The role of genetics in the development of diabetes

The role of genetics in the development of diabetes: complex review

Diabetes, a global epidemic that affects hundreds of millions of people around the world, is a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia. The pathogenesis of diabetes is multifactorial, due to the complex interaction of genetic factors, environmental factors and lifestyle. Although the influence of environmental factors, such as diet, physical activity and obesity, is undeniable, genetic predisposition plays a decisive role in determining a person’s susceptibility to the development of diabetes. This comprehensive review is deepened into the complex role of genetics in pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D), exploring specific genes, genetic options and hereditary models participating in each type. We will also consider the latest achievements in the field of genetic studies of diabetes, including wide -hectic associative studies (GWAS), the next generation (NGS) and genes editing, as well as their potential effect on the prevention, diagnosis and treatment of diabetes.

Type 1 diabetes genetics (T1D)

Type 1 diabetes, previously known as insulin-dependent diabetes or juvenile diabetes, is an autoimmune disease characterized by the selective destruction of insulin-producing pancreatic beta cells by the immune system. This autoimmune attack leads to absolute insulin insufficiency, which requires lifelong replacement therapy with insulin therapy for survival. Although the exact causes of the T1D remain not fully understandable, it is obvious that the genetic predisposition plays an important role in its development.

The main histocompatibility complex (MHC) and T1D

The most powerful genetic association with T1D falls on the region of the main histocompatibility complex (MHC) on the short shoulder of the chromosome 6 (6P21.3). The MHC region, also known as the region of human leukocyte antigen (HLA), contains genes encoding proteins that play a decisive role in the presentation of antigen to immune cells. Alleli HLA class II, especially HLA-DR and HLA-DQ, were closely related to the risk of developing T1D.

• HLA-DR3 и HLA-DR4: These class II HLA alleles were most very connected with T1D. Individuals carrying alleles HLA-DR3 or HLA-DR4 have an increased risk of developing the disease compared to individuals who do not carry these alleles. The DR3/DR4 genotype demonstrates the highest risk.

• HLA-DQ: HLA-DQ genes also play an important role in susceptibility to T1D. Specific dq alleles, such as dqb10302, are associated with increased risk, while others, such as DQB10602, have a protective effect. DQB1 gene product0302, for example, contains the remainder of asparaginic acid in position 57, which can affect the binding of peptide and presentation of antigen, increasing the susceptibility to autoimmune. On the contrary, dqb10602 contains the remainder of Alanin in position 57, which is believed to protect against T1D.

Genes that are different from HLA, and T1D

While the HLA region is responsible for about 40-50% of the T1D genetic risk, numerous genes other than HLA were also identified as contributing to susceptibility to the disease. These genes are involved in various immune processes, including the regulation of immune cells, the signaling of cytokines and apoptosis.

• INS (Insulin): The insulin gene is located on a short shoulder of the chromosome 11 (11p15.5) and contains a variable number of tandem repetitions (VNTR) in its promoter region. Learn VNTR alleles are associated with an increased risk of developing T1D. It is believed that these alleles affect the expression of insulin in Timus, where T cells are selected. The reduced expression of insulin in Timus can lead to inadequate removal of autoreactive T cells directed against beta cells, which leads to autoimmune destruction.

• CTLA4 (cytotoxic T-lymphocytic antigen 4): CTLA4 is an inhibitor expressed on T cells, which plays a decisive role in regulating the immune response. Polymorphisms in the CTLA4 gene were associated with an increased risk of developing T1D. It is believed that these polymorphisms affect the CTLA4 function, which leads to a violation of the regulation of the immune response and increased susceptibility to autoimmune.

• PTPN22 (protein-tyroshosphatase non -ception type 22): PTPN22 encodes cytoplasmic tyrosinphosphatase, which regulates the alarm of T cells. The R620W PTPN22 allele is a risk factor for the development of T1D and various other autoimmune diseases. This allele functionally increases the activity of PTPN22, which leads to a violation of the alarm of T cells and impaired immune tolerance.

• IL2RA (Interleukin 2 alpha receptor): IL2RA encodes the alpha-to-the-clod of the Interleukin 2 (IL-2) receptor, which plays a decisive role in the development and function of regulatory T cells (TREGS). Polymorphisms in the IL2RA gene were associated with the risk of developing T1D. It is believed that these polymorphisms affect the expression or function of IL-2RA, which leads to a violation of the TREGS function and increased susceptibility to autoimmune.

