Pro12Ala polymorphism in the PPARG gene is not assocIated wIth the development of insulIin resistance and type 2 diabetes in the Turkish population: A case-control study

Yıl 2021, Cilt: 31 Sayı: 4, 339 - 343, 15.12.2021

Dudu Erkoç Kaya , Hilal Arikoglu , Funda İşçioğlu , Suleyman Ipekci , Süleyman Baldane

https://doi.org/10.54005/geneltip.1017082

Öz

Objective: Type 2 diabetes (T2D) is the most common type of diabetes and has become a serious public health problem in our country as worldwide. Reduction of insulin secretion and/or insulin resistance (IR) development are two major defects in T2D pathogenesis. PPARG2, which is encoded by the peroxisome proliferator activated receptor gamma (PPARG) gene, located chromosome 3p25, is mainly expressed in adipocytes and regulates a large number of key genes involved in regulation of glucose and lipid metabolism. The first reported candidate gene associated with T2D is PPARG2 (Pro12Ala variant), due to its functional importance. We aimed to evaluate the effects of Pro12Ala on IR development and T2D risk in 650 individuals, which of 387 (181 non-obese/ 206 obese) individuals with T2D and 264 (137 nonobese/127 obese) healthy individuals in Konya region.
Method: T2D-related biochemical parameters were analyzed from blood samples and HOMA-IR (HOMA index) was calculated. Individuals with a HOMAIR index higher than 2.5 were considered resistant to insulin. Pro12Ala genotyping was performed by RT-PCR technique in DNA samples isolated from lymphocytes. P<0.05 was considered statistically significant.
Results: Patient and control groups except Obese patient group were not in HardyWeinberg equilibrium (p<0.05). Pro12Ala polymorphism had no effect on T2D risk and biochemical parameters according to association analysis under dominant, recessive, additive models (p>0.05).
Conclusion: Consequently, the Pro12Ala in PPARG gene was not associated with T2D and biochemical phenotypes in the Turkish population. The polygenic nature of the disease and complexity of environmental factors makes it difficult to understand the effect of the genes in the pathogenesis of T2D. Further studies in larger populations are needed to reveal the possible role of PPARG in the genetic background of the disease. The study is the first report of PPARG and T2D association Turkish.

Anahtar Kelimeler

Type 2 diabetes, PPARG, Pro12Ala, Turkish population

Proje Numarası

213S035

PPARG genindeki Pro12Ala polimorfizmi, Türk populasyonunda insülin direnci ve tip 2 diyabet ile ilişkili değildir: Bir vaka-kontrol çalışması

Öz

Amaç: Tip 2 diyabet (T2D), diyabetin en sık görülen türüdür ve tüm dünyada olduğu gibi ülkemizde de ciddi bir halk sağlığı sorunu haline gelmiştir. İnsülin sekresyonunun azalması ve/veya insülin direnci (İR) gelişimi, T2D patogenezinde yer alan iki ana bozukluktur. Kromozom 3p25'te yer alan peroksizom proliferatör aktive reseptör gama (PPARG) geni tarafından kodlanan ve esas olarak adipositlerde eksprese edilen PPARG2, glikoz ve lipid metabolizmasının düzenlenmesinde yer alan çok sayıda anahtar geni düzenler. Fonksiyonel önemi dolayısıyla, T2D gelişimi ile ilişkisi ilk rapor edilen aday gen PPARG2 (Pro12Ala varyantı)’dir. Çalışmamızda, PPARG genindeki Pro12Ala'nın IR gelişimi ve T2D riski üzerine etkilerini Konya bölgesinde yaşayan 387 (181 non-obez/ 206 obez) T2D ve 264 (137 non-obez/127 obez) sağlıklı birey olmak üzere toplam 650 kişide değerlendirmeyi amaçladık.
Yöntem: Bireylerden alınan kan örneklerinden, T2D ilişkili biyokimyasal parametreler analiz edildi ve sonrasında HOMA-IR (HOMA indeksi) hesaplandı. HOMAIR indeksi 2.5'ten yüksek olan kişiler insüline dirençli olarak kabul edildi. İzole edilen DNA örneklerinde, Pro12Ala genotiplendirmesi RT-PCR tekniği ile yapıldı. İstatistiksel analiz için SPSS18.0 programı kullanıldı. P<0.05 istatistiksel olarak anlamlı kabul edildi.
Bulgular: Obez hasta grubu dışında diğer hasta ve ve kontrol grupları Hardy-Weinberg dengesinde değildi (p<0.05). Dominant, resesif ve aditif modeller kurularak yapılan ilişkilendirme analizine göre Pro12Ala polimorfizminin T2D riski ve ilişkili biyokimyasal parametreler üzerine bir etkisi bulunmadı (p>0.05).
Sonuç: Hastalığın poligenik doğası ve çevresel faktörlerin karmaşıklığı, genlerin T2D patogenezindeki etkisinin anlaşılmasını zorlaştırmaktadır. Bu nedenle, PPARG'nin hastalığın genetik zeminindeki olası rolünü ortaya çıkarmak için daha büyük popülasyonlarda daha fazla çalışmaya ihtiyaç vardır. Çalışma Türk toplumunda PPARG ve T2D ilişkisi bakımından sunulan ilk rapordur.

