman WA, Kamsani YS, Khalid Z, Abdul Rahman A. TMPRSS6 gene polymorphisms associated with iron deficiency anaemia among global population. Egyptian Journal of Medical Human Genetics 2022; 23: 147.
• Shinta D, Asmarinah, Adhiyanto C, Htet MK, Fahmida U. The association of TMPRSS6 gene polymorphism and iron intake with iron status among under-two-year-old children in Lombok, Indonesia. Nutrients 2019; 11: 878.
• Bhatia P, Singh A, Hegde A, Jain R, Bansal D. Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations. British Journal of Haematology 2017; 177: 311-318.
• Piao W, Wang L, Zhang T, Wang Z, Shangguan S, Sun J, Huo J. A single-nucleotide polymorphism in transferrin is associated with soluble transferrin receptor in Chinese adolescents. Asia Pacific Journal of Clinical Nutrition 2017; 26: 1170-1178.
• Athiyarath R, Shaktivel K, Abraham V, Singh D, Bondu JD, Chapla A, et al. Association of genetic variants with response to iron supplements in pregnancy. Genes & Nutrition 2015; 10: 1-8.
• Kamatani Y, Matsuda K, Okada Y, Kubo M, Hosono N, Daigo Y, et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature genetics 2010; 42: 210-215.
• Seiki T, Naito M, Hishida A, Takagi S, Matsunaga T, Sasakabe T, et al Association of genetic polymorphisms with erythrocyte traits: verification of SNPs reported in a previous GWAS in a Japanese population. Gene 2018; 642: 172-177.
• Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nature genetics 2009; 41: 1173-1175.
• Delbini P, Vaja V, Graziadei G, Duca L, Nava I, Refaldi C, Cappellini MD. Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. British journal of haematology 2010; 151: 281-284.
• Batar B, Bavunoglu I, Hacioglu Y, Cengiz M, Mutlu T, Yavuzer S, et al. The role of TMPRSS6 gene variants in iron-related hematological parameters in Turkish patients with iron deficiency anemia. Gene 2018; 673: 201-205.
• Garofalo V, Condorelli RA, Cannarella R, Aversa A, Calogero AE, La Vignera S. Relationship between Iron Deficiency and thyroid function: a systematic review and meta-analysis. Nutrients 2023; 15: 4790.
• Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clinic Proceedings: Elsevier; 2009. p. 65-71.
• Ravanbod M, Asadipooya K, Kalantarhormozi M, Nabipour I, Omrani GR. Treatment of iron-deficiency anemia in patients with subclinical hypothyroidism. The American journal of medicine 2013; 126: 420-424.
• da Conceição RR, Giannocco G, Herai RH, Petroski LP, Pereira BG, de Oliveira KC, et al. Thyroid dysfunction alters gene expression of proteins related to iron homeostasis and metabolomics in male rats. Molecular and Cellular Endocrinology 2024; 579: 112086.
• Gan W, Guan Y, Wu Q, An P, Zhu J, Lu L, et al. Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. The American journal of clinical nutrition 2012; 95: 626-632.
• De Falco L, Tortora R, Imperatore N, Bruno M, Capasso M, Girelli D, et al. The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. American journal of hematology 2018; 93: 383-393.
• Moremi K, Van Rensburg S, Fisher LR, Davis W, Cronje FJ, Dashti JSM, et al. Association of an iron-related TMPRSS6 genetic variant c. 2207 C> T (rs855791) with functional iron deficiency and its effect on multiple sclerosis risk in the South African population. South African Journal of Psychiatry 2013;19(3): 120-121.
• Jallow MW, Campino S, Prentice AM, Cerami C. Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians. Scientific reports 2021; 11: 8075.
• Buerkli S, Pei S-N, Hsiao SC, Lee CT, Zeder C, Zimmermann MB, Moretti D. The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption–a stable iron isotope study in Taiwanese women. haematologica 2020; 106: 2897.
• Elmahdy M, Elhakeem H, Gaber F, Mourad F. TMPRSS6 gene polymorphism and serum hepcidin in iron deficiency anemia. The Egyptian Journal of Hospital Medicine 2018; 73: 7090-7103.
• Poggiali E, Andreozzi F, Nava I, Consonni D, Graziadei G, Cappellini MD. The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment. American Journal of Hematology 2015; 90: 306-309.
• Elli L, Poggiali E, Tomba C, Andreozzi F, Nava I, Bardella MT, et al. Does TMPRSS6 RS855791 polymorphism contribute to iron deficiency in treated celiac disease? Official journal of the American College of Gastroenterology| ACG 2015; 110: 200-202.
• Liu PJ, Yao A, Chen XY, Liu Y, Ma L, Hou YX. Associations of TMPRSS6 polymorphisms with gestational diabetes mellitus in Chinese Han pregnant women: a preliminary cohort study. Biological Trace Element Research 2021; 199: 473-481.