• IFIH1 (Interferon, induced by spiral DNA, Helica 1): IFIH1 encodes the cytoplasmic sensor of RNA, which plays a role in an innate immune response to viral infections. Polymorphisms in the IFIH1 gene were associated with the risk of developing T1D. The mechanism with which the IFIH1 contributes to the T1D is not fully studied, but it is believed that it includes a violation of the regulation of congenital immune ways and increased susceptibility to viral infections that can cause autoimmune.

• ERBB3 (receptor 3 families of an epidermal growth factor): ERBB3 encodes a tyrosinkinase receptor, which plays a role in the growth and development of cells. Polymorphisms in the ERBB3 gene were associated with the risk of developing T1D. The mechanism with which ERBB3 contributes to the T1D is not fully studied, but, as it is believed, it includes a violation of the regulation of survival and the function of beta cells.

Inheritance and genetic counseling at T1D

T1D is not a classic Mendeleeval disease, but rather a complex disease that is inherited polygenically. This means that several genes, as well as environmental factors, contribute to susceptibility to the disease. The risk of developing T1D in humans depends on its genetic background, as well as on the effects of environmental factors, such as viral infections and diet.

The risk of developing T1D in relatives of the first degree (parents, brothers and sisters and children) of the patient T1D is higher than in the general population. The risk of developing T1D in a brother or sister of a patient T1D is approximately 5-10%, while the risk for offspring is approximately 2-5%. The risk of developing T1D in single -eating twins is much higher than in multi -tier twins, which emphasizes the important role of genetic factors in the etiology of the disease.

Genetic counseling can be useful for families with T1D history. Genetic counseling can provide people with information about the risk of developing T1Ds, available variants of genetic testing and risk management possibilities. Genetic testing can be used to identify individuals at risk of developing T1D, but it is important to note that genetic testing cannot predict who will develop the disease.

Type 2 diabetes genetics (T2D)

Type 2 diabetes, the most common form of diabetes, is characterized by resistance to insulin and progressive insufficiency of beta cells. Insulin resistance means that the body cells do not properly respond to insulin, a hormone that regulates the level of glucose in the blood. As a result, the pancreas compensates for this, producing more insulin. However, over time, the pancreas cannot produce enough insulin to maintain the normal level of glucose in the blood, which leads to hyperglycemia.

The pathogenesis of T2D is complicated and includes the complex interaction of genetic factors, environmental factors and lifestyle. Obesity, lack of physical activity and malnutrition are well -established T2D risk factors. However, a genetic predisposition also plays an important role in determining a person’s susceptibility to the development of the disease.

Wide -heated associative studies (GWAS) and T2D

Wide -heated associative studies (GWAS) revealed hundreds of genetic options associated with the risk of developing T2D. GWAS is a powerful tool that allows researchers to scan the whole genome to identify general genetic options (single -okleotide polymorphisms or SNP), which are associated with a specific sign or disease. GWAS has revealed numerous shoes of genes related to the risk of developing T2D, many of which are involved in the functions of beta cells, insulin secretion and insulin sensitivity.

• TCF7L2 (transcription factor 7-like 2): TCF7L2 encodes a transcription factor, which plays a role in the alarm of WNT and the development of cells. The options in the TCF7L2 gene were most strongly and consistently associated with the risk of developing T2D in many GWAS. It is believed that these options affect the function of beta cells and insulin secretion.

• PPARG (receptor activated by proliferator with a gamma peroxis): Pparg encodes a nuclear receptor that plays a role in the differentiation of adipocytes and glucose metabolism. The PRO12Ala option in the PPARG gene was associated with increased sensitivity to insulin and reduced risk of T2D development. Tiazolidindins (TZD), a class of drugs used for T2D treatment act by activating PPARG.

• KCNJ11 (potassium channel, inside straightening subfamily j, member 11): KCNJ11 encodes the Kir6.2 subunit Kitp, which plays a decisive role in the secretion of insulin. The options in the KCNJ11 gene were associated with the risk of developing T2D. Sulfonelmochevin, a class of drugs used to treat T2D, acts by blocking the KATP channel in beta cells, stimulating insulin secretion.