Anahtar Kelimeler

Tip 2 diyabet, PPARG, Pro12Ala, Türk populasyonu

Destekleyen Kurum

TÜBİTAK

Proje Numarası

213S035

Kaynakça

• 1. Sun X, Yu W, Hu C. Genetics of Type 2 Diabetes: Insights into the Pathogenesis and Its Clinical Application. BioMed Research International 2014;926713.doi:10.1155/2014/926713.
• 2. Glass CK and Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity, Nature Reviews Immunology. 2006;6(1):44–55.
• 3. Mangelsdorf DJ and Evans RM. The RXR heterodimers andorphan receptors, Cell. 1995;83(6):841–850.
• 4. Perissi V and Rosenfeld MG. Controlling nuclear receptors: the circular logic of cofactor cycles. Nature Reviews Molecular Cell Biology. 2005;6(7):542–554.
• 5. Tontonoz P and Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem. 2008;77:289–312.
• 6. Knouff C and Auwerx J. Peroxisome proliferator-activated receptor-𝛾 calls for activation in moderation: lessons from genetics and pharmacology. Endocr Rev. 2004;25(6):899-918.
• 7. Fajas L, Auboeuf D, Raspe E, et al. The organization, ´ promoter analysis, and expression of the human PPAR𝛾 gene. Journal of Biological Chemistry. 1997;272(30):18779–18789.
• 8. Ahmadian M, Suh JM, Hah N, et al. PPAR𝛾 signaling and metabolism: the good, the bad and the future, Nature Medicine. 2013;19:557–566.
• 9. Bragt MC and Popeijus HE. Peroxisome proliferatoractivated receptors and the metabolic syndrome. Physiology and Behavior. 2008;94(2):187–197. 10. Rosen ED and Spiegelman BM. PPAR𝛾: a nuclear regulator of metabolism, differentiation, and cell growth. Journal of Biological Chemistry. 2001;276(41):37731–37734.
• 11. Ahmed W, Ziouzenkova O, Brown J, et al. PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? Journal of Internal Medicine. 2007;262(2):184–198.
• 12. Yen CJ, Beamer BA, Negri C, et al. 1997. Molecular scanning of the human Peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic Caucasians: identification of a Pro12Ala PPARγ2 missense mutation. Biochem Biophys Res Commun. 1997;241:270-274.
• 13. Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20:284-287.
• 14. Altshuler D, Hirschhorn JN, Klannemark M, et al. 2000. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.
• 15. Vergotine Z, Yako YY, Kengne AP, et al. T. E. Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa. BMC Genet. 2014 Jan 21;15:10.
• 16. Lyon HN, Hirschorn JN. Genetics of common forms of obesity: A brief overview. Am J Clin Nutr. 2005;82:2152-2157
• 17. Grarup N, Sandholt CH, Hansen, T and Pedersen O. Genetic Susceptibility to Type 2 Diabetes and Obesity: from Genome-wide Association Studies to Rare Variants and beyond. Diabetologia. 2014;57:1528–1541.
• 18. Barak YM, Nelson C, Ong ES, et al. PPARγ is required for placental, cardiac, and adipose tissue development. Molecular Cell. 1999;4(4):585–595.
• 19. Lehrke M and Lazar MA. The many faces of PPARγ. Cell. 2005;123(6):993–999.
• 20. Saxena R, Voight BF, Lyssenko V, et al. 2007. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331-1336.
• 21. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007; 316(5829):1341-1345.
• 22. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770-775.
• 23. Hara M, Higaki Y, Taguchi N, et al. Effect of the PPARG2 Pro12Ala polymorphism and clinical risk factors for diabetes mellitus on HbA1c in the Japanese general population. J Epidemiol 2012;22:523–31.
• 24. Mori H, Ikegami H, Kawaguchi Y, et al. The Pro12 → Ala substitution in PPAR-𝛾 is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes. 2001;50:891–894.
• 25. Meshkani R, Taghikhani M, Larijani B, et al. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2(PPARγ-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population. Clinical Chemistry and Laboratory Medicine. 2007;45(4):477–482.
• 26. Wang X, Liu J, Ouyang Y, et al. The Association between the Pro12Ala Variant in the PPARγ2 Gene and Type 2 Diabetes Mellitus and Obesity in a Chinese Population. PLoS ONE. 2013;8(8): e71985.
• 27. Barroso I, Gurnell M, Crowley VEF, et al. Dominant negative mutations in human PPAR𝛾 associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402(6764):880–883.
• 28. Evans D, de Heer J, Hagemann C, et al. Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor γ (PPARγ) gene and type 2 diabetes. Experimentaland Clinical Endocrinology and Diabetes. 2001;109(3):151–154.
• 29. Herder C, Rathmann W, Strassburger K, et al. Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies. Hormone and Metabolic Research. 2008;40(10):722–726.
• 30. Majithiaa AR, Flannicka J, Shahiniana P, et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. PNAS. 2014;111(36): 13127–13132 31. Bouassida KZ, Chouchane L, Jellouli K, et al. The peroxisome proliterator activated receptorγ2 (PPAR γ2) Pro12Ala variant: lack of association with type 2 diabetes in obese and non obese Tunisian patients. Diabetes and Metabolism 2005;31(2):119–123.
• 32. Malecki MT, Frey J, Klupa T, et al. The Pro12Ala polymorphism of PPAR γ2 gene and susceptibility to type 2 diabetes mellitus in a Polish population, mDiabetes Research and Clinical Practice, 2003;62(2):105–111.
• 33. Mato EPM, Pokam-Fosso PE, Atogho-Tiedeu B, et al. The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated to obesity and type 2 diabetes mellitus in a Cameroonian population. BMC Obes. 2016;3:26.
• 34. Al-Naemi AH, Ahmad AJ. Is the rs1801282 (G/C) Polymorphism of PPAR - Gamma Gene Associated with T2DM in Iraqi People? Open Access Maced J Med Sci. 2021;6(3):447-55.
• 35. Hashemian L, Sarhangi N, Afshari M, et al. The role of the PPARG (Pro12Ala) common genetic variant on type 2 diabetes mellitus risk. Journal of Diabetes & Metabolic Disorders. 2021; doi:10.1007/s40200-021-00872-6
• 36. Kang ES, Park SY, Kim HJ, Kim, et al. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther. 2005;78:202–208.
• 37. Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci. 2010;1212:59–77.
• 38. Meybodi HRA, Hasanzad M and Larijani B. Path to personalized medicine for type 2 diabetes mellitus: reality and hope. Acta Med Iran.2017; 55(3): 166–174.
• 39. Ye E, Yang H, Chen L, et al. Adiponectin and peroxisome proliferator-activated receptor-γ gene polymorphisms and gene-gene interactions with type 2 diabetes Life Sciences. 2014;98:55–59.