RU2822360C1 - Panel for determining predisposition to increased body mass index, metabolic syndrome and type 2 diabetes mellitus and its use - Google Patents

Abstract

FIELD: medicine; biotechnology.

SUBSTANCE: described is a panel which includes an original set of means for detecting a number of polymorphisms in a patient's sample. Developed is a method for determining a predisposition to developing metabolic disorders based on the use of a unique combination of genotypes of polymorphisms in the genes: pancreatic beta cell function (TCF7L, KCNJ11, PPARG), insulin secretion (TCF7L, CDKAL), associated with index of body weight and obesity (ADIPOQ, FTO, HHEX, MC4R, KCNQ1), high glucose level (SLC30A8, TCF7L, CDKAL), insulin resistance (TCF7L), gestational diabetes (MTNR1B, CDKAL1, HHEX), associated with type 2 diabetes mellitus (TCF7L, KCNJ11, PPARG, CDKAL, ADIPOQ, FTO, HHEX, SLC30A8, MC4R, KCNQ1, MTNR1B). Group can be used to determine the probability of developing functional disorders of metabolism and utilization of glucose, etiologically caused by various polymorphic variants in genes responsible for insulin synthesis, cells susceptibility to insulin, pancreatic beta-cell function, glucose utilization.

EFFECT: high accuracy of determining predisposition to developing glucose metabolic disorders, developing obesity, metabolic syndrome and type 2 diabetes mellitus based on a unique combination of polymorphisms, which allows simultaneous detection of the most common polymorphisms, makes it possible to conduct a more complete diagnostic coverage and not miss possible changes in the genotype; developed panel will also allow preventive correction of patient’s diet type, way of life, selection of effective dosage of medicinal preparations.

2 cl, 1 dwg, 18 tbl, 5 ex

Description

Field of technology to which the invention relates

The group of inventions relates to the field of medicine, namely to endocrinology and genetics, and can be used to determine the likelihood of developing functional disorders of metabolism and glucose utilization, etiologically caused by various polymorphic variants in the genes responsible for insulin synthesis, cell sensitivity to insulin, beta function pancreatic cells, glucose utilization.

The study of hereditary predisposition to multifactorial diseases is extremely important for their diagnosis and therapy. Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, which results from impaired insulin secretion, insulin action, or both. In 1999, the World Health Organization introduced a classification of diabetes based on differences in the mechanisms of development of this disease:

Type 1 diabetes. Develops due to autoimmune or idiopathic destruction of pancreatic β-cells, usually leading to absolute insulin deficiency.

Type 2 diabetes can develop in two ways:

• with predominant insulin resistance and relative insulin deficiency;

• with a predominant defect in insulin secretion with or without insulin resistance.

Other specific types of diabetes (genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas, endocrinopathies, infections, other genetic syndromes combined with diabetes) and gestational diabetes that occurs during pregnancy.

Type 2 diabetes, as well as other multifactorial diseases, is characterized by polygeny, that is, the clinical phenotype is the result of the action of several genetic loci.

Currently, the key links in the pathogenesis of type 2 diabetes are considered to be insulin resistance (IR), impaired insulin secretion, increased glucose production by the liver, as well as hereditary predisposition and lifestyle and nutritional characteristics leading to obesity. The genetic contribution can be divided into two types: genes influencing the development of insulin resistance in peripheral tissues (muscle, liver) and genes associated with impaired development, growth, proliferation and function of pancreatic β-cells (Fig. 1. Factors in the development of diabetes mellitus 2 type).

As our understanding of the pathogenesis of diabetes mellitus increases, the possibilities for applying this knowledge to clinical practice are expanding. This will make it possible to select therapy for treatment of disorders of glucose metabolism based on genetic data, according to all the principles of preventive and predictive medicine.

State of the art

Currently, assessment of glucose metabolism is carried out based on the results of laboratory determination of the level of glucose, insulin, insulin resistance index, glycated hemoglobin, which, in combination with other clinical and laboratory indicators, determine further tactics for patient management. Based on the results of this examination, a conclusion is made about disturbances in glucose metabolism and certain therapy, diet and other therapeutic measures are prescribed. In some cases, disorders of glucose metabolism are caused by genetic disorders in the genes: pancreatic beta cell function (TCF7L, KCNJ11, PPARG), insulin secretion (TCF7L, CDKAL), associated with body mass index and obesity (ADIPOQ, FTO, HHEX, MC4R, KCNQ1), elevated glucose levels (SLC30A8, TCF7L, CDKAL), insulin resistance (TCF7L), gestational diabetes (MTNR1B, CDKAL1, HHEX), associated with type 2 diabetes (TCF7L, KCNJ11, PPARG, CDKAL, ADIPOQ, FTO, HHEX , SLC30A8, MC4R, KCNQ1, MTNR1B).

Some polymorphic gene variants are well known for their association with T2DM, such as PPARA, while others are new and potentially open up new opportunities for further research. In the work [Liuetal. BMC SystemsBiology 2012, 6(Suppl 3):S15] data sets obtained from practically healthy individuals (3004 people) were examined in comparison with a data set obtained from 1999 patients with type 2 diabetes mellitus. As a result, more than 10 significant polymorphisms associated with type 2 diabetes were shown. The associations found can be used to better understand the pathogenesis of type 2 diabetes.

