Gestasyonel Diyabet ile IL8/CXCL8 rs4073 Gen Polimorfizmi Arasındaki İlişkinin Araştırılması

Öz

Amaç: Gestasyonel Diyabet (GDM) ilk defa gebelikte tanı konulan glukoz intoleransıdır. Hem anne hem de bebekte komplikasyon riskini artıran GDM için ileri gebelik yaşı, çok sayıda parite, önceki gebelikte GDM öyküsü, genetik faktörler gibi birçok risk faktörü tanımlanmıştır. Ayrıca bazı inflamatuar mediatörler, kemokinler ve onları kodlayan genlerin polimorfizmlerinin GDM ile ilişkisi gösterilmiştir. Biz bu çalışmada GDM tanısı konulan gebelerle sağlıklı gebelerdeki genotip ve allel frekans dağılımlarını karşılaştırarak, GDM yatkınlığı ile IL8/CXCL8 rs4073 (251A/T) gen polimorfizminin ilişkisini belirlemeyi amaçladık. Gereç ve Yöntemler: Çalışmamıza GDM tanılı 100 gebe ve kontrol grubu olarak 100 sağlıklı gebe dahil edilmiştir. Tüm katılımcılar Zonguldak Bülent Ecevit Üniversitesi Tıp Fakültesi Hastanesi Kadın Hastalıkları ve Doğum Anabilim Dalı’nda takip edilmiştir. IL8/ CXCL8 rs4073 gen polimorfizminin genotiplenmesi, polimeraz zincir reaksiyonu bazlı restriksiyon fragman uzunluk polimorfizmi (PCR-RFLP) yöntemi kullanılarak belirlenmiştir. GDM hastalarında ve kontrollerde her bir gen polimorfizminin genotip sıklığını karşılaştırmak için χ2 testi kullanıldı. Bulgular: Gestasyonel diyabetli gebelerle sağlıklı gebeler arasında rs4073 polimorfizmi genotip ve allel frekans dağılımları açısından istatistiksel olarak anlamlı bir farklılık saptanmamıştır (sırasıyla; p=0,260, p=1,000). Sonuç: Bulgularımız IL8/CXCL8 rs4073 gen polimorfizminin GDM’ye yatkınlıkla ilişkili olmadığını göstermekle birlikte bulgularımızın doğrulanması için farklı etnik grupları içeren geniş örneklem büyüklükleriyle, katılımcıların vücut kütle indeksleri, gebelik öncesi kiloları gibi klinik parametreler de dahil edilerek yapılacak ileri çalışmalara ihtiyaç vardır

Anahtar Kelimeler

• Gestasyonel Diyabet
• IL-8
• CXCL8
• rs4073
• gen polimorfizm

Investigation of the Relationship Between Gestational Diabetes Mellitus and IL8/CXCL8 rs4073 Gene Polymorphism

Öz

Aim: Gestational Diabetes (GDM) is glucose intolerance that is first diagnosed during pregnancy. Many risk factors such as advanced gestational age, multiparity, history of GDM in a previous pregnancy, and genetic factors have been defined for GDM, which increases the risk of complications in both mother and baby. In addition, some inflammatory mediators, chemokines, and polymorphisms of the genes encoding them are associated with GDM. In this study, we aimed to determine the relationship between GDM susceptibility and IL8/CXCL8 rs4073 (-251A/T) gene polymorphism by comparing the genotype and allele frequency distributions in pregnant women diagnosed with GDM and healthy pregnant women. Material and Methods: One hundred pregnant patients diagnosed with GDM and 100 healthy pregnant as the control group, were included in our study. All participants were followed up in Zonguldak Bülent Ecevit University Medical Faculty Hospital, Department of Obstetrics and Gynecology. Genotyping of the IL8/CXCL8 rs4073 gene polymorphism was determined using the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. The χ2 test was used to compare the genotype frequency of each gene polymorphism in GDM patients and controls. Results: There was no statistically significant difference between pregnant women with GDM and healthy pregnant women in terms of rs4073 polymorphism genotype and allele frequency distributions (p=0.260, p=1.000, respectively). Conclusion: Although our findings show that IL8/CXCL8 rs4073 gene polymorphism is not associated with susceptibility to GDM, further studies with large sample sizes including different ethnic groups and clinical parameters of participants such as body mass index and pre-pregnancy weight, are needed to confirm our findings

