Links between FTO Gene Variations and Thyroid Hormone Levels in Uyghur Chinese People with Type 2 Diabetes

There are an estimated 463 million patients with diabetes across the world, and this number continues to increase every year. China, which has 116 million patients with diabetes, has the largest population of diabetics in the world [1]. Diabetes can account for up to 20 percent of the national health budget. There are 4.2 million diabetes-associated deaths every year which majorly affect health and socioeconomic conditions of the population. The number of patients with thyroid dysfunction in diabetic patients was significantly higher than that in non-diabetic patients.

There is a common etiological basis for diabetes mellitus and thyroid disease which may be based on genetic defects or susceptibility. A meta-analysis of the global data suggests that about 11% of the patients with diabetes also exhibit some form of thyroid dysfunction [2]. This thyroid dysfunction may be related to genetics, but the mechanism remains unclear.

The fat mass and obesity associated (FTO) gene contains 9 exons and 8 introns, expresses a 410.50 kbp full-length construct, and is located on human chromosome 16. The FTO gene which plays an important role in controlling energy balance has been closely linked to obesity. Many diseases, including obesity [3], T2DM [4], and cancer, have been reported to be associated with the FTO gene. A study has shown [5] that FTO expression correlates with thyroid stimulating hormone (TSH) regulation in overweight/obese children. It suggested that FTO may be a common genetic susceptibility gene for diabetes and thyroid dysfunction which caused the two diseases to overlap. However, there are relatively few reports that discuss the correlation between FTO gene polymorphisms and thyroid hormone abnormalities in T2DM. Therefore, it is of vital importance to early diagnose susceptible genes of thyroid dysfunction in T2DM for diabetic control. In this study, we evaluated the relationship between FTO gene polymorphisms and TSH level in Uyghur patients with diabetes in Xinjiang.

The rapidly increasing prevalence of diabetes that affects blood vessels and nerves and accelerates the occurrence and development of neuropathy, microvascular, and macrovascular complications, as well as premature death, is a global public health problem. Developing countries, especially China, with a population of 116.4 million adults living with diabetes and with the highest prevalence of the disease in the world, are particularly at risk [1].

Studies have shown that the prevalence of thyroid dysfunction including both subclinical and significant hypothyroidism [6] is significantly increased in patients with T2DM [7, 8]. Changes in thyroid hormone levels in T2DM patients are associated with inflammation, cardiovascular events (CVE) [9, 10], peripheral neuropathy [11], diabetic nephropathy (DN) [12], and increased mortality. Even when the TSH levels are reported within the reference range, significant changes in these levels can predict fatal coronary heart disease. Changes in thyroid function are related to blood glucose, blood lipid, and IR in patients with diabetes, which may affect glucose tolerance and metabolic control and may have adverse effects on glucose control in patients with diabetes [13]. Patients with diabetes along with thyroid disease may be at increased risk for cardiovascular and microvascular complications [14]. Diabetes combined with hypothyroidism may damage vascular endothelium by inducing abnormal lipid metabolism, by increasing hypersensitivity, and by aggravating disorders in the blood clotting system. Underproduction of thyroid hormones may also affect the heart and cause myocardial damage, thereby increasing the risk of cardiovascular events. When the heart's ejection volume decreases, it might indirectly result in renal perfusion insufficiency and decreased glomerular filtration rates, thereby increasing the risk of nephropathy in these patients. Therefore, identifying the causes of thyroid dysfunction in T2DM patients and facilitating earlier assessment and effective intervention for these risk factors are the keys to the prevention and control of diabetes and its complications.

Genetic factors may be the basis underlying concurrent or successive onset of diabetes and thyroid disease. T2DM may also be associated with thyroid disease via genetic defects and susceptibility, as well as environmental, emotional, viral, and other factors. Studies have reported that HLA-DR3, CTLA4, and PTPN22 may be common genetic susceptibility genes for diabetes and hypothyroidism. The prevalence of T2DM is different between different populations. There are also differences in the impact on the Han and non-Han groups [15], especially in ethnic minority areas, like Xinjiang. The prevalence of T2DM in the Uyghur population in Xinjiang is significantly higher than that in the Han population as a result of genetic and lifestyle differences, including high BMIs, unhealthy diets, and low physical activity, which means that this group is also at a higher risk for the cardiovascular complications associated with diabetes [16]. Therefore, it is of great significance to select Uyghur population. FTO is located on chromosome 16, and SNPs in this locus have been linked to changes in fat mass and obesity, which are closely associated with type 2 diabetes [17]. Xiao et al. [18] reported that single-nucleotide mutations in rs8050136 and rs9939609 may be related to T2DM and obesity in Uyghur populations (P < 0.05). A study on children found a positive correlation between FTO rs9939609 polymorphism and serum TSH level (β = 0.10Z-score, P = 5.8 × 10⁻³) [5]. Therefore, the influence of FTO gene on the TSH level in T2DM patients in Xinjiang Uygur population was investigated.