The scientific literature describes various polymorphisms associated with gestational diabetes mellitus (GDM), which can affect one or more functions, in the article [Ortega-Contreras B, Armella A, Appel J, et al (2022) Pathophysiological Role of Genetic Factors Associated With Gestational Diabetes Mellitus. Front. Physiol. 13:769924.doi: 10.3389/fphys.2022.769924] summarizes the main tissues and organs that may be affected by polymorphisms associated with GDM during pregnancy.

Comprehensive phenotyping and genotyping of diabetic patients at the prediabetic stage helps in accurate diagnosis, prevention, prognosis and therapy. Improvements in genomic technologies have led to the identification of several genetic loci associated with T2DM. However, the complete set of T2DM susceptibility gene variants remains inadequate, which requires additional genetic studies among representatives of different ethnic groups [Venkatachalapathy et al, Pharmacogenomics and Personalized Medicine in Type 2 Diabetes Mellitus: Potential Implications for Clinical Practice Pharmacogenomics and Personalized Medicine 2021:14 https:/ /doi.org/10.2147/PGPM.S329787; https://www.snpedia.com/index.php/Rs2241766].

The closest analogue of the diagnostic panel we developed is the diagnostic panel for studying the risks of developing type 2 diabetes, which already exists on the market of medical laboratory services [https://genomed.ru, https://web.archive.org/web/20221129171801/https :/price.genomed.ru/analysis/view?id=618]. The known panel contains tools for determining the following polymorphisms: TCF7L2 - rs7903146, rs12255372, MTNR1B - rs10830963, CDKAL1 - rs7754840, rs7756992, KCNJ11-rs5219. The well-known panel proposed the use of a combination of genotypes of polymorphisms in genes: pancreatic beta cell function (TCF7L, KCNJ11), insulin secretion (TCF7L, CDKAL), associated with body mass index and obesity (FTO), elevated glucose levels (TCF7L, CDKAL) , insulin resistance (TCF7L), gestational diabetes (MTNR1B, CDKAL1), associated with type 2 diabetes (TCF7L, KCNJ11, CDKAL, FTO, MTNR1B).

However, the use of this well-known panel for full diagnostics is limited by the fact that not all regions of genes associated with the development of metabolic syndrome, diabetes and obesity are examined, which does not allow for full diagnostic coverage of possible predispositions to these disorders.

Technical problem The solution to the present invention was the original choice of a combination of genes/polymorphisms/genotypes, suitable for accurately identifying a predisposition to the development of diabetes mellitus, as evidenced by the virtual absence on the market of diagnostic panels of polymorphisms (SNPs) suitable for diagnosing glucose metabolism disorders, the development of obesity, metabolic syndrome and type 2 diabetes.

Disclosure of the invention

The achieved technical result of the present invention is to increase the accuracy of determining the predisposition to the development of glucose metabolism disorders, the development of obesity, metabolic syndrome and type 2 diabetes, based on a unique combination of polymorphisms, which allows one to simultaneously identify the most common polymorphisms, making it possible to conduct more complete diagnostic coverage and not miss possible changes in the genotype. This panel will also allow you to preventively adjust the patient’s diet and lifestyle, and select an effective dosage of medications.

Achievement of the specified technical result is ensured by the proposed panel for determining the predisposition to the development of metabolic disorders based on the use of a unique combination of genotypes of polymorphisms in genes: pancreatic beta cell function (TCF7L, KCNJ11, PPARG), insulin secretion (TCF7L, CDKAL), associated with mass index body and obesity (ADIPOQ, FTO, HHEX, MC4R, KCNQ1), elevated glucose levels (SLC30A8, TCF7L, CDKAL), insulin resistance (TCF7L), gestational diabetes (MTNR1B, CDKAL1, HHEX), associated with type 2 diabetes (TCF7L , KCNJ11, PPARG, CDKAL, ADIPOQ, FTO, HHEX, SLC30A8, MC4R, KCNQ1, MTNR1B).

The created panel includes tools for detecting the following polymorphisms in a patient sample:

PPARG-rs1801282

TCF7L2 - rs7903146, rs12255372, rs7901695

MC4R - rs2229616

ADIPOQ - rs1501299, rs182052, rs2241766

KCNQ1 - rs2237892

FTO - rs17817449, rs1121980, rs1421085

MTNR1B - rs10830963

CDKAL1 - rs7754840, rs7756992, rs9465871,

SLC30A8 - rs13266634

HHEX - rs5015480

KCNJ11- rs5219, rs5215

Achieving the specified technical result is also ensured by the proposed method for determining the predisposition to the development of metabolic disorders based on the use of a unique combination of genotypes of polymorphisms in the genes: pancreatic beta cell function (TCF7L, KCNJ11, PPARG), insulin secretion (TCF7L, CDKAL), associated with body mass index and obesity ( ADIPOQ, FTO, HHEX, MC4R, KCNQ1), elevated glucose levels (SLC30A8, TCF7L, CDKAL), insulin resistance (TCF7L), gestational diabetes (MTNR1B, CDKAL1, HHEX), associated with type 2 diabetes (TCF7L, KCNJ11, PPARG, CDKAL, ADIPOQ, FTO, HHEX, SLC30A8, MC4R, KCNQ1, MTNR1B).

The proposed method is characterized by the use of tools for detecting gene polymorphisms associated with disorders of glucose metabolism in a patient sample, and identifying, based on the results of detection of polymorphisms, the patient’s possible predisposition to the development of obesity, metabolic syndrome and type 2 diabetes.

