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NLRP3 İnflamazom Geni rs4925648, rs121908149 ve rs121908152 Varyantları ile Tip 2 Diyabet Riski

Yıl 2019, Cilt: 41 Sayı: 2, 153 - 160, 01.04.2019
https://doi.org/10.20515/otd.460753

Öz

Tip 2 diyabet (T2DM), insülinin
tamamen veya kısmi eksikliğine bağlı olarak gelişen ve hiperglisemi ve insülin
direnci ile karakterize bir hastalıktır. İnflamasyon, zararlı, yabancı veya
yıkıcı etkilere karşı organizmanın doğal savunma yanıtıdır. Son çalışmalar,
inflamasyon, insülin direnci ve tip 2 diyabetin patogenezi arasındaki
bağlantıyı vurgulamıştır. İnflamazom, inflamasyon üretme potansiyeli olan
uyaranları tanıyan ve buna yanıt olarak proinflamatuar sitokinlerin üretimi ve
salgılanmasından sorumlu bir süreci yöneten protein kompleksidir.  Farklı tipte inflamazom yapıları bulunmakla
birlikte tip 2 diyabet, insülin direnci ve obezite ile ilişkisi rapor edilen
inflamazom NLRP3 (Nod-like receptor pyrin domain-containing 3) inflamazomdur.
Makrofajlarda, NLRP3 inflamasyonu aktive eder ve insülin sinyalini bozar, ve bu
hem TNF-bağımlı hem de TNF bağımsız yolaklar vasıtası ile insülinin hedefi olan
hücrelerde insülin direncine neden olur. Çalışmamızın amacı NLRP3 geninin
rs4925648, rs121908149, rs121908152 varyantlarının ilişkisini araştırmaktır. Bu
amaçla 100 T2DM hastası ve 100 kontrol bireye ait DNA’lar NLRP3 geni rs4925648,
rs121908149, rs121908152 varyantları için Sequenom MassARRAY® sistemi ve İplex
GOLD SNP protokolü kullanarak genotiplendirildi ve sonrasında uygun istatistik
yöntemler ile değerlendirildi. Çalışmamız sonucunda rs4925648
(p=0.0108), rs121908149,
rs121908152 varyantlarına ait genotip frekansları ile T2DM riski arasında
istatistiksel olarak anlamlı fark bulunmamıştır.  rs4925648 bölgesi için hasta ve kontrol
bireylerde polimorfik genotip olan TT genotipine sahip olan birey bulunmazken, bireylerin
CC ve CT genotip dağılımlarının benzer düzeyde olduğu tespit edilmiştir.
Bununla birlikte rs4925648 varyasyonu için heterozigot ve dominant modeller
istatistiksel olarak anlamlıydı (p=0.048).  rs121908149 bölgesi için tüm bireyler, atasal
genotip olan CC genotpine sahip olarak belirlenmiştir. rs121908152 bölgesinde
de tüm bireyler atasal TT genotip olarak sekanslanmıştır. Bu iki varyantın
genotipik çeşitlilik göstermesi bu bölgenin korunmuş bir bölge olabileceği
şekilde yorumlanabilir. Sonuç olarak, inflamazom yapısında yer alan NLRP3
genine ait rs121908149 ve rs121908152 varyantları Türk toplumunda T2DM riski
ile ilişkili bulunmamakla birlikte rs4925648 varyantı tip 2 diyabetle ilişkili
bulunmuştur.

