Integrating Common Risk Factors with Polygenic Scores Improves the Prediction of Type 2 Diabetes

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jan 21

PMID 36674502

Authors

Yanina Timasheva

Zhanna Balkhiyarova

Diana Avzaletdinova

Irina Rassoleeva

Tatiana V Morugova

Gulnaz Korytina

Inga Prokopenko

Olga Kochetova

Affiliations

Soon will be listed here.

Abstract

We tested associations between 13 established genetic variants and type 2 diabetes (T2D) in 1371 study participants from the Volga-Ural region of the Eurasian continent, and evaluated the predictive ability of the model containing polygenic scores for the variants associated with T2D in our dataset, alone and in combination with other risk factors such as age and sex. Using logistic regression analysis, we found associations with T2D for the rs6749704 (OR = 1.68, P = 3.40 × 10), rs333 (OR = 1.99, P = 0.033), rs17366743 (OR = 3.17, P = 2.64 × 10) rs114758349 (OR = 1.77, P = 9.37 × 10), and rs1024611 (OR = 1.38, P = 0.033) polymorphisms. We showed that the most informative prognostic model included weighted polygenic scores for these five loci, and non-genetic factors such as age and sex (AUC 85.8%, 95%CI 83.7-87.8%). Compared to the model containing only non-genetic parameters, adding the polygenic score for the five T2D-associated loci showed improved net reclassification (NRI = 37.62%, 1.39 × 10). Inclusion of all 13 tested SNPs to the model with age and sex did not improve the predictive ability compared to the model containing five T2D-associated variants (NRI = -17.86, = 0.093). The five variants associated with T2D in people from the Volga-Ural region are linked to inflammation () and glucose metabolism regulation (). Further studies in independent groups of T2D patients should validate the prognostic value of the model and elucidate the molecular mechanisms of the disease development.

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References

Muhlbauer M, Bosserhoff A, Hartmann A, Thasler W, Weiss T, Herfarth H . A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Gastroenterology. 2003; 125(4):1085-93. DOI: 10.1016/s0016-5085(03)01213-7. View

Munoz-Barrios S, Guzman-Guzman I, Munoz-Valle J, Salgado-Bernabe A, Salgado-Goytia L, Parra-Rojas I . Association of the HindIII and S447X polymorphisms in LPL gene with hypertension and type 2 diabetes in Mexican families. Dis Markers. 2012; 33(6):313-20. PMC: 3810718. DOI: 10.3233/DMA-2012-00940. View

Kochetova O, Avzaletdinova D, Morugova T, Mustafina O . Chemokine gene polymorphisms association with increased risk of type 2 diabetes mellitus in Tatar ethnic group, Russia. Mol Biol Rep. 2018; 46(1):887-896. DOI: 10.1007/s11033-018-4544-6. View

Xue A, Wu Y, Zhu Z, Zhang F, Kemper K, Zheng Z . Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018; 9(1):2941. PMC: 6063971. DOI: 10.1038/s41467-018-04951-w. View

Zhao J, Arafat D, Brigham K, Gibson G . Genetic risk prediction in a small cohort of healthy adults in Atlanta. Genet Res (Camb). 2013; 95(1):30-7. DOI: 10.1017/S0016672313000025. View

Morris A, Voight B, Teslovich T, Ferreira T, V Segre A, Steinthorsdottir V . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44(9):981-90. PMC: 3442244. DOI: 10.1038/ng.2383. View

Flak J, Myers Jr M . Minireview: CNS Mechanisms of Leptin Action. Mol Endocrinol. 2015; 30(1):3-12. PMC: 4695630. DOI: 10.1210/me.2015-1232. View

Pham M, Hawa M, Roden M, Schernthaner G, Pozzilli P, Buzzetti R . Increased serum concentrations of adhesion molecules but not of chemokines in patients with Type 2 diabetes compared with patients with Type 1 diabetes and latent autoimmune diabetes in adult age: action LADA 5. Diabet Med. 2011; 29(4):470-8. DOI: 10.1111/j.1464-5491.2011.03546.x. View

Karrer S, Bosserhoff A, Weiderer P, Distler O, Landthaler M, Szeimies R . The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis. J Invest Dermatol. 2005; 124(1):92-8. DOI: 10.1111/j.0022-202X.2004.23512.x. View

10.

Scott L, Mohlke K, Bonnycastle L, Willer C, Li Y, Duren W . A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007; 316(5829):1341-5. PMC: 3214617. DOI: 10.1126/science.1142382. View

11.

Pencina M, DAgostino Sr R, DAgostino Jr R, Vasan R . Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2007; 27(2):157-72. DOI: 10.1002/sim.2929. View

12.

Lopez-Pineda A, Vernekar M, Moreno-Grau S, Rojas-Munoz A, Moatamed B, Lee M . Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research. Hum Genomics. 2022; 16(1):37. PMC: 9452874. DOI: 10.1186/s40246-022-00406-y. View

13.

Chang T, Lin L, Chen J . A Novel Resolution of Diabetes: C-C Chemokine Motif Ligand 4 Is a Common Target in Different Types of Diabetes by Protecting Pancreatic Islet Cell and Modulating Inflammation. Front Immunol. 2021; 12:650626. PMC: 8102776. DOI: 10.3389/fimmu.2021.650626. View

14.

Warren L, Li L, Nelson M, Ehm M, Shen J, Fraser D . Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation. Diabetes. 2012; 61(5):1297-301. PMC: 3331741. DOI: 10.2337/db11-0985. View

15.

Aly D, Dwivedi O, Prasad R, Karajamaki A, Hjort R, Thangam M . Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes. Nat Genet. 2021; 53(11):1534-1542. DOI: 10.1038/s41588-021-00948-2. View

16.

Ahlqvist E, Prasad R, Groop L . Subtypes of Type 2 Diabetes Determined From Clinical Parameters. Diabetes. 2020; 69(10):2086-2093. DOI: 10.2337/dbi20-0001. View

17.

Burke S, Karlstad M, Regal K, Sparer T, Lu D, Elks C . CCL20 is elevated during obesity and differentially regulated by NF-κB subunits in pancreatic β-cells. Biochim Biophys Acta. 2015; 1849(6):637-52. PMC: 4437873. DOI: 10.1016/j.bbagrm.2015.03.007. View

18.

Timpson N, Lindgren C, Weedon M, Randall J, Ouwehand W, Strachan D . Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes. 2008; 58(2):505-10. PMC: 2628627. DOI: 10.2337/db08-0906. View

19.

Chen J, Sun M, Adeyemo A, Pirie F, Carstensen T, Pomilla C . Genome-wide association study of type 2 diabetes in Africa. Diabetologia. 2019; 62(7):1204-1211. PMC: 6560001. DOI: 10.1007/s00125-019-4880-7. View

20.

Tourniaire F, Romier-Crouzet B, Lee J, Marcotorchino J, Gouranton E, Salles J . Chemokine Expression in Inflamed Adipose Tissue Is Mainly Mediated by NF-κB. PLoS One. 2013; 8(6):e66515. PMC: 3688928. DOI: 10.1371/journal.pone.0066515. View