In this case, the proposed method involves the use of the specified panel of polymorphisms, namely, the method includes identifying the following polymorphisms in a sample from a patient:

1. PPARG - rs1801282

2. TCF7L2 - rs7903146, rs12255372, rs7901695

3. MC4R - rs2229616

4. ADIPOQ - rs1501299, rs182052, rs2241766

5. KCNQ1 - rs2237892

6. FTO - rs17817449, rs1121980, rs1421085

7. MTNR1B - rs10830963

8. CDKAL1 - rs7754840, rs7756992, rs9465871,

9. SLC30A8 - rs13266634

10. HHEX - rs5015480

11. KCNJ11-rs5219, rs5215,

where the presence of at least one of these polymorphisms in a patient indicates a possible predisposition to the development of metabolic disorders.

According to our data, when using an alternative diagnostic panel to diagnose predispositions to the risk of developing T2DM, obesity and insulin resistance, due to insufficient coverage of risk alleles in genes associated with the development of metabolic disorders, it is possible to establish an erroneous conclusion, for example, that there is no risk of DM. When comparing the results of the study of Patient No. 3 using an alternative diagnostic panel, it was revealed that there are no risks of developing glucose metabolism disorders, a low risk of developing diabetes, insulin resistance and obesity, while when analyzing polymorphisms using the proposed panel, polymorphisms were found in the melatonin 1B receptor genes (MTNR1B), perexis proliferator-activated receptor type 2 (PPARG2), in the transmembrane zinc transporter type 8 gene (SLC30A8), and this genotype is associated with an increase in the risk of T2DM and metabolic syndrome by more than 2 times, as evidenced by data from additional laboratory studies ( table 8). To find a combination of polymorphisms suitable for creating a panel that would make it possible to make an unambiguous assumption about the risk of metabolic disorders, a study was conducted taking into account the following factors indicated in Table 1.

Table 1

Genes and polymorphic variants Pathological genotype Possible effects KCNJ11 rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > * (Ter)) Homozygote - T/T, heterozygote C/T T/T - increase in risk of T2DM by 2.5
S/T - increase in risk of T2DM by 1.7 rs5215 NC_000011.10:g.17387083C>T ( V (Val) > I (Ile)) Homozygote - T/T risk factor for developing T2DM Transcription factor 7 gene (TCF7L2)
CYP2C9 rs7903146 NC_000010.11:g.112998590C>T Homozygote - T/T, heterozygote C/T T/T - increase in the risk of T2DM by 3.5 times. Decreased insulin production on an empty stomach and with increased glucose levels.
S/T – increase in the risk of T2DM by 2.1 times. Decreased insulin production on an empty stomach and with increased glucose levels. rs 12255372 NC_000010.11:g.113049143G>T Homozygote - T/T heterozygote G/T G/T - increase in the risk of T2DM by 1.3 times, a higher level with a glucose load.
T/T - increase in the risk of T2DM by 1.5 times, a higher level with a glucose load. rs7901695 NC_000010.11:g.112994329T>C Homozygote - C/C increase in the risk of T2DM by 1.2 times Transmembrane zinc transporter type 8 gene (SLC30A8) rs13266634 NC_000008.11:g.117172544C>T Homozygote S/C heterozygote S/T S/S - 3-fold increase in risk of T2DM, decreased insulin production
S/T - increase in risk of T2DM by 2.5 times Cyclin-dependent kinase type 5 regulatory subunit-associated protein gene (CDKAL1) rs13266634 NC_000008.11:g.117172544C>T Homozygote S/S risk factor for increased BMI and gestational diabetes rs7756992 NC_000006.12:g.20679478A>G Homozygote - G/G heterozygote A/G A/G - risk factor for gestational diabetes, increased glucose levels, worsening insulin secretion
G/G - increase in the risk of T2DM by 1.3 times, a risk factor for gestational diabetes, increased glucose levels, worsening insulin secretion rs9465871 NC_000006.12:g.20717024T>C Homozygote S/C heterozygote S/T S/S - increase in risk of T2DM by 2.2 times
S/T - increase in risk of T2DM by 1.2 times Chromosomal region HHEX-IDE rs5015480 NC_000010.11:g.92705802C>T Homozygote - T/T T/T - risk factor for gestational diabetes Adiponectin protein gene (ADIPOQ) rsrs2241766, NC_000018.10:g.60372043C>T Pathological genotype and associations: there is no pathological variant! S/S and S/T – reducing the risk of type 2 diabetes, metabolic syndrome and BMI rs182052 NC_000003.12:g.186842993G>A Homozygote - A/A A/A – decreased adiponectin levels, a risk factor for polycystic ovary syndrome and increased BMI Gene associated with obesity and increased adipose tissue (FTO) rs1421085 NC_000016.10:g.53767042T>C Homozygote S/C heterozygote S/T C/C – increases the risk of obesity by 1.7 times
S/T - increases the risk of obesity by 1.3 times rs17817449 NC_000016.10:g.53779455T>G Homozygote - G/G heterozygote - G/T G/G – increases the risk of obesity by 1.7 times
G/T - increases the risk of obesity by 1.3 times rs1121980 NC_000016.10:g.53775335G>A Homozygote - A/A heterozygote G/A A/A – increases the risk of obesity by 2.8 times
G/A - increases the risk of obesity by 1.6 times Perexis proliferator-activated receptor γ2 (PPARG2) NC_000003.12:g.12351626 C>T, rs1801282 (Pro12Ala) Homozygote - T/T, heterozygote C/T C/T, T/T - increased risk of T2DM, metabolic syndrome, insulin resistance, increased BMI. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1) rs2237892 NC_000011.10:g.2818521C>T Homozygote - T/T T/T – increased risk of T2DM, gestational diabetes, rapid weight gain in children, worsening response to treatment of T2DM with sulfonylureas Melanocortin 4 receptor gene (MC4R) rs3816873 NC_000004.12:g.99583507T>C Homozygote - T/T, heterozygote T/C T/C, T/T – reduction in the risk of developing type 2 diabetes by 2 times. Melatonin receptor 1B gene (MTNR1B) rs7754840 NC_000006.12:g.20661019G>C Homozygote C/C heterozygote C/G S/C – risk of developing gestational diabetes, increase in the risk of developing type 2 diabetes by 1.5 times, increase in fasting glucose levels.
C/G – increase in the risk of developing type 2 diabetes by 1.3 times

