The Gene-gene Interaction of INSIG-SCAP-SREBP Pathway on the Risk of Obesity in Chinese Children

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2014 Jul 17

PMID 25028659

Citations 12

Authors

Fang-Hong Liu

Jie-Yun Song

Xiao-Rui Shang

Xiang-Rui Meng

Jun Ma

Hai-Jun Wang

Affiliations

Soon will be listed here.

Abstract

Background: Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG-SCAP-SREBP pathway with obesity in Chinese children.

Methods: A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP-SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions.

Results: Single polymorphism analyses showed that SCAP rs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses (P = 0.001), involving 3 genetic variants of INSIG2, SCAP, and SREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR = 1.799, 95% CI: 1.475-2.193, P = 6.61 × 10(-9)).

Conclusion: We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect.

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References

Gao X . Multiple testing corrections for imputed SNPs. Genet Epidemiol. 2011; 35(3):154-8. PMC: 3055936. DOI: 10.1002/gepi.20563. View

Lyon H, Emilsson V, Hinney A, Heid I, Lasky-Su J, Zhu X . The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet. 2007; 3(4):e61. PMC: 1857727. DOI: 10.1371/journal.pgen.0030061. View

Wang Y, Lim H . The global childhood obesity epidemic and the association between socio-economic status and childhood obesity. Int Rev Psychiatry. 2012; 24(3):176-88. PMC: 4561623. DOI: 10.3109/09540261.2012.688195. View

Wang H, Zhang H, Zhang J, Wang Y, Ma J . [Association of abnormal lipid metabolism with INSIG2 gene variant in overweight and obese children]. Zhonghua Liu Xing Bing Xue Za Zhi. 2010; 31(6):650-4. View

Brown A, Sun L, Feramisco J, Brown M, Goldstein J . Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell. 2002; 10(2):237-45. DOI: 10.1016/s1097-2765(02)00591-9. View

Baylin A, Deka R, Tuitele J, Viali S, Weeks D, McGarvey S . INSIG2 variants, dietary patterns and metabolic risk in Samoa. Eur J Clin Nutr. 2012; 67(1):101-7. PMC: 3634362. DOI: 10.1038/ejcn.2012.124. View