Kaynakça

  • 1. Halifeoğlu İ, Karataş F, Çolak R, Canatan H, Selda T. Tip 2 diyabetik hastalarda tedavi öncesi ve tedavi sonrası oksidan ve antioksidan durum. Fırat Tıp Dergisi. 2005;10:117-22.2. Burtis CA, Ashwood ER, Bruns DE. Tietz fundamentals of clinical chemistry. 2001.3. Katz MJ, Ness SM. Diabetes Mellitus, Type 2. 2014.4. Özbayer C, Kurt H, Yangı B. TLR4 ve TLR4 Sinyal Yolağındaki Genetik Varyantların İnsülin Direnci ve Diyabet Riski İle İlişkisi. Journal of Clinical and Analytical Medicine. 2014;5:168-72.5. Ginter E, Simko V: Type 2 diabetes mellitus, pandemic in 21st century. In: Diabetes. edn.: Springer; 2013: 42-50.6. Kumar V, Abbas AK, Aster JC: Robbins basic pathology: Elsevier Health Sciences; 2012.7. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes research and clinical practice. 2014;105:141-50.8. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. Journal of Clinical Investigation. 2006;116:1793.9. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481:278-86.10. Vandanmagsar B, Youm Y-H, Ravussin A et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature medicine. 2011;17:179-88.11. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821-32.12. Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194-204.13. Jourdan T, Godlewski G, Cinar R et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nature medicine. 2013;19:1132-40.14. Westwell-Roper C, Nackiewicz D, Dan M, Ehses JA. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunology and cell biology. 2014;92:314-23.15. Dixit VD. Nlrp3 inflammasome activation in type 2 diabetes: is it clinically relevant? Diabetes. 2013;62:22-4.16. Shenfield GM. Genetic polymorphisms, drug metabolism and drug concentrations. Clin Biochem Rev. 2004;25:203-6.17. Vignal A, Milan D, SanCristobal M, Eggen A. A review on SNP and other types of molecular markers and their use in animal genetics. Genet Sel Evol. 2002;34:275-305.18. Ekmekçi A, Konaç E, Önen Hİ. Gen polimorfizmi ve kansere yatkınlık. Gen. 2008;21:282-95.19. Millis MP. Medium-throughput SNP genotyping using mass spectrometry: multiplex SNP genotyping using the iPLEX(R) Gold assay. Methods Mol Biol. 2011;700:61-76.20. Zhang H-x, Wang Z-t, Lu X-x, Wang Y-g, Zhong J, Liu J. NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn’s disease (CD), in Chinese Han population. Inflammation Research. 2014;63:979-85.21. Ji X, Hou Z, Wang T et al. Polymorphisms in inflammasome genes and risk of coal workers' pneumoconiosis in a Chinese population. PLoS One. 2012;7:e47949.

The rs4925648, rs121908149 and rs121908152 Genetic Variations in the NLRP3 Inflammasome and Risk of Type 2 Diabetes

Yıl 2019, Cilt: 41 Sayı: 2, 153 - 160, 01.04.2019
https://doi.org/10.20515/otd.460753

Öz

Type 2 diabetes (T2DM) is a disease characterized by a complete or
partial deficiency of insulin, hyperglycaemia and insulin resistance.
Inflammation is the natural defensive response of the organism against any
harmful, foreign or destructive effect. Recent studies have emphasized the link
between inflammation, insulin resistance and pathogenesis of type 2 diabetes.
Inflammasome is a protein complex that recognizes stimulants with the potential
to produce inflammation and, in response, processes a process responsible for
the production and secretion of proinflammatory cytokines.
There are different types of inflammatory structures, but
NLRP3
(Nod-like
receptor pyrin domain-containing-3)
inflammasome has been
associated with type 2 diabetes, insulin resistance and obesity.
In macrophages, NLRP3 activates inflammation and
impairs insulin signaling, causes insulin resistance by TNF-dependent and
TNF-independent pathways in cells targeted to insulin. The aim of our study is
to investigate the relationship of rs10925027 and rs4925659 variants of the
NLRP3 gene. For this purpose, DNA samples isolated from blood samples of 100
T2DM patients and 100 control individuals were genotyped using the Sequenom
MassARRAY system and the Iplex GOLD SNP protocol for the NLRP3 rs10925027 and
rs4925659 variants and then evaluated with appropriate statistical methods. As
a result of our study genotype frequencies of rs4925648 (p=0.108), rs121908149,
rs121908152 variants between the risk of T2DM was not statistically significant
difference. While there was no individuals with TT genotype which were
polymorphic genotypes in the patient and control subjects for rs4925648 site,
it was found that CC and CT genotype distributions were similar. But in
heterozygous and dominant model rs4925648 site show statistically significant distribution
(p=0.048). The all individuals have CC genotype which is ancestral genotype in
the rs121908149. Also in the rs121908152 region, all individuals were sequenced
as ancestral TT genotype. The genotypic variation of these variants can be
interpreted as this region can be a protected region. In conclusion,
rs121908149 and rs121908152 variants from the NLRP3 gene in the structure of
the inflammasome could not be associated with T2DM risk in patients with
Turkish origin while rs4925648 variant was found to be associated with type 2
diabetes.