According to the results of the studies, eleven genes were selected from a statistically significant cohort of patients, namely PPARG, TCF7L2, MC4R, ADIPOQ, KCNQ1, FTO, MTNR1B, CDKAL1, SLC30A8, HHEX, KCNJ11, certain polymorphisms of these genes were identified and those most associated with disorders were identified metabolism genotypes of the specified polymorphisms, where the patient has at least one of the following polymorphisms:

1. PPARG - rs1801282

2. TCF7L2 - rs7903146, rs12255372, rs7901695

3. MC4R - rs2229616

4. ADIPOQ - rs1501299, rs182052, rs2241766

5. KCNQ1 - rs2237892

6. FTO - rs17817449, rs1121980, rs1421085

7. MTNR1B - rs10830963

8. CDKAL1 - rs7754840, rs7756992, rs9465871,

9. SLC30A8 - rs13266634

10. HHEX - rs5015480

11. KCNJ11-rs5219, rs5215

where the presence of at least one of these polymorphisms in a patient indicates a possible predisposition to the development of metabolic disorders.

Determining exactly this combination of genotypes of polymorphisms of these genes is diagnostically significant, since it covers a sufficient number of genes involved in the function of pancreatic beta cells, insulin secretion, associated with body mass index and obesity, associated with elevated glucose levels, the development of insulin resistance, and gestational diabetes , and type 2 diabetes.

Implementation of the invention.

The proposed invention is based on a molecular genetic study of samples of cells, tissues or physiological fluids from patients. As a non-limiting example, a study of a peripheral blood sample from patients over the age of 18 years is given for the following groups of mutations in the genes PPARG, TCF7L2, MC4R, ADIPOQ, KCNQ1, FTO, MTNR1B, CDKAL1, SLC30A8, HHEX, KCNJ11.

The molecular genetic research procedure is carried out as follows:

For genotyping, DNA isolated from human blood cells is used. For isolation, for example, the “PROBA-GS-GENETIKA” kit (DNA technology, Russia) or another set of reagents is used that allows you to isolate DNA from peripheral blood with a concentration above 5 ng/μl. The isolation procedure follows the manufacturer's protocol.

As reagents for performing real-time polymerase chain reaction (RT-PCR), for example, the “5X ScreenMix-HS” kit (Evrogen, Russia) is used. In polymerase chain reaction, probes such as TaqMan are used. The selection of oligonucleotides (primers and probes) was carried out using, for example, PrimerExpress v3 software (Thermo, USA). The synthesis of oligonucleotides is carried out, for example, on an AppliedBiosistems 3900 device (Thermo, USA) by order from Lumiprob Rus LLC (Russia).

To carry out PCR, for example, a CFX96 c1000 Touch amplifier (BioRad) with real-time detection of amplification products is used.

Diagnosis is carried out according to data obtained from the results of molecular genetic analysis of gene sections for the presence of risk alleles - pathological genotypes (Table 2).

Table 2.

Gene Polymorphism Pathological genotype KCNJ11 gene rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > * (Ter)) Homozygote - T/T, heterozygote C/T rs5215 NC_000011.10:g.17387083C>T ( V (Val) > I (Ile)) Homozygote - T/T Transcription factor 7 gene (TCF7L2)
CYP2C9 rs7903146 NC_000010.11:g.112998590C>T Homozygote - T/T, heterozygote C/T rs 12255372 NC_000010.11:g.113049143G>T Homozygote - T/T heterozygote G/T rs7901695 NC_000010.11:g.112994329T>C Homozygote - C/C Transmembrane zinc transporter type 8 gene (SLC30A8) rs13266634 NC_000008.11:g.117172544C>T Homozygote S/C heterozygote S/T Cyclin-dependent kinase type 5 regulatory subunit-associated protein gene (CDKAL1) rs13266634 NC_000008.11:g.117172544C>T Homozygote S/S rs7756992 NC_000006.12:g.20679478A>G Homozygote - G/G heterozygote A/G rs9465871 NC_000006.12:g.20717024T>C Homozygote S/C heterozygote S/T Chromosomal region HHEX-IDE rs5015480 NC_000010.11:g.92705802C>T Homozygote - T/T Adiponectin protein gene (ADIPOQ) rs2229616, NC_000018.10:g.60372043C>T Pathological genotype and associations: there is no pathological variant! rs182052 NC_000003.12:g.186842993G>A Homozygote - A/A Gene associated with obesity and increased adipose tissue (FTO) rs1421085 NC_000016.10:g.53767042T>C Homozygote S/C heterozygote S/T rs17817449 NC_000016.10:g.53779455T>G Homozygote - G/G heterozygote - G/T rs1121980 NC_000016.10:g.53775335G>A Homozygote - A/A heterozygote G/A Perexis proliferator-activated receptor γ2 (PPARG2) NC_000003.12:g.12351626 C>T, rs1801282 (Pro12Ala) Homozygote - T/T, heterozygote C/T Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1) rs2237892 NC_000011.10:g.2818521C>T Homozygote - T/T Melanocortin 4 receptor gene (MC4R) rs3816873 NC_000004.12:g.99583507T>C Homozygote - T/T, heterozygote T/C Melatonin receptor 1B gene (MTNR1B) rs7754840 NC_000006.12:g.20661019G>C Homozygote C/C heterozygote C/G

