The associations of polymorphisms of TSH receptor and thyroid hormone receptor genes with L-thyroxine treatment in hypothyroid patients

A paper pointing out the possibility that one particular genetic polymorphism appears to result in the need for a higher dose of levothyroxine than otherwise.

SNP rs939348 was on my 23andme analysis.

HORMONES 2014, 13(3):389-397

DOI: 10.14310/horm.2002.1488

Research Paper

The associations of polymorphisms of TSH receptor and thyroid hormone receptor genes with L-thyroxine treatment in hypothyroid patients

Sayer I. Al-Azzam,1 Karem H. Alzoubi,1 Omar Khabour,2 Ola Al-Azzeh1

1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology; 2Department of Medical Laboratory Sciences, Faculty Applied Medical Sciences, Jordan University of Science and Technology; Irbid, Jordan


OBJECTIVE: To investigate the possible association between response to levothyroxine (L-T4) doses in hypothyroid patients and variation in thyroid stimulating hormone receptor (TSHR) gene and thyroid hormone receptor (THRα) gene.

DESIGN: This cross-sectional correlation study included 228 patients with primary hypothyroidism who were using L-T4 replacement therapy. Thyroid function test was performed using standard techniques. Genotyping of rs939348 of the THRα gene, and rs2268458 and rs2239610 of the TSHR gene was performed using the polymerase chain reaction-based restriction fragment length polymorphism assay (PCR-RFLP). Patient history of illness, medication and compliance data were collected using the patients’ medical files.

RESULTS: The THRα rs939348 polymorphism was associated with L-T4 replacement doses in hypothyroid patients and in central obesity. No significant correlation was detected between the examined SNPs to TSHR and L-T4 doses or the different clinical and biochemical parameters. Finally, L-T4 dose was associated with lower BMI, waist circumference and TSH, and higher free T4 (fT4) among hypothyroid patients.

CONCLUSIONS: Whereas the two tested TSHR polymorphisms were not associated with the dose of T4, the THRα rs939348 polymorphism was associated with L-T4 dose and central obesity among hypothyroid patients. T4 dose was also associated with multiple beneficial effects among hypothyroid patients.


Hypothyroidism, Levothyroxine, Jordan, Thyroid hormone, TSH receptor



In this study, we hypothesized that there might be an association between polymorphisms in the THR and TSHR genes and the replacement doses of L-T4. The role of thyroid hormones receptors (THRα and THRβ) in mediating the functions of the thyroid gland is well documented.16,17 In addition, thyroid gland functions are regulated by the action of TSH, which exerts its role through binding to TSHR.21-23 Many studies have investigated the role of mutations in genes encoding TSHR and THR in the development of different thyroid diseases.5,24-26

This study showed no association between TSHR SNPs rs2268458 and rs2239610, and the replacement doses of L-T4. Additionally, the current study found no correlation between these polymorphisms and the studied biochemical and clinical markers including thyroid function tests (TSH, fT3 and fT4). A previous study by Gu LQ and colleagues found that rs2239610 CC genotype was associated with higher serum concentrations of fT4.28 Another study by Louwerens et al. detected a modest effect for TSHR-Asp727Glu polymorphism on fatigue in patients with differentiated thyroid carcinoma.5

In our study, we found a positive correlation between the THRα rs939348 polymorphism and both L-T4 replacement doses and central obesity. On the other hand, our study showed lack of association between THRα rs939348 and elevated blood pressure, yet an association was shown in Goumidi L and colleagues’ study among US populations.20 This could be due to the small number of hypertensive patients included in the present study (n = 53).

In the current study, a positive association that was found between central obesity and THRα rs939348 polymorphism suggests that this SNP could have a role in development of metabolic syndrome, which is known to be a risk factor for coronary heart disease.15,37 The rs939348 SNP was studied in addition to a wide range of other SNPs by Arnaud-Lopez L. and colleagues and a positive correlation was detected among its variations and TSH serum level.24

Factors other than genetic variations were shown to be associated with the dose of L-T4. For example, high L-T4 dose was associated with lower BMI, lower body weight and TSH and higher levels of fT4. These results are in agreement with the previous knowledge about L-T4 treatment among hypothyroid patients38 and generally support our genetic findings.

The clinical consequence of this study is the proposal that hypothyroidism patients with rs939348 TT genotypes might need to be identified prior to treatments, as they are expected to require higher doses of L-T4. More studies are required in other populations to generalize the present finding.

In conclusion, hypothyroid patients with rs939348 TT genotype had more central obesity and those who carry the T allele needed higher replacement doses of L-T4. We therefore suggest that this SNP might have a role in control of both hypothyroidism, of metabolic syndrome and its associated risk and of resistance to L-T4 therapy.

1 Reply

  • Yes but, No but...

    Surely, the sensible conclusion would be that patients with higher BMI and waist measurements on L-T4 should be given higher doses, as a way to protect them from metabolic syndrome and all its evils? Presumably not all those patients complaining of weight gain despite 'normal' Ts aren't genetic deviants? Well, unless they have a genetic 'defect' that makes them unable to utilise L-T4 properly.

    Its one of those studies that really doesn't address the central issue.

    The Tayside study shows that suppressed TSH (from T3 medication) doesn't cause any great harm, so surely, the way to go is to increase dosage until the patient feels well, or goes OTT on T3/T4 without any increase in wellbeing.

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