Anahtar Kelimeler

• Gestational diabetes mellitus
• IL-8
• CXCL8
• rs4073
• gene polymorphism

Kaynakça

1. 1. American Diabetes Association. Erratum. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetes-2016. Diabetes Care. 2016;39(Suppl. 1):S13-S22.
2. 2. Zhu Y, Zhang C. Prevalence of gestational diabetes and risk of progression to type 2 diabetes: A global perspective. Curr Diab Rep. 2016;16(1):7.
3. 3. Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, Butler PC. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53(10):2167-2176.
4. 4. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: Risks and management during and after pregnancy. Nat Rev Endocrinol. 2012;8(11):639-649.
5. 5. HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002.
6. 6. Thomas F, Balkau B, Vauzelle-Kervroedan F, Papoz L. Maternal effect and familial aggregation in NIDDM. The CODIAB Study. CODIAB-INSERM-ZENECA Study Group. Diabetes. 1994;43(1):63-67.
7. 7. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;373(9677):1773-1779.
8. 8. Sullivan SD, Umans JG, Ratner R. Gestational diabetes: Implications for cardiovascular health. Curr Diab Rep. 2012;12(1):43-52.

9. 9. HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Int J Gynaecol Obstet. 2002;78(1):69-77.
10. 10. Carpenter MW. Gestational diabetes, pregnancy hypertension, and late vascular disease. Diabetes Care. 2007;30 Suppl 2:S246-S250.
11. 11. Kitzmiller JL, Dang-Kilduff L, Taslimi MM. Gestational diabetes after delivery. Short-term management and longterm risks. Diabetes Care. 2007;30 Suppl 2:S225-S235.
12. 12. Kirwan, JP, Hauguel-De Mouzon, S, Lepercq, J, Challier, JC, Huston-Presley, L, Friedman, JE, Kalhan, SC, Catalano, PM. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207-2213.
13. 13. Altinova AE, Toruner F, Bozkurt N, Bukan N, Karakoc A, Yetkin I, Ayvaz G, Cakir N, Arslan M. Circulating concentrations of adiponectin and tumor necrosis factoralpha in gestational diabetes mellitus. Gynecol Endocrinol. 2007;23(3):161-165.
14. 14. Gao XL, Yang HX, Zhao Y. Variations of tumor necrosis factoralpha, leptin and adiponectin in mid-trimester of gestational diabetes mellitus. Chin Med J (Engl). 2008;121(8):701-705.
15. 15. López-Tinoco C, Roca M, Fernández-Deudero A, García- Valero A, Bugatto F, Aguilar-Diosdado M, Bartha JL. Cytokine profile, metabolic syndrome and cardiovascular disease risk in women with late-onset gestational diabetes mellitus. Cytokine. 2012;58(1):14-19.
16. 16. Guzmán-Flores JM, Escalante M, Sánchez-Corona J, García- Zapién AG, Cruz-Quevedo EG, Muñoz-Valle JF, Moran- Moguel MC, Saldaña-Cruz AM, Flores-Martínez SE. Association analysis between -308G/A and -238G/A TNFalpha gene promoter polymorphisms and insulin resistance in Mexican women with gestational diabetes mellitus. J Investig Med. 2013;61(2):265-269.
17. 17. Zhang J, Chi H, Xiao H, Tian X, Wang Y, Yun X, Xu Y. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) single nucleotide polymorphisms (SNPs), inflammation and metabolism in gestational diabetes mellitus in inner Mongolia. Med Sci Monit. 2017;23:4149-4157.
18. 18. Mukaida N, Harada A, Matsushima K. Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions. Cytokine Growth Factor Rev. 1998;9(1):9-23.
19. 19. Hull J, Thomson A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax. 2000;55(12):1023-1027.
20. 20. Taguchi A, Ohmiya N, Shirai K, Mabuchi N, Itoh A, Hirooka Y, Niwa Y, Goto H. Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev. 2005;14 (11 Pt 1):2487-2493.
21. 21. Hart PMB, Stephenson NL, Scime NV, Tough SC, Slater DM, Chaput KH. Second trimester cytokine profiles associated with gestational diabetes and hypertensive disorders of pregnancy. PLoS One. 2022;17(12):e0279072. 22. Abell SK, De Courten B, Boyle JA, Teede HJ. Inflammatory and Other biomarkers: Role in pathophysiology and prediction of gestational diabetes Mellitus. Int J Mol Sci. 2015;16(6):13442- 13473.
