Comment on 'Real-World Evidence of the Effectiveness and Safety of Biosynthetic Semaglutide in Type 2 Diabetes: A Multicentre Study From Pakistan'.

Autoimmune thyroid diseases are a group of chronic conditions affecting the thyroid gland, of which the most common is autoimmune hypothyroidism; that is, hypothyroidism resulting from Hashimoto’s thyroiditis. Hashimoto’s thyroiditis is a common disease, affecting ~3% of US and European populations. In Hashimoto’s thyroiditis, the immune system attacks the thyroid gland, eventually resulting in decreased production of thyroid hormones (hypothyroidism). The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are essential for normal growth and differentiation of cells and tissues, regulation of energy metabolism and development and physiological function of virtually all human tissues. Therefore, patients with hypothyroid Hashimoto’s thyroiditis require lifelong T4 replacement therapy (levothyroxine). However, this treatment does not treat the underlying immune dysregulation that is actively destroying the thyroid. Hashimoto’s thyroiditis has been associated with a wide range of adverse health outcomes, including a higher risk of several comorbidities such as obesity, type 2 diabetes, infertility and pregnancy complications, depression, cognitive dysfunction and cardiovascular diseases, as well as an increased risk of overall mortality. The pathophysiology of Hashimoto’s thyroiditis involves initial damage to thyroid cells followed by subsequent auto-antigen release and presentation. These autoreactive immune cells attack the thyroid, resulting in the activation of immune responses (both cellular and humoral), including cytokine production and cytotoxicity. In the majority of Hashimoto’s thyroiditis cases, antibodies against thyroperoxidase (TPOAb) are detectable in blood. Hashimoto’s thyroiditis development is influenced by a combination of genetic and environmental factors, including sex, age, socioeconomic status and iodine intake. The prevalence of diagnosed overt hypothyroidism (low T4, high thyroid-stimulating hormone (TSH)) in the general population ranges from 0.2% to 5.3% in Europe and 0.3% to 3.7% in the USA. Prevalence estimates differ owing to the case definition and the population differences between studies. The NHANES III study, based on census data from the USA, determined that the prevalence of hypothyroidism was similar in white and Hispanic individuals (4.6%) but was significantly lower in individuals of African descent (1.7%). Additionally, the prevalence of hypothyroidism, specifically Hashimoto’s thyroiditis, is approximately four times greater in females than males. Twin studies have suggested that genetic factors are major determinants in the development of Hashimoto’s thyroiditis, with an estimated heritability of ~65%. A substantial part of our current understanding of the genetics of Hashimoto’s thyroiditis comes from genome-wide association studies (GWAS). Previous Hashimoto’s thyroiditis GWAS associations implicated thyroid-specific genes and genes involved in general immune response regulation, T cell regulation, cell-mediated destruction and auto-antigen presentation. Although previous GWAS have been productive, their limitations include the use of an overly broad case definition (that is, including non-autoimmune hypothyroidism or other autoimmune thyroid diseases), small sample sizes and focus on single ancestries, predominantly European genetic ancestry. Here, we conducted multi-ancestry and sex-stratified GWAS meta-analyses using a precise definition of cases and disease-free controls in ten multi-ancestry cohorts. Having a comparable number of cases compared to previous large autoimmune thyroid disease GWAS, our results yielded novel associations, demonstrating the importance of having a precise case definition for a highly heterogeneous disease. We conducted a GWAS meta-analysis of Hashimoto’s thyroiditis comprising 48,694 cases and 1,044,134 controls across ten cohorts from Europe, the USA and Japan (Fig. and Supplementary Table ). The individuals included were predominantly but not exclusively similar to European ancestry reference populations (European, 75%; East Asian, 16%; African, 2%; South Asian and Middle Eastern, 1%; admixed or unknown, 6%) (Supplementary Table ). Genetically determined larger non-European ancestry populations include individuals similar to African, East and South Asian reference populations in the UK Biobank and to African and admixed Americans in the ‘’ Research Program. Cases were defined using ICD9/10 codes for autoimmune hypothyroidism and unspecified hypothyroidism, and importantly excluded other thyroid diseases known to cause hypothyroidism or Hashimoto’s thyroiditis, such as post-partum thyroiditis, hyperthyroidism, thyroid cancer and medication-induced hypothyroidism. Individuals without thyroid dysfunction and over the age of 18 years were considered as controls. Details of the case and control definitions are provided in Supplementary Table . In total, 8,148,325 variants were analyzed using METAL after quality control filtering