In this study, 498 Uyghur T2DM patients were selected, 354 subjects with a TSH < 2.5 mU/L and 144 ones with a TSH ≥ 2.5 mU/L. The relationship between the TSH level and two common SNPs of FTO gene was studied in the subjects. We found that the recessive models of FTO SNPs rs8050136 (P = 0.047) and rs9939609 (P = 0.023) correlated with the TSH level in T2DM Uyghur patients in Xinjiang. The TSH level was also associated with the recessive models of rs8050136 (OR = 2.281, 95% CI = 1.024~5.080, P = 0.044) and rs9939609 (OR = 2.417, 95% CI = 1.257~4.649, P = 0.008) after adjusting for age, sex, and BMI. To our knowledge, this is the first study to demonstrate that variations in the FTO gene correlate with the TSH level in T2DM patients. Variations in FTO have been linked to weight gain and increased energy intake. Several studies on animal models have also shown that variations in FTO influence metabolic rates and energy expenditure [19, 20]. Additionally, FTO has been shown to exert an independent effect on BMI [21]. Genome-Wide Association Studies (GWAS) detected that common SNPs including rs8050136 and rs9939609 in the FTO gene were strongly associated with fat mass and obesity as well as increased risk for T2DM and thyroid disease [22, 23]. Although the association between FTO and obesity and diabetes mellitus has been demonstrated by many studies, the effects of FTO variation on TSH have not been reported. There was only one previous research that examined the relationship between FTO variation and childhood obesity which was conducted in India and found that rs9939609 variation was associated with the TSH level (β = 0.10Z-score, P = 5.8 × 10⁻³) and that mutations at rs8050136, which is in strong linkage disequilibrium with rs9939609 (r² = 0.97), had similar results [5]. FTO is also widely expressed in the pituitary, and variations in FTO have been linked to changes in TSH production within these tissues. Studies have also shown that slight changes in TSH levels are associated with weight gain and increased fat mass [24]. However, the association between FTO alleles and TSH level and its BMI dependence on leptin levels suggests that FTO may be linked to metabolic regulation via the hypothalamic-pituitary-thyroid axis. And it is possible that FTO may play a role in the regulation of metabolism, possibly by regulating the expression of genes in metabolically active tissues [25].

We found that the TSH levels were significantly distinct in different rs8050136 and rs9939609 FTO genotypes. It suggests that genetic factors that influence obesity and T2DM may also play a role in the relationship between FTO and thyroid dysfunction in our study population. The thyroid gland is a critical component of the human endocrine system and continuous hyperglycemia, and the body's constant correction of carbohydrate imbalances has significant effects on thyroid activities [26]. Thyroid hormones stimulate glycogen synthesis and gluconeogenesis in the liver, thus aiding insulin in the regulation of the glucose metabolism. Thyroid hormones can also facilitate liver glucose release which may be regulated by the interactions of glucose transporter 4, insulin, and the hypothalamic [27]. Additionally, thyroid hormones also play an important regulatory role in insulin secretion and clearance. There was a study that had shown [28] that thyroid hormones regulate the behavior of many metabolic pathways associated with resting energy expenditure. TSH levels were positively correlated with BMI in obese patients with normal thyroid function. FTO is associated with fat mass and obesity, while TSH, a crucial hormone regulating energy metabolism, can affect lipid metabolism via a thyroid-independent pathway. However, there was no statistical significance between FTO and other metabolic indices such as the levels of FT3, FT4, FPG, and HbA1c. Two studies reported that the FTO polymorphism rs9939609 was not associated with levels of fasting glucose [29, 30]. The observed results might be due to insufficient statistical power contributed by small sample size. It may also be related to the limitations of the study population we selected.

There was a difference in metabolic indexes between male and female due to hormonal differences. Therefore, we further compared the relationship between different genotypes of rs8050136 and rs9939609 of FTO gene and TSH level and other metabolic indicators in different gender population. The significant association between rs8050136 and rs9939609 genotypes of FTO and TSH levels was found only in male patients. It indicated that the TSH levels related to the genotypes of rs8050136 and rs9939609 of FTO gene in the male population were different from those in the female population. The reason and whether other loci of FTO gene also have same relationship with TSH levels remains to be further studied.

There are some limitations in this study. First, the sample size of our study is relatively small, reducing the ability of genetic association, and there may be insufficient statistical power to detect weak genetic effects, resulting in fluctuations in estimates. Secondly, we assessed the correlation between FTO gene polymorphism and TSH level in diabetic patients, and there may be other unstudied SNPS affecting the TSH level. Third, our study population is the Uyghur, which is a mixed population originated from intermarriage between Caucasians and Mongolians. The Uygur is also a homogenous population which have their own genetic background, language, culture, lifestyle, and dietary habits. This special genetic background affects the strength and direction of genetic association.

We found that the polymorphism of FTO genes rs8050136 and rs9939609 was correlated with the serum TSH level in T2DM patients in Xinjiang Uyghur population. But the difference was only found in male T2DM patients. Patients especially men with diabetes should be screened for related risk factors and implemented intervention of mental health early. Thyroid function should also be regularly investigated based on the complex relationship between diabetes and thyroid dysfunction, as well as the role of FTO gene polymorphism in diabetes and thyroid dysfunction. In addition, it is necessary to further explore the influence of FTO gene polymorphisms rs8050136 and rs9939609 on the TSH level and the possible mechanism in different populations.