Kaynakça

  • 1. Halifeoğlu İ, Karataş F, Çolak R, Canatan H, Selda T. Tip 2 diyabetik hastalarda tedavi öncesi ve tedavi sonrası oksidan ve antioksidan durum. Fırat Tıp Dergisi. 2005;10:117-22.2. Burtis CA, Ashwood ER, Bruns DE. Tietz fundamentals of clinical chemistry. 2001.3. Katz MJ, Ness SM. Diabetes Mellitus, Type 2. 2014.4. Özbayer C, Kurt H, Yangı B. TLR4 ve TLR4 Sinyal Yolağındaki Genetik Varyantların İnsülin Direnci ve Diyabet Riski İle İlişkisi. Journal of Clinical and Analytical Medicine. 2014;5:168-72.5. Ginter E, Simko V: Type 2 diabetes mellitus, pandemic in 21st century. In: Diabetes. edn.: Springer; 2013: 42-50.6. Kumar V, Abbas AK, Aster JC: Robbins basic pathology: Elsevier Health Sciences; 2012.7. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes research and clinical practice. 2014;105:141-50.8. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. Journal of Clinical Investigation. 2006;116:1793.9. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481:278-86.10. Vandanmagsar B, Youm Y-H, Ravussin A et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature medicine. 2011;17:179-88.11. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821-32.12. Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194-204.13. Jourdan T, Godlewski G, Cinar R et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nature medicine. 2013;19:1132-40.14. Westwell-Roper C, Nackiewicz D, Dan M, Ehses JA. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunology and cell biology. 2014;92:314-23.15. Dixit VD. Nlrp3 inflammasome activation in type 2 diabetes: is it clinically relevant? Diabetes. 2013;62:22-4.16. Shenfield GM. Genetic polymorphisms, drug metabolism and drug concentrations. Clin Biochem Rev. 2004;25:203-6.17. Vignal A, Milan D, SanCristobal M, Eggen A. A review on SNP and other types of molecular markers and their use in animal genetics. Genet Sel Evol. 2002;34:275-305.18. Ekmekçi A, Konaç E, Önen Hİ. Gen polimorfizmi ve kansere yatkınlık. Gen. 2008;21:282-95.19. Millis MP. Medium-throughput SNP genotyping using mass spectrometry: multiplex SNP genotyping using the iPLEX(R) Gold assay. Methods Mol Biol. 2011;700:61-76.20. Zhang H-x, Wang Z-t, Lu X-x, Wang Y-g, Zhong J, Liu J. NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn’s disease (CD), in Chinese Han population. Inflammation Research. 2014;63:979-85.21. Ji X, Hou Z, Wang T et al. Polymorphisms in inflammasome genes and risk of coal workers' pneumoconiosis in a Chinese population. PLoS One. 2012;7:e47949.
Toplam 1 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Sağlık Kurumları Yönetimi
Bölüm ORİJİNAL MAKALELER / ORIGINAL ARTICLES
Yazarlar

Cansu Ozbayer 0000-0002-1120-1874

Medine Nur Kebapçı Bu kişi benim 0000-0002-8286-5256

Emine Yağcı Bu kişi benim 0000-0003-2179-1318

Hülyam Kurt Bu kişi benim 0000-0003-2433-9925

Hasan Veysi Güneş Bu kişi benim 0000-0002-0932-906X

İrfan Değirmenci Bu kişi benim 0000-0001-7666-0230

Yayımlanma Tarihi 1 Nisan 2019
Yayımlandığı Sayı Yıl 2019 Cilt: 41 Sayı: 2

Kaynak Göster

Vancouver Ozbayer C, Kebapçı MN, Yağcı E, Kurt H, Güneş HV, Değirmenci İ. NLRP3 İnflamazom Geni rs4925648, rs121908149 ve rs121908152 Varyantları ile Tip 2 Diyabet Riski. Osmangazi Tıp Dergisi. 2019;41(2):153-60.


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