Below are examples demonstrating the possibility of achieving the specified technical result, which show the results of studies of samples from patients and confirmation of the possibility of predicting differences in the function of pancreatic beta cells, insulin secretion, glucose metabolism, which were confirmed by additional clinical and laboratory studies.

Examples of implementation of the invention

EXAMPLE 1: Patient, born in 1974, female, height 165 cm, weight 84 kg, BMI = 30.1.

The results of the analysis for genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus are presented in Table 3.

Table 3

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766 NC_000018.10:g.60372043 C>T Genotype T/T. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/A. Genotype is not associated with the development of pathology. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/T. The genotype has no association with the development of pathology. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype has no association with the development of pathology. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/G. The genotype is associated with the risk of developing gestational diabetes, increased glucose levels, and worsened insulin secretion Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype T/S. The genotype is associated with a 1.5-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype T/G. The genotype is associated with a 1.3-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype C/G. The genotype is associated with a 1.6-fold increase in the risk of obesity. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/T. Genotype is not associated with the development of pathology. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype C/T. The genotype is associated with a 1.7-fold increase in the risk of T2DM. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype C/T. Genotype is not associated with the development of pathology. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/C. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype C/C. No pathological allele was detected. Melatonin receptor 1B gene (MTNR1B), polymorphism rs7754840 NC_000006.12:g.20661019 G>C Genotype G/C. The genotype is associated with a 1.3-fold increase in the risk of developing type 2 diabetes Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype C/C. No pathological genetic variant was detected. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype C/T. The genotype is associated with a 2.1-fold increase in the risk of T2DM. Decreased insulin production on an empty stomach and with increased glucose levels. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/T. Genotp is associated with a 1.3-fold increase in the risk of T2DM, higher blood glucose concentrations after meals. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/C. The genotype has no association with pathological conditions.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the gene for the protein associated with regulatory subunit 1 of cyclin-dependent kinase type 5 (CDKAL1), the gene associated with obesity and increased adipose tissue (FTO), the gene for the potassium ion channel protein Kir6.2 (KCNJ11), the gene for melatonin receptor 1B ( MTNR1B), transcription factor 7 gene (TCF7L2), in genotypes associated with an increase in the risk of obesity, development of T2DM, and insulin resistance by 1.3-2.1 times.

The identified changes in the genotype were confirmed by laboratory data (Table 4).

Table 4.

Test name Result Unit change Norm Fasting insulin 18.9 µIU/ml 2 - 27 HOMA Insulin Resistance Index 5.71 Units 0.00 - 2.77 Fasting glucose 6.8 mmol/l 3.8 - 6.1 Glycated hemoglobin (HbA1c) 5.7 % 4.0 - 6.0

The data obtained indicate that the mechanisms of metabolism and utilization of glucose are disrupted, the insulin resistance index significantly exceeds the upper limit of normal, the glucose value is significantly higher than normal, the value of glycated hemoglobin tends to the upper limit of normal, i.e. laboratory values indicate hyperglycemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 2: Patient, born in 2010, male, BMI>25.

Results of analysis for genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 5).

Table 5.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the gene for the protein associated with regulatory subunit-1 of cyclin-dependent kinase type 5 (CDKAL1), a gene associated with obesity and increased adipose tissue (FTO), in genotypes associated with the risk of increased glucose levels, worsening insulin secretion, and an increased risk of obesity, 1.3 times.

The identified changes in the genotype were confirmed by laboratory data presented in Table 6.

Table 6.

Test name Result Unit change Norms Fasting insulin 41.8 µIU/ml 2 - 27 C-reactive protein (CRP) ultrasensitive 1,060 mg/l <1 Low risk HOMA Insulin Resistance Index 10.03 Units 0.00 - 2.77 Fasting glucose 5.4 mmol/l 3.8 - 6.1

The data obtained indicate that the mechanisms of metabolism and utilization of glucose are disrupted, insulin and the insulin resistance index significantly exceed the upper limit of normal, but the glucose value is within normal limits, i.e. laboratory values indicate hyperinsulinemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 3: Patient, born in 1951, female, BMI=30. Results of analysis for genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 7).

Table 7.

