Association of the rs3730089 Nucleotide Sequence of the PIK3R1 Gene with Dyslipidemia in Type 1 Diabetes Mellitus

Aim. To analyze the association of the rs3730089 nucleotide sequence variant of the PIK3R1 gene with various metabolic disorders in patients with type 1 diabetes mellitus (T1DM).

Design. A one-stage cross-sectional study.

Materials and methods. 147 unrelated patients with T1DM were examined. Their height, body weight, waist and hip circumferences, and body mass index were measured. Laboratory tests included the determination of total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides. The variant of the nucleotide sequence was investigated using a polymerase chain reaction. Using the χ² criterion, the correspondence of the frequency of genotypes to the Hardy — Weinberg equilibrium was estimated. The association of genotypes with insulin resistance was analyzed using the online SNPStats program. Association analysis is presented in codominant, dominant, recessive, overdominant, and additive models, as well as during the allele test.

Results. The distribution of genotypes and alleles of the rs3730089 nucleotide sequence variant of the PIK3R1 gene in all patients corresponded to the Hardy — Weinberg equilibrium. There was a significant association of A/C and A/A genotypes in dominant models with elevated levels of low-density lipoproteins and cholesterol. In the overdominant model, the association of the A/C genotype with elevated triglyceride levels, as well as with increased waist circumference and overweight in patients with Т1DM was determined (odds ratio — 10.5, 95% confidence interval: 3.94–27.99, p < 0.0001, р^FDR = 0.0001 and odds ratio — 5.70, 95% confidence interval: 2.28–14.26, p = 0.0001, р^FDR = 0.0002, respectively). For all of the above indicators, allele A was risky. Associations of genotypes and alleles of the rs3730089 nucleotide sequence variant of the PIK3R1 gene with a reduced level of high-density lipoproteins have not been found.

Conclusion. The nucleotide sequence rs3730089 of the PIK3R1 gene is associated with lipid metabolism disorders in patients with Т1DM.

Allele A is risky. This variant of the nucleotide sequence may be associated with insulin resistance in people with T1DM. 

1. Potocka N., Skrzypa M., Zadarko-Domaradzka M., Barabasz Z. et al. Effects of the Trp64Arg polymorphism in the ADRB3 gene on body composition, cardiorespiratory fitness, and physical activity in healthy adults. Genes (Basel). 2023;14(8):1541. DOI: 10.3390/genes14081541

2. Li S., He C., Nie H., Pang Q. et al. G allele of the rs1801282 polymorphism in PPARγ gene confers an increased risk of obesity and hypercholesterolemia, while t allele of the rs3856806 polymorphism displays a protective role against dyslipidemia: a systematic review and meta-analysis. Front. Endocrinol. (Lausanne). 2022;13:919087. DOI: 10.3389/fendo.2022.919087

3. Kochetova O.V., Shangareeva Z.A., Avzaletdinova D.Sh., Viktorova T.V. et al. The role of the AKT1 gene in the pathogenesis of type 2 diabetes mellitus and its complications. Molecular Medicine. 2024;22(3):57–65. (in Russian). DOI: 10.29296/24999490-2024-03-09

4. Cadby G., Giles C., Melton P.E., Huynh K. et al. Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease. Nat. Commun. 2022;13(1):3124. DOI: 10.1038/s41467-022-30875-7

5. Lavens A., De Block C., Oriot P., Crenier L. et al. Metabolic health in people living with type 1 diabetes in Belgium: a repeated cross-sectional study. Diabetologia. 2024;67(12):2678–90. DOI: 10.1007/s00125-024-06273-7

6. Mori R.C., Santos-Bezerra D.P., Pelaes T.S., Admoni S.N. et al. Variants in HSD11B1 gene modulate susceptibility to diabetes kidney disease and to insulin resistance in type 1 diabetes. Diabetes Metab. Res. Rev. 2021;37(1):e3352. DOI: 10.1002/dmrr.3352

7. Maguolo A., Rioda M., Zusi C., Emiliani F. et al. Cardiovascular risk factors in children and adolescents with type 1 diabetes mellitus: the role of insulin resistance and associated genetic variants. Horm. Res. Paediatr. 2023;96(3):306–15. DOI: 10.1159/000527520

8. Miller R.G., McGurnaghan S.J., Onengut-Gumuscu S., Chen W.M. et al. Insulin resistance-associated genetic variants in type 1 diabetes. J. Diabetes Complications. 2021;35(4):107842. DOI: 10.1016/j.jdiacomp.2020.107842

9. Tsay A., Wang J.C. The role of PIK3R1 in metabolic function and insulin sensitivity. Int. J. Mol. Sci. 2023;24(16):12665. DOI: 10.3390/ijms241612665

10. Wu W., Xia X., Tang L., Luo J. et al. Phosphoinositide 3-kinase as a therapeutic target in angiogenic disease. Exp. Eye Res. 2023;236:109646. DOI: 10.1016/j.exer.2023.109646

11. Donlon T.A., Chen R., Masaki K.H., Willcox B.J. et al. Association with longevity of phosphatidylinositol 3-kinase regulatory subunit 1 gene variants stems from protection against mortality risk in men with cardiovascular disease. Gerontology. 2022;68(2):162–70. DOI: 10.1159/000515390

12. Mir R., Elfaki I., Duhier F.M.A., Alotaibi M.A. et al. Molecular determination of mirRNA-126 rs4636297, phosphoinositide-3-kinase regulatory subunit 1-gene variability rs7713645, rs706713 (Tyr73Tyr), rs3730089 (Met326Ile) and their association with susceptibility to T2D. J. Pers. Med. 2021;11(9):861. DOI: 10.3390/jpm11090861

13. Park M., Kim J.S., Park Y.A., Lee D.H. et al. Association between insulin-associated gene polymorphisms and new-onset diabetes mellitus in statin-treated patients. Eur. J. Clin. Invest. 2025;55(4):e14366. DOI: 10.1111/eci.14366

14. Sun H., Saeedi P., Karuranga S., Pinkepank M. et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 2022;183:109119. DOI: 10.1016/j.diabres.2021.109119

15. Almind K., Delahaye L., Hansen T., Van Obberghen E. et al. Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. Proc. Natl. Acad. Sci. USA. 2002;99(4):2124–8. DOI: 10.1073/pnas.042688799

16. Baier L.J., Wiedrich C., Hanson R.L., Bogardus C. Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women. Diabetes. 1998;47(6):973–5. DOI: 10.2337/diabetes.47.6.973

17. Karadoğan A.H., Arikoglu H., Göktürk F., İşçioğlu F. et al. PIK3R1 gene polymorphisms are associated with type 2 diabetes and related features in the Turkish population. Adv. Clin. Exp. Med. 2018;27(7):921–7. DOI: 10.17219/acem/68985

18. Hansen T., Andersen C.B., Echwald S.M., Urhammer S.A. et al. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes. 1997;46(3):494–501. DOI: 10.2337/diab.46.3.494

19. Chen S., Yan W., Huang J., Ge D. et al. Association analysis of the variant in the regulatory subunit of phosphoinositide 3-kinase (p85alpha) with type 2 diabetes mellitus and hypertension in the Chinese Han population. Diabet. Med. 2005;22(6):737–43. DOI: 10.1111/j.1464-5491.2005.01490.x