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Effects of TLR4 Variants on Fasting Glucose Levels in a Korean Population

한국인에서 TLR4 변이가 공복 시 혈당에 미치는 효과

  • Kim, Gi Tae (Department of Senior Healthcare, General Graduate School, Eulji University) ;
  • Sull, Jae Woong (Department of Senior Healthcare, General Graduate School, Eulji University) ;
  • Jee, Sun Ha (Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University)
  • 김기태 (을지대학교 대학원 시니어헬스케어학과) ;
  • 설재웅 (을지대학교 대학원 시니어헬스케어학과) ;
  • 지선하 (연세대학교 보건대학원)
  • Received : 2017.07.20
  • Accepted : 2017.09.20
  • Published : 2017.12.31

Abstract

Diabetes mellitus is associated with a variety of adverse health outcomes, including metabolic syndrome and cardiovascular diseases. Recently, diabetes has been receiving increased scientific attention because of the rapid increase in the diabetic population. One of the features of type-2 diabetes mellitus is an elevated glucose level in blood. Fasting glucose level, which is the most basic test, is widely used as a diagnostic indicator of diabetes. Several previous studies reported that TLR4 expression is relatively high in the heart. However, few studies have investigated the association between TLR4 variants and fasting blood glucose to date. Thus, this study tested the association between single nucleotide polymorphisms (SNPs) in the TLR4 gene and fasting glucose in the Korean population. A total of 994 subjects recruited from Seoul were used for the present study. When compared to fasting blood glucose, the TLR4 gene region was shown as a linkage disequilibrium owing to the relatively large gene range. This region also presented as several LD blocks. We found that specific SNPs in the TLR4 gene were associated with the mean fasting glucose (p<0.01). The minor allele frequency of rs1329067 was 16.4%, and individuals with the AA genotype had a higher fasting blood glucose level than those with the GG genotype, suggesting that genetic variants in TLR4 influence glucose levels in Korean adults.

당뇨병은 대사 증후군 및 심혈관 질환을 비롯한 다양한 건강상의 부작용과 관련이 있다. 또한 당뇨병의 증가로 사회 및 의학적 관심이 증가하고 있다. 제 2 형 당뇨병의 특징 중 하나는 혈당이 증가한다는 것이다. 공복 혈당치는 가장 기본적이고 널리 사용되는 당뇨병의 지표이다. TLR4 발현은 심장에서 비교적 높다. 그러나 공복 시 혈당과 TLR4의 관련성에 대한 연구가 있었다. 한국인에서 TLR4 유전자와 공복 시 혈당의 단일 염기 다형성(SNP)의 관련성을 알아 보았다. 서울시에서 총 994 명을 대상으로 TLR4 SNP를 이용한 연구를 실시했다. 공복 시 혈당과 관련하여 TLR4 유전자 영역은 연쇄 불균형으로 나타 났으며 유전자의 범위가 매우 크기 때문에 여러 개의 LD 블록으로 보였다. TLR4 유전자의 SNP는 평균 공복 시 혈당과 관련이 있었다(p<0.01). 공복 시 혈당과 관련 크기는 p-value를 $-log^{10}$의 값으로 하였다. rs1329067의 minor allele frequency는 16.4%였고 AA 유전자형을 가진 사람들은 GG 유전자형을 가진 사람들 보다 공복 시 혈당이 높았다. 이 연구는 TLR4의 유전 적 변이가 한국 성인의 혈당 수치에 영향을 미친다는 것을 암시한다.

Keywords

References

  1. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015:4:212283.doi:10.7573/dic.212283.
  2. Kwon SY, Na YA. The cutoff value of HbA1c in predicting diabetes and impaired fasting glucose. Korean J Clin Lab Sci. 2017;49(2):114-120. https://doi.org/10.15324/kjcls.2017.49.2.114
  3. Li M, Song L, Gao X, Chang W, Qin X. Toll-like receptor 4 on islet ${\beta}$ cells senses expression changes in high-mobility group box 1 and contributes to the initiation of type 1 diabetes. Exp Mol Med. 2012;44(4):260-7. https://doi.org/10.3858/emm.2012.44.4.021
  4. Trudler D, Farfara D, Frenkel D. Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application. Mediators Inflamm. 2010;2010. http://dx.doi.org/10.1155/2010/497987.
  5. Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, et al. Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis. 1998;24(3):340-355. https://doi.org/10.1006/bcmd.1998.0201
  6. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors-redefining innate immunity. Nat rev Immunol. 2013; 13(6):453-460. https://doi.org/10.1038/nri3446
  7. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015-3025. https://doi.org/10.1172/JCI28898
  8. Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes. 2008; 57(10):2595-2602. https://doi.org/10.2337/db08-0038
  9. Weyrich P, Staiger H, Stancakova A, Machicao F, Machann J, Schick F, et al. The D299G/T399I Toll-like receptor 4 variant associates with body and liver fat: results from the TULIP and METSIM Studies. PLoS One. 2010;5(11):e13980. doi:10.1371/journal.pone.0013980.
  10. Illig T, Bongardt F, Schopfer A, Holle R, Muller S, Rathmann W, et al. The endotoxin receptor TLR4 polymorphism is not associated with diabetes or components of the metabolic syndrome. Diabetes. 2003;52(11):2861-2867. https://doi.org/10.2337/diabetes.52.11.2861
  11. Kolz M, Baumert J, Muller M, Khuseyinova N, Klopp N, Thorand B, et al. Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol. BMC Med Genet. 2008;9:9. doi:10.1186/1471-2350-9-9.
  12. de Araujo MFM, Veras VS, de Freitas RWJF, de Paula MDL, de Araujo TM, Uchoa LRA, et al. The effect of flour from the rind of the yellow passion fruit on glycemic control of people with diabetes mellitus type 2: a randomized clinical trial. J Diabetes Metab Disord. 2017;16(4):18. doi:10.1186/s40200-017-0300-z.
  13. American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;36(suppl1):11-66. https://doi.org/10.2337/dc13-S011.
  14. Dom M, Calder A, Mat R. Clinical epidemiological characteristics of acute complications of diabetes in the emergency ward at Atizapan General Hospital. Rev Fac Med. 2013;56(2):25-36.
  15. Al-Daghri NM, Clerici M, Al-Attas O, Forni D, Alokail MS, Alkharfy KM, et al. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J Immunol. 2013;190(7):3716-3720. https://doi.org/10.4049/jimmunol.1202936
  16. Peng D, Jiang F, Zhang R, Tang S, Chen M, Yan J, et al. Association of Toll-like Receptor 4 Gene polymorphisms with susceptibility to type 2 diabetes mellitus in the Chinese population. J Diabetes. 2015;7(4):485-492. https://doi.org/10.1111/1753-0407.12206
  17. Ahmad R, Al-Mass A, Atizado V, Al-Hubail A, Al-Ghimlas F, Al-Arouj M, et al. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J Inflamm (Lond). 2012;9(1):48. doi:10.1186/1476-9255-9-48.
  18. Jiang ZS, Wang SX, Jia HX, Wang J, Liu YT. Association of toll-like receptor 4 polymorphisms with type 2 diabetes mellitus. Inflammation. 2013;36(1):251-257. https://doi.org/10.1007/s10753-012-9541-7
  19. U.S. National Library of Medicine. Reference SNP (refSNP) Cluster Report: rs1329067 [Internet]. Rockville: National Center for Biotechnology information; 2013 [cited 2017 June 16]. Available from: https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1329067.

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