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766NC_000018.10:g.60372043 C>T Genotype T/T. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/A. Genotype is not associated with the development of pathology. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/G. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype has no association with the development of pathology. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/A. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype T/T. No pathological genetic variant detected Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype G/G. No pathological genetic variant was detected. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/T. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype C/C. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype C/C. No pathological genetic variant was detected. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/T. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype C/C. No pathological allele was detected. Melatonin receptor 1B gene (MTNR1B), polymorphism rs7754840 NC_000006.12:g.20661019 G>C Genotype G/C. The genotype is associated with a 1.3-fold increase in the risk of developing type 2 diabetes Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype C/T. The genotype is associated with an increased risk of T2DM, metabolic syndrome, insulin resistance, and increased BMI. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype is associated with a 2.5-fold increase in the risk of T2DM. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/G. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/C. The genotype has no association with pathological conditions.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the proliferator-activated receptor type 2 gene (PPARG2), the transmembrane zinc transporter type 8 gene (SLC30A8), in genotypes associated with an increased risk of T2DM (2.5 times), metabolic syndrome, insulin resistance, and increased BMI.

The identified changes in the genotype were confirmed by laboratory data presented in Table 8:

Table 8.

Test name Result Unit change Norms HOMA Insulin Resistance Index 4.49 Units 0.00 - 2.77 C-reactive protein (CRP) ultrasensitive 0.930 mg/l less than 1 Low risk Fasting insulin 20.6 µIU/ml 2 - 27 Fasting glucose 4.9 mmol/l 3.8 - 6.1 Glycated hemoglobin (HbA1c) 5.8 % 4.0 - 6.0 HDL cholesterol 0.86 mmol/l 1.15-1.68 moderate risk,
more than 1.68 there is no risk,
less than 1.15 high risk

The data obtained indicate that the mechanisms of metabolism and utilization of glucose are impaired, the insulin resistance index significantly exceeds the upper limit of normal, the value of glycated hemoglobin tends to the upper limit of normal, and lipid metabolism is also impaired, and the HDL cholesterol indicator corresponds to a high risk of developing atherosclerosis, i.e. e. laboratory values indicate hyperglycemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 4: Patient, born in 1948, female, BMI=29. Results of analysis for genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 9):

Table 9.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the genes of the protein associated with the regulatory subunit-1 of cyclin-dependent kinase type 5 (CDKAL1), the gene associated with obesity and increase in adipose tissue (FTO), in the chromosomal region HHEX-IDE, the melatonin receptor 1B gene (MTNR1B), in genotypes, associated with an increase in the risk of T2DM (1.3-2.2 times), and obesity by 2 times.

The identified changes in the genotype were confirmed by laboratory data presented in Table 10:

Table 10.

Test name Result Unit change Norms HOMA Insulin Resistance Index 7.94 Units 0.00 - 2.77 Fasting insulin 28.79 µIU/ml 2 - 27 Fasting glucose 6.2 mmol/l 3.8 - 6.1

The data obtained indicate that the mechanisms of metabolism and utilization of glucose are disrupted, the insulin resistance index significantly exceeds the upper limit of normal, the glucose value is significantly higher than normal, the value of glycated hemoglobin tends to the upper limit of normal, i.e. laboratory values indicate hyperglycemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 5: Patient, born in 1992, male, BMI=25. Results of analysis for genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 11):

Table 11.

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766 NC_000018.10:g.60372043 C>T Genotype T/T. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/G. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/G. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype has no association with the development of pathology. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/A. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype C/S. The genotype is associated with a 2-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype G/G. The genotype is associated with a 1.7-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype G/A. The genotype is associated with a 1.6-fold increase in the risk of obesity. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/T. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype C/C. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype C/C. No pathological genetic variant was detected. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/C. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype T/T. The genotype is associated with a 2-fold reduction in the risk of developing type 2 diabetes. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype C/C. No pathological allele was detected. Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype C/C. No pathological genetic variant was detected. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype C/T. The genotype is associated with a 2.1-fold increase in the risk of T2DM. Decreased insulin production on an empty stomach and increased glucose levels. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/T. Genotp is associated with a 1.3-fold increase in the risk of T2DM, higher blood glucose concentrations after meals. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/T. No pathological genetic variant was detected.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the gene associated with obesity and increased adipose tissue (FTO) - 1.6-2 times, in the gene of transcription factor 7 (TCF7L2, in genotypes associated with an increase in the risk of T2DM by 2.1 times.

The identified changes in the genotype were confirmed by laboratory data presented in Table 12:

Table 12.

Test name Result Unit change Norms Triglycerides 2.5 mmol/l up to 1.7 Atherogenic index 5.4 less than 5.0 LDL cholesterol 4.00 mmol/l less than 2.59-3.34 optimal level;
3.34-4.12 borderline level;
4.12-4.89 high risk; more than 4.89 very high risk Fasting glucose 5.2 mmol/l 3.8 - 6.1

The data obtained indicate that lipid metabolism is impaired, a high atherogenic index indicates a risk of atherosclerosis, but the glucose value is within normal limits, i.e. laboratory values indicate hyperlipidemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 6: Patient, born in 1993, female, BMI=26. The results of the analysis of genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 13):

Table 13.

