High genetic burden of type 2 diabetes can promote the high prevalence of disease: a longitudinal cohort study in Iran

Abstract

Type 2 diabetes (T2D) is emerging as one of the serious public health issues in both developed and developing counties. Here, we surveyed the worldwide population differentiation in T2D-associated variants and assessed the genetic burden of the disease in an ongoing Tehran Cardio-Metabolic Genetic Study (TCGS) cohort represented the Iranian population. We found multiple SNPs that were significantly depleted or enriched in at least one of the five populations of 1,000 Genome Project (African, American, East Asian, European, and South Asian) as well as the Iranian population. Interestingly, TCF7L2, a well-known associated gene with T2D, harbors the highest number of enriched risk alleles almost in all populations except for East Asian, where this gene embraces the largest number of significantly depleted risk alleles. The polygenic risk score (PRS) of the enriched risk alleles was calculated for 1,867 diabetic and 2,855 non-diabetic participants in the TCGS cohort, interestingly demonstrating that the risk of developing T2D was almost two times higher in top PRS quintile compared with the lowest quintile after adjusting for other known risk factors. Type 2 diabetes (T2D) is one of the major life-threatening diseases globally, accounting for 4.2 million deaths worldwide in 2019 as assessed by International Diabetes Federation (IDF) consortium 1,2. According to the IDF report, among 20 countries belongs to the Middle East and North Africa (MENA) region, Iran is ranked third with the highest number of adults (5.4 million) who suffered from diabetes. The prevalence of diabetes in Iran's adult population was 11.4% in 2014, estimating 9.2 million Iranian individuals will have diabetes by the year 2030 3. Type 2 diabetes is a common multifactorial metabolic disease, resulting from both genetic and non-genetic (environmental) factors. The heritability of T2D ranges from 20 to 80%, suggesting the considerable role of genetic factors in the development of T2D; the heritable component of the disease is polygenic where many genes and their variants contribute to an enhanced risk of T2D development 4. The advent of high-throughput genotyping technologies has created a significant breakthrough in understanding the underlying genetic components of complex diseases, including T2D. A large number of common and low-frequency T2D susceptibility variants have been characterized by the genome-wide association studies (GWAS) and the whole-genome sequencing 5-9. Most of these variants are located near genes that were previously known to be involved in diabetes pathogenesis, such as TCF7L2, CDKAL1, CDKN1C, and IGF2BP2 10. Among them, TCF7L2 is responsible for the largest proportion of the T2D-associated variance in the various ethnic groups 11. TCF7L2 encodes a transcription factor played a central role in the Wnt signaling pathway to regulate glucose homeostasis 12. Since not all individuals are equally affected by type 2 diabetes through the unhealthy lifestyle and some are more sensitive than others, the corresponding genetic variants ...

Title: Cohort profile update: Tehran Cardiometabolic Genetic Study, a path toward precision medicine

“…Hence, the high genetic burden of T2D across the Iranian population can contribute to the enhanced prevalence of the disease in this population. In line with this nding, they demonstrated a high hazard of T2D development in the genetically high-risk individuals compared to the genetically low-risk individuals in the model adjusted for age, sex, BMI, and other biochemical T2D risk factors [17].…”

“…Complex segregation analysis revealed that the polygenic model well illustrated the mode of inheritance of T2D among the TLGS participants. As a rst step toward the prediction of T2D development using the person-speci c genetic pro le, Moazzam-Jazi et al in 2020 recognized multiple T2D-associated SNPs signi cantly enriched in the TCGS cohort, compared to the global population [17].…”

Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula

“…Such multiple genetic variants used to build PRS can differ in allele frequencies across populations due to reasons such as natural selection and population expansion leading to adaptation to local environmental factors. A recent study from Iran [30] found multiple T2D-risk SNPs that were significantly depleted or enriched in at least one of the five populations of the 1000 Genome Project (African, American, East Asian, European, and South Asian) as well as the Iranian population. They further found that a PRS built using the enriched risk alleles in Iran was significantly associated with type 2 diabetes incidence in their longitudinal cohort study.…”

The relationship between health-related quality of life and melancholic depressive symptoms is modified by brain insulin receptor gene network

“…The risk of developing depression is influenced by lifestyle choices, environment, and genetics 21 . One approach to evaluate the genetic risk, is to convert genetic data from genome wide association studies (GWASs) into polygenic risk scores (PRSs) 22 .…”