• IRS1 (insulin receptor substrate 1): IRS1 encodes substrate protein, which plays a role in transmitting insulin signals. Options in the IRS1 gene were associated with the risk of developing T2D. It is believed that these options affect the transmission of insulin signals, which leads to insulin resistance.

• CDKal1 (cyclin-dependent kinase 5 of the regulatory subunit associated with CDK51): CDKal1 encodes a protein that plays a role in the function of beta cells and insulin secretion. Options in the CDKal1 gene were associated with the risk of developing T2D.

• MTNR1B (melatonin receptor 1b): MTNR1b encodes melatonin receptor, which plays a role in regulating insulin secretion. Options in the MTNR1B gene were associated with the risk of developing T2D. It is believed that these options affect the secretion of insulin, especially the early secretion of insulin after eating.

• FTO (a gene associated with fat mass and obesity): FTO encodes an enzyme deemlamlase of nucleic acids, which plays a role in the regulation of energy and metabolism. Options in the FTO GEC were associated with obesity and increased risk of developing T2D. Although the main mechanism with which FTO affects the risk of developing T2D is not fully studied, it is believed that it includes the effect on body weight and the distribution of fat.

Rare genes and t2D options

While GWAS is mainly focused on identifying general genetic options associated with T2D, rare genes can also play an important role in susceptibility to the disease, especially in monogenic forms of diabetes. Monogenic diabetes, also known as the diabetes of young adults (Mody), is a group of diabetes formed by mutations in one gene. Mody is usually characterized by the beginning of diabetes at a young age (usually up to 25 years) and an autosomal dominant type of inheritance.

Several genes were identified as causing MODY, including:

• Gck (glucokinase): GCK encodes glucokinase, an enzyme that plays a decisive role in glucose metabolism and insulin secretion. Mutations in the GCK gene lead to MODY type 2, which is characterized by soft, non -progressive hyperglycemia. Individuals with GCK mutations usually do not require insulin treatment.

• HNF1A (hepatocytic nuclear factor 1 alpha): HNF1A encodes a transcription factor that plays a role in the development of the liver and the function of beta cells. Mutations in the HNF1A gene lead to MODY type 3, which is characterized by progressive insufficiency of beta cells and requires insulin treatment.

• HNF4A (hepatocytic nuclear factor 4 alpha): HNF4A encodes a transcription factor that plays a role in the development of the liver and the functions of beta cells. Mutations in the HNF4A gene lead to MODY type 1, which is characterized by the progressive insufficiency of beta cells and requires insulin treatment.

• PDX1 (factor 1 of the pancreas and duodenum): PDX1 encodes a transcription factor that plays a role in the development and function of the pancreas. Mutations in the PDX1 gene lead to MODY type 4, which is characterized by insufficiency of beta cells and requires insulin treatment.

• HNF1b (hepatocytic nuclear factor 1 beta): HNF1b encodes a transcription factor that plays a role in the development of kidneys, pancreas and other organs. Mutations in the HNF1B gene are associated with a wide range of manifestations, including diabetes, kidney diseases and genital abnormalities.

• Neurod1 (neurogenic differential factor 1): Neurod1 encodes a transcription factor that plays a role in the development of the nervous system and pancreas. Mutations in the Neurod1 gene lead to a type 6, which is characterized by the lack of beta cells and requires insulin treatment.

Epigenetics and T2D

Epigenetics refers to changes in genes expression, which are not associated with changes in the DNA sequence. Epigenetic mechanisms, such as DNA methylation, modification of histones and RNA that do not encode, can affect the expression of genes and play a role in the development of T2D. Environmental factors, such as diet, physical activity and the effects of toxins, can cause epigenetic changes that can be inherited from generation to generation.

Several studies have shown that epigenetic changes, such as DNA methylation in specific genes, are associated with the risk of developing T2D. For example, DNA methylation in the promoter region of the PDX1 gene was associated with a decrease in PDX1 expression and a violation of the beta cell function. Perinatal malnutrition and the effect of environmental toxins were also associated with epigenetic changes that could increase the risk of developing T2D in further life.