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766 NC_000018.10:g.60372043 C>T Genotype T/T. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/A. Genotype is not associated with the development of pathology. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/G. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/A. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype C/S. The genotype is associated with a 2-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype G/G. The genotype is associated with a 1.7-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype G/A. The genotype is associated with a 1.6-fold increase in the risk of obesity. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/T. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype C/T. The genotype is associated with a 1.7-fold increase in the risk of T2DM. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype C/T. Genotype has no association with the development of pathological conditions. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/C. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype C/C. No pathological allele was detected. Melatonin receptor 1B gene (MTNR1B), polymorphism rs7754840 NC_000006.12:g.20661019 G>C Genotype G/G. No pathological genetic variant was detected. Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype C/T. The genotype is associated with an increased risk of T2DM, metabolic syndrome, insulin resistance, and increased BMI. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype is associated with a 2.5-fold increase in the risk of T2DM. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype T/T. The genotype is associated with a 3.5-fold increase in the risk of T2DM. Decreased insulin production on an empty stomach and with increased glucose levels. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/T. The genotype is associated with a 1.3-fold increase in the risk of T2DM, higher blood glucose concentrations after meals. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/T. No pathological genetic variant was detected.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the gene associated with obesity and increase in adipose tissue (FTO) - 1.6-1.7 times, in the gene for the potassium ion channel protein Kir6.2 (KCNJ11), Proliferator-activated receptor type 2 (PPARG2), Gene transmembrane zinc transporter type 8 (SLC30A8), transcription factor 7 gene (TCF7L2), in genotypes associated with an increase in the risk of T2DM by 1.7-3.5 times, the development of metabolic syndrome, insulin resistance, and increased BMI.

The identified changes in the genotype were confirmed by laboratory data presented in Table 14:

Table 14.

Test name Result Unit change Norms Total cholesterol 6.8 mmol/l 5.2-6.2 border level,
less than 5.2 is the desired level,
more than 6.2 high level LDL cholesterol 4.35 mmol/l less than 2.59-3.34 optimal level; 3.34-4.12 borderline level;
4.12-4.89 high risk; less than 4.89 very high risk Fasting glucose 4.5 mmol/l 3.8 - 6.1

The data obtained indicate that lipid metabolism is disturbed, but the glucose value is within normal limits, i.e. laboratory values indicate hyperlipidemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 7: Patient, born in 1964, female, BMI=28. The results of the analysis of genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 15):

Table 15.

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766 NC_000018.10:g.60372043 C>T Genotype T/T. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/G. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/G. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/A. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype T/T. No pathological genetic variant was detected. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype G/G. No pathological genetic variant was detected. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/T. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype C/C. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype C/C. No pathological genetic variant was detected. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/C. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype C/C. No pathological allele was detected. Melatonin receptor 1B gene (MTNR1B), polymorphism rs7754840 NC_000006.12:g.20661019 G>C Genotype C/C. The genotype is associated with a 1.5-fold increase in the risk of developing type 2 diabetes and with an increase in fasting glucose levels. Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype T/T. The genotype is associated with an increased risk of T2DM, metabolic syndrome, insulin resistance, and increased BMI. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype T/T. The genotype is associated with a 3.5-fold increase in the risk of T2DM. Decreased insulin production on an empty stomach and with increased glucose levels. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/T. Genotp is associated with a 1.3-fold increase in the risk of T2DM, higher blood glucose concentrations after meals. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/T. No pathological genetic variant was detected.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the melatonin receptor 1B gene (MTNR1B), the proliferator-activated receptor gene type 2 (PPARG2), the transmembrane zinc transporter type 8 gene (SLC30A8), the transcription factor 7 gene (TCF7L2), in genotypes associated with an increased risk of T2DM in 1, 3-3.5 times, development of metabolic syndrome, insulin resistance, increase in BMI.

The identified changes in the genotype are confirmed by laboratory data presented in Table 16:

Table 16.

Test name Result Unit change Norms HOMA Insulin Resistance Index 5.9 Units 0.00 - 2.77 Fasting insulin 19.9 µIU/ml 2 - 27 Fasting glucose 6.7 mmol/l 3.8 - 6.1

The data obtained indicate that the mechanisms of metabolism and utilization of glucose are disrupted, the insulin resistance index is significantly higher than the upper limit of normal, the glucose value is significantly higher than normal, i.e. laboratory values indicate hyperglycemia, clinical indicators indicate metabolic syndrome.

EXAMPLE 8: Patient, born in 1961, female, BMI=23. The results of the analysis of genetic risk factors for increased body mass index, metabolic syndrome and type 2 diabetes mellitus (Table 17):

Table 17.