22. 23. Ajmera V, Perito ER, Bass NM, Terrault NA, Yates KP, Gill R, Loomba R, Diehl A M, Aouizerat BE, NASH Clinical Research Network. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology. 2017;65(1):65-77.
23. 24. Van Sickle BJ, Simmons J, Hall R, Raines M, Ness K, Spagnoli A. Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus. Cytokine. 2009;48(3):290-294.
24. 25. Milas O, Gadalean F, Vlad A, Dumitrascu V, Velciov S, Gluhovschi C, Bob F, Popescu R, Ursoniu S, Jianu DC, Matusz P, Pusztai AM, Secara A, Simulescu A, Stefan M, Patruica M, Petrica F, Vlad D, Petrica L. Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients. J Diabetes Complications. 2020;34(2):107479.
25. 26. Lee WP, Tai DI, Lan KH, Li AF, Hsu HC, Lin EJ, Lin YP, Sheu ML, Li CP, Chang FY, Chao Y, Yen SH, Lee SD. The -251T allele of the interleukin-8 promoter is associated with increased risk of gastric carcinoma featuring diffuse-type histopathology in Chinese population. Clin Cancer Res. 2005;11(18):6431-6441.
26. 27. Urbanek M, Hayes MG, Lee H, Freathy RM., Lowe LP, Ackerman C, Jafari N, Dyer AR, Cox NJ, Dunger DB, Hattersley AT, Metzger BE, Lowe WL Jr. The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. PLoS One. 2012;7(3):e32958.
27. 28. Tashiro K, Koyanagi I, Saitoh A, Shimizu A, Shike T, Ishiguro C, Koizumi M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. Urinary levels of monocyte chemoattractant protein-1 (MCP- 1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab Anal. 2002;16(1):1-4.
28. 29. Rovin BH, Lu L, Zhang X. A novel interleukin-8 polymorphism is associated with severe systemic lupus erythematosus nephritis. Kidney Int. 2002;62(1):261-265.
29. 30. Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, Venkatesan R, Rai TS, Sud K, Singal PK. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians. PLoS One. 2009;4(4):e5168.
30. 31. Ricci F, Staurenghi G, Lepre T, Missiroli F, Zampatti S, Cascella R, Borgiani P, Marsella LT, Eandi CM, Cusumano A, Novelli G, Giardina E. Haplotypes in IL-8 gene are associated to age-related macular degeneration: A case-control study. PLoS One. 2013;8(6):e66978.
31. 32. Benakanakere MR, Finoti LS, Tanaka U, Grant GR, Scarel- Caminaga RM, Kinane DF. Investigation of the functional role of human Interleukin-8 gene haplotypes by CRISPR/Cas9 mediated genome editing. Sci Rep. 2016;6:31180.
32. 33. Yahya MJ, Ismail PB, Nordin NB, Akim ABM, Yusuf WSBM, Adam NLB, Yusoff MJ. Association of CCL2, CCR5, ELMO1, and IL8 Polymorphism with Diabetic Nephropathy in Malaysian Type 2 Diabetic Patients. Int J Chronic Dis. 2019;2019:2053015.
33. 34. Dong L, Bai J, Jiang X, Yang MM, Zheng Y, Zhang H, Lin D. The gene polymorphisms of IL-8(-251T/A) and IP-10(- 1596C/T) are associated with susceptibility and progression of type 2 diabetic retinopathy in northern Chinese population. Eye (Lond). 2017;31(4):601-607.
34. 35. Kurt İ. Trakya Üniversitesi Sağlık Araştırma ve Uygulama Merkezinde takip edilen Tip2 diyabetli hastalarda interlökin- 8-251A/T polimorfizminin nefropati gelişimine etkisinin araştırılması. Trakya Üniversitesi Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, İç Hastalıkları Ana Bilim Dalı, Uzmanlık Tezi. 2017.
35. 36. Kuzmicki M, Telejko B, Zonenberg A, Szamatowicz J, Kretowski A, Nikolajuk A, Laudanski P, Gorska M. Circulating pro- and anti-inflammatory cytokines in Polish women with gestational diabetes. Horm Metab Res. 2008;40(8):556-560.
36. 37. Kuzmicki M, Telejko B, Zonenberg A, Szamatowicz J, Kretowski A, Nikolajuk A, Laudanski P, Gorska M. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond). 2006;30(9):1347-1355.
37. 38. Keckstein S, Pritz S, Amann N, Meister S, Beyer S, Jegen M, Kuhn C, Hutter S, Knabl J, Mahner S, Kolben T, Jeschke U, Kolben TM. Sex specific expression of interleukin 7, 8 and 15 in placentas of women with gestational diabetes. Int J Mol Sci. 2020;21(21):8026.