Interactions of smoking with rs833061 polymorphism on the risk of non-alcoholic fat liver disease in Hubei Han population: a preliminary case–control study

Document Type : Original Article

Authors

1 Department of Gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road, Wuhan, China

2 Department of Gastroenterology, Renmin Hospital of Tongcheng, Minzhu Road 120, Hubei, China

Abstract

Objective(s):Vascular endothelial growth factor (VEGF) has biological actions on energy homeostasis, inflammation and insulin resistance. The present study aimed to investigate the association between VEGF -460 T/C (rs833061), and +936 C/T (rs3025039) polymorphism and risk of non-alcohol fatty liver disease (NAFLD) in Hubei Han population and to further explore the interactions of smoking with rs833061 and rs3025039.
Materials and Methods:341 healthy controls and 246 cases were recruited. Two variants, rs833061 and rs3025039, were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The unconditional logistic regression (ULR) was performed to assess the association of the two variants with risk of NAFLD. Gene-environment interactions on the risk of NAFLD were preliminarily explored by generalized multifactor dimensionality reduction (GMDR) and further confirmed by ULR methods.
Results:After adjusting for covariates, increased risk of NAFLD was observed in patients carrying CT/CC genotypes in rs833061 and rs3025039 (ORa=1.80, 95% confidence interval (CI): 1.51, 2.36, Pa=0.000; ORa=1.89, 95% CI: 1.41, 2.82, Pa=0.000, respectively). Interaction of smoking with rs833061 was found by GMDR, with maximum prediction accuracy (67.91%) and a maximum cross-validation consistency (10/10). ULR method confirmed that, smoking-positive patients with genotype CT/CC had 4.93 times risk of NAFLD compared to smoking-negative participants with genotype TT (ORadda=4.93, 95% CI:2.91, 8.54, Padda=0.000), which further confirmed synergistic effects.
Conclusion: The results indicated that both rs833061 and rs3025039 are associated with NAFLD risk. Furthermore, rs833061 is likely to have an interaction with smoking, and they have synergistic effects on risk of NAFLD in Hubei Han population.

Keywords


1. Mendez-Sanchez N, Arrese M, Zamora-Valdes D, Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver disease. Liver Int 2007; 27:423-433.
2. Zhou YJ, Li YY, Nie YQ, Ma JX, Lu LG, Shi SL, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol 2007; 13:6419-6424.
3. Macut D, Bjekic-Macut J, Savic-Radojevic A. Dys-lipidemia and oxidative stress in PCOS. Front Horm Res 2013; 40:51-63.
4. San Millan JL, Corton M, Villuendas G, Sancho J, Peral B, Escobar-Morreale HF. Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab 2004; 89:2640-2646.
5. Zhang C, Guo L, Guo X. [Interaction of polymer-phisms of Leptin receptor gene Gln223Arg, MnSOD9Ala/Val genes and smoking in nonalcoholic fatty liver disease]. Wei Sheng Yan Jiu 2014; 43:724-731. (China)
6. Yang Z, Wen J, Li Q, Tao X, Ye Z, He M, et al. PPARG gene Pro12Ala variant contributes to the development of non-alcoholic fatty liver in middle-aged and older Chinese population. Mol Cell Endocrinol 2012; 348:255-259.
7. Oniki K, Hori M, Saruwatari J, Morita K, Kajiwara A, Sakata M, et al. Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease. Toxicol lett 2013; 220:143-149.
8. Elias I, Franckhauser S, Bosch F. New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance. Adipocyte 2013; 2:109-112.
9.Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci USA 2012; 109:5874-5879.
10. Murray CJ, Roth G. Progress and challenges in the fight against smoking and cardiovascular disease. Eur Heart J 2014; 35:1625-1627.
11.Liu Y, Dai M, Bi Y, Xu M, Xu Y, Li M, et al. Active smoking, passive smoking, and risk of nonalcoholic fatty liver disease (NAFLD): a population-based study in China. J Epidemiol 2013; 23:115-121.
12. Fatty Liver and Alcoholic Liver Disease Study Group of Chinese Liver Disease Association. Diagnostic criteria of nonalcoholic fatty liver disease. Chin J Hepatol 2003; 11:71. (China)
13. Jiang LL, Li L, Hong XF, Li YM, Zhang BL. Patients with nonalcoholic fatty liver disease display increased serum resistin levels and decreased adiponectin levels. Eur J Gastroenterol Hepatol 2009; 21:662-666.
14. Lou XY, Chen GB, Yan L, Ma JZ, Zhu J, Elston RC, et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet 2007; 80:1125-1137.
15. Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A. Calculating measures of biological interaction. Eur J Epidemiol 2005; 20:575-579.
16. Belo VA, Souza-Costa DC, Luizon MR, Izidoro-Toledo TC, Lanna CM, Pinheiro LC, et al. Vascular endothelial growth factor haplotypes associated with childhood obesity. DNA Cell Biol 2011; 30:709-714.
17. Moradzadegan A, Vaisi-Raygani A, Nikzamir A, Rahimi Z. Angiotensin converting enzyme insertion/-deletion (I/D) (rs4646994) and Vegf polymorphism (+405G/C; rs2010963) in type II diabetic patients: Association with the risk of coronary artery disease. J Renin Angiotensin Aldosterone Syst 2014; 16:672-680.
18. Guruvaiah P, Govatati S, Reddy TV, Lomada D, Deenadayal M, Shivaji S, et al. The VEGF +405 G>C 5' untranslated region polymorphism and risk of PCOS: a study in the South Indian Women. J Assist Reprod Genet 2014; 31:1383-1389.
19. Sivaprasad S, Govardhan B, Harithakrishna R, Venkat Rao G, Pradeep R, Kunal B, et al. Association of vascular endothelial growth factor (VEGF) gene polymorphism and increased serum VEGF concentration with pancreatic adenocarcinoma. Pancreatology 2013; 13:267-272.
20. Kim HW, Ko GJ, Kang YS, Lee MH, Song HK, Kim HK, et al. Role of the VEGF 936 C/T polymorphism in diabetic microvascular complications in type 2 diabetic patients. Nephrology (Carlton) 2009; 14:681-688.
21. Chiolero A, Faeh D, Paccaud F, Cornuz J. Consequences of smoking for body weight, body fat distribution, and insulin resistance. Am J Clin Nutr 2008; 87:801-809.
22. Zhang LW, Li JP, Duan FF, Liu ZK, Zhan SY, Hu YH, et al. Interaction of type 2 diabetes mellitus with chromosome 9p21 rs10757274 polymorphism on the risk of myocardial infarction: a case-control study in Chinese population. BMC Cardiovasc Disord 2014; 14:170.
23. Fesinmeyer MD, North KE, Lim U, Buzkova P, Crawford DC, Haessler J, et al. Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study. BMC Med Genet 2013; 14:6.
24. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 2008; 28:386-395.