Inheritance and genetic counseling at T2D

T2D is not a classic Mendeleeval disease, but rather a complex disease that is inherited by polygenically. This means that several genes, as well as environmental factors, contribute to susceptibility to the disease. The risk of developing T2D in humans depends on its genetic background, as well as on the influence of environmental factors, such as obesity, lack of physical activity and malnutrition.

The risk of developing T2D in relatives of the first degree (parents, brothers and sisters and children) of the patient T2D is higher than in the general population. The risk of developing T2D in a brother or sister of a patient T2D is approximately 30-40%, while the risk for offspring is approximately 15-20%. The risk of developing T2D in single -eating twins is much higher than in multi -tier twins, which emphasizes the important role of genetic factors in the etiology of the disease.

Genetic counseling can be useful for families with the history of T2D, especially in cases with the early beginning or atypical features. Genetic counseling can provide people with information about the risk of developing T2Ds, available variants of genetic testing and risk management possibilities. Genetic testing can be used to identify individuals at risk of developing T2D, but it is important to note that genetic testing cannot predict who will develop the disease. Genetic testing can also be useful for identifying individuals with monogenic forms of diabetes, such as Mody that may require a different approach to treatment.

Recent achievements in the field of genetic studies of diabetes

The area of ​​genetic studies of diabetes is rapidly developing due to the development of new technologies and analytical approaches. Some of the latest achievements in the field of genetic studies of diabetes include:

• The next generation (NGS): NGS is a powerful technology that allows researchers to secure large areas of the genome quickly and economically. NGS is used to identify rare genes that can be associated with the risk of diabetes.

• Genes editing: Genes editing is a technology that allows researchers to accurately edit genes in cells and organisms. CRISPR-CAS9 genes editing technology has become a powerful tool for studying the function of genes associated with diabetes and developing new methods of treating the disease.

• Multidimensional genomic: The multidimensional genomics includes the integration of various types of genomic data, such as genetic, epigenetic and transcriptive data, to obtain a more complete understanding of the complex genetic foundations of diabetes.

• Personalized medicine: Personalized medicine is an approach to treatment, which is adapted to the individual characteristics of each person, including his genetic background. Genetic testing can be used to determine people who may be more likely to respond to specific treatment of diabetes or who are more likely to develop complications of the disease.

Clinical meaning of diabetes genetics

Genetic studies of diabetes had a significant impact on our understanding of the pathogenesis of the disease and the development of new prophylaxis and treatment strategies. Some of the clinical consequences of diabetes genetics include:

• Risk assessment: Genetic testing can be used to assess the risk of diabetes in individuals, especially in those who have a family history of the disease. This information can be used to manage interference in a lifestyle, such as diet and physical exercises, to reduce the risk of developing the disease.

• Diagnosis: Genetic testing can be used to diagnose monogenic forms of diabetes, such as Mody, which may require a different approach to treatment than T1D or T2D.

• Forecasting: Genetic testing can be used to predict a response to treatment in people with diabetes. For example, genetic options in the PPARG gene can predict a response to thiazolidinders (TZD).

• Drug development: Genetic studies have identified new goals for the development of diabetes. For example, the TCF7L2 gene was identified as a potential goal for the development of new drugs that improve the function of beta cells and insulin secretion.

Calls and future directions

Although significant progress has been achieved in the field of genetic studies of diabetes, several problems and future areas for research remained.

• Identification of rare genes: While GWAS has successfully identified numerous general genetic options associated with the risk of diabetes, rare genes can also play an important role in susceptibility to the disease. NGS and other genomic sequencing technologies are used to identify rare genes, which can be associated with the risk of diabetes.

• Understanding the interactions of the gene-environment: The pathogenesis of diabetes is complex and includes the complex interaction of genetic factors and environmental factors. Further research is necessary for understanding how genes and the environment interact with each other to influence the risk of diabetes.

• Development of targeted treatment methods: Genetic studies have identified new goals for the development of diabetes. Further studies are necessary for the development of targeted treatment methods, which are aimed at specific genetic pathways involved in the pathogenesis of the disease.

• Expansion of diversity in genetic research: Most genetic studies of diabetes were carried out in populations of European origin. Further studies are necessary to expand diversity in genetic research and to identify genetic options that are specific to different ethnic groups.

Conclusion (not included in accordance with the instructions)

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Summary (not included in accordance with the instructions)

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