Index Genotype Adiponectin protein gene (ADIPOQ), polymorphism rs2241766 NC_000018.10:g.60372043 C>T Genotype S/T. Reducing the risk of type 2 diabetes, metabolic syndrome and BMI Adiponectin protein gene (ADIPOQ), polymorphism rs182052 NC_000003.12:g.186842993 G>A Genotype G/G. No pathological genetic variant was detected. Adiponectin protein gene (ADIPOQ), polymorphism rs1501299 NC_000003.12:g.186853334 G>T Genotype G/G. No pathological genetic variant was detected. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/T. The genotype has no association with the development of pathology. Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs7756992 NC_000006.12:g.20679478 A>G Genotype A/G. The genotype is associated with the risk of developing gestational diabetes, increased glucose levels, and worsened insulin secretion Cyclin-dependent kinase type 5 regulatory subunit-1 associated protein gene (CDKAL1), polymorphism rs9465871 NC_000006.12:g.20717024 T>C Genotype T/C. The genotype is associated with a 1.2-fold increase in the risk of T2DM. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1421085 NC_000016.10:g.53767042T>C Genotype T/S. The genotype is associated with a 1.5-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs17817449 NC_000016.10:g.53779455T>G Genotype T/G. The genotype is associated with a 1.3-fold increase in the risk of obesity. Gene associated with obesity and increase in adipose tissue (FTO), polymorphism rs1121980 NC_000016.10:g.53775335G>A Genotype G/G. No pathological genetic variant was detected. Chromosomal region HHEX-IDE, polymorphism rs5015480 NC_000010.11:g.92705802 C>T Genotype C/C. No pathological genetic variant was detected. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5219 NC_000011.10:g.17388025 C>T (K (Lys) > (Ter)) Genotype T/T. The genotype is associated with a 2.5-fold increase in the risk of T2DM. Potassium ion channel protein gene Kir6.2 (KCNJ11), polymorphism rs5215 NC_000011.10:g.17387083 C>T ( V (Val) > I (Ile)) Genotype T/T. Genotype is associated with an increased risk of T2DM. Potassium voltage-gated channel gene, subfamily Q 1 (KCNQ1), polymorphism rs2237892 NC_000011.10:g.2818521 C>T Genotype C/T. No pathological genetic variant was detected. Melanocortin 4 receptor gene (MC4R), polymorphism rs3816873 NC_000004.12:g.99583507 T>C Genotype T/C. The genotype is associated with a 2-fold reduction in the risk of developing type 2 diabetes. Melatonin receptor 1B gene (MTNR1B), polymorphism rs7754840 NC_000006.12:g.20661019 G>C Genotype G/G. No pathological genetic variant was detected. Perexis proliferator-activated receptor type 2 (PPARG2), polymorphism rs1801282 NC_000003.12:g.12351626 C>T, Genotype C/C. No pathological genetic variant was detected. Transmembrane zinc transporter gene type 8 (SLC30A8), polymorphism rs13266634 NC_000008.11:g.117172544 C>T Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7903146 NC_000010.11:g.112998590 C>T, Genotype C/C. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs12255372 NC_000010.11:g.113049143 G>T Genotype G/G. No pathological genetic variant was detected. Transcription factor 7 gene (TCF7L2), polymorphism rs7901695 NC_000010.11:g.112994329 T>C Genotype T/T. No pathological genetic variant was detected.

Thus, it can be assumed that metabolic disorders may develop in this patient, because polymorphisms were identified in the gene for the protein associated with the regulatory subunit-1 of cyclin-dependent kinase type 5 (CDKAL1), the gene associated with obesity and increased adipose tissue (FTO), the gene for the potassium ion channel protein Kir6.2 (KCNJ11), in genotypes associated with an increase in the risk of T2DM by 1.2-3.5 times, obesity by 1.3-1.5 times.

At the same time, polymorphisms were also identified in the Adiponectin protein genes (ADIPOQ) and the melanocortin 4 receptor gene (MC4R), which, on the contrary, are associated with a 2-fold reduction in the risk of developing T2DM and metabolic syndrome.

The data indicate that the use of the proposed panel made it possible to more accurately determine the patient’s genotype, because Risk calculations included genes that are associated with a prognosis for risk reduction.

The identified changes in the genotype were confirmed by laboratory data presented in Table 18:

Table 18.

Test name Result Unit change Norms HOMA Insulin Resistance Index 2.3 Units 0.00 - 2.77 Fasting insulin 9.5 µIU/ml 2 - 27 Fasting glucose 5.4 mmol/l 3.8 - 6.1 LDL cholesterol 3.27 optimal level <2.59-3.34 optimal level;
3.34-4.12 borderline level;
4.12-4.89 high risk; >4.89 very high risk HDL cholesterol 1.73 mmol/l 1.15-1.68 moderate risk, >1.68 no risk,
<1.15 high risk

The data obtained indicate that the mechanisms of metabolism and utilization of glucose and lipid metabolism are carried out adequately. There were no clinical signs of metabolic syndrome and/or diabetes at the time of the study. BMI is within normal limits. The results of the analysis of genetic factors revealed two genetic variants associated with a reduced risk of MS and diabetes, and also identified only one genetic variant associated with an increased risk of gestational diabetes.

Claims (13)

1. A panel to determine susceptibility to increased body mass index, metabolic syndrome and type 2 diabetes mellitus, including means for detecting the following polymorphisms in a patient sample: 1) PPARG - rs1801282; 2) TCF7L2 - rs7903146, rs12255372, rs7901695; 3) MC4R - rs2229616; 4) ADIPOQ - rs1501299, rs182052, rs2241766; 5) KCNQ1 - rs2237892; 6) FTO - rs17817449, rs1121980, rs1421085; 7) MTNR1B - rs10830963; 8) CDKAL1 - rs7754840, rs7756992, rs9465871; 9) SLC30A8 - rs13266634; 10) HHEX - rs5015480; 11) KCNJ11 - rs5219, rs5215. 2. A method for determining a predisposition to an increase in body mass index, metabolic syndrome and type 2 diabetes mellitus, including the use of a panel according to claim 1, where the presence in a patient of at least one of the polymorphisms determined using said panel indicates a predisposition to an increase body mass index, metabolic syndrome and type 2 diabetes.