Association between MTHFR Gene Polymorphisms (C677T, A1298C) and Subclinical Hypothyroidism Susceptibility

Research Article

J Endocr Disord. 2020; 6(1): 1034.

Association between MTHFR Gene Polymorphisms (C677T, A1298C) and Subclinical Hypothyroidism Susceptibility

Kvaratskhelia E1*, Kvaratskhelia T1, Surmava S1, Kvintradze M1, Asatiani K2, Abzianidze E1

¹Department of Molecular and Medical Genetics, Tbilisi State Medical University, Georgia

²National Institute of Endocrinology, Georgia

*Corresponding author: Kvaratskhelia E, Department of Molecular and Medical Genetics, Tbilisi State Medical University, Georgia

Received: May 08, 2020; Accepted: June 03, 2020; Published: June 10, 2020

Abstract

Introduction: Methylenetetrahydrofolate Reductase (MTHFR) is a key enzyme for f olate and homocysteine metabolism. Two common polymorphisms of MTHFR gene (C677T and A1298C) reduce the MTHFR activity by various degrees. This study is aimed to investigate the association between MTHFR gene polymorphisms and Subclinical Hypothyroidism (SCH) in the Georgian population.

Materials and Methods: 87 patients with SCH and 87 age-matched healthy controls were enrolled in this study. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in the patient and control groups were evaluated using the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method.

Results: A significant difference was observed in frequency of both 677CT and 677TT genotypes between SCH and control groups (for CT 40% vs. 17%; OR = 3.89, 95% CI: 1.90 – 7.96, p<0.001; For TT 12% vs. 2%; OR = 8.33 95% CI: 1.74–39.88, p<0.001). Similarly, T allele frequency was significantly higher in the SCH group compared to the healthy controls (36.1% vs. 10.9%; OR = 3.84, 95% CI: 2.16 – 6.81, p<0.001). No difference in genotypic and allelic distributions was observed between SCH and control groups for the MTHFR A1298G polymorphism.

Conclusions: The data indicate that the MTHFR C677T polymorphism, but not A1298G, is a significant risk factor for the subclinical hypothyroidism in Georgian population.

Keywords: Subclinical Hypothyroidism; MTHFR; SNPs

Introduction

Hypothyroidism is a clinical condition in which the thyroid gland does not produce enough thyroid hormones, most often due to thyroid failure (primary hypothyroidism) [1]. Overt hypothyroidism is diagnosed when serum Thyroxine levels (T4) are lower than the reference range. In overt hypothyroidism due to thyroid dysfunction, Thyroid-Stimulating Hormone (TSH) levels are appropriately elevated. The population reference range of TSH is around 0.4–4.5 mIU/L and most patients with overt hypothyroidism have TSH above 10 mIU/L [2]. Subclinical Hypothyroidism (SCH) is defined as mild elevation of thyroid-stimulating hormone levels when serum thyroid hormone levels are within normal reference range [3]. Approximately 90% of patients with subclinical hypothyroidism have serum thyrotropin levels lower than 10mU/L [4].

Homocysteine (Hcy) is a sulfur-containing amino acid naturally found in human blood. Increased circulating levels of Hcy or Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for cardiovascular disease [5,6]. Additionally, decreased folate and increased plasma Hcy levels are associated with a variety of common conditions such as neural tube defects [7], strokes [8], Alzheimer’s disease [9], Parkinson’s disease [10], certain types of cancer [11], osteoporosis [12], insulin resistance [13], Gastrointestinal disorders [14], Down’s syndrome [15], and cleft palate [16]. Plasma Hcy concentration was reported to be elevated in hypothyroidism and subclinical hypothyroidism patients [17-20].

Methylenetetrahydrofolate Reductase (MTHFR) is an enzyme that plays a central role in folate and Hcy metabolism by catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulatory form of folate which is utilized in Hcy remethylation to methionine [21]. Also, Hcy can be considered as an intermediate in the S-Adenosyl Methionine (SAM) cycle. SAM is a universal methyl-group donor for methylation of a wide variety of biological substrates [22].

The gene for 5,10-methylenetetrahydrofolate reductase or the MTHFR gene is located on the short (p) arm of chromosome 1 (1p36.22) [23,24]. The MTHFR gene has been identified to possess two common variants, rs1801133 (C677T) and rs1801131(A1298C). The C to T transition at nucleotide 677 in exon 4 of the MTHFR gene results in an Alanine (A) to Valine (V) substitution (A222V). Individuals with homozygous variant 677TT and heterozygote 677CT genotypes have only about 30% and 65%, respectively, of in vitro enzyme activity as compared to those with 677CC wild type. The frequency of C677T polymorphism varies in different populations [25-27]. Another common SNP is A to C change in 1298 position (A1298C) at exon 7 causing glutamate to alanine substitution on the 429th position, resulting the decreased MTHFR activity, which is more pronounced in the homozygous than heterozygous state. Neither homozygosity nor heterozygosity is associated with higher plasma Hcy or a lower plasma folate concentration [28].

To our knowledge, few studies have addressed the association between MTHFR genotypes and the risk of thyroid disorders [29-31].

In this study we investigated associations between MTHFR variants and mild thyroid failure defined as a Subclinical Hypothyroidism (SCH) which have not been previously studied.

Materials and Methods

Subjects

A total 174 individuals were enrolled in this study (87 patients with SCH and 87 age-matched healthy controls). Patients were recruited in this study from the National Institute of Endocrinology and medical center “Medimedi” (Tbilisi, Georgia) between 2016 and 2019. The study protocol was approved by the Ethics Committee of Tbilisi State Medical University. Written informed consent was obtained from all patients and controls. Detailed information on medical history was obtained from all study subjects. Patients inclusion criteria provided in a Table 1; Patients with known history of autoimmune thyroiditis were excluded. Controls (n = 87) which showed no evidence of thyroid disorder were recruited. Baseline demographic data and a medical history were obtained from each control subject. Clinical and demographic characteristics of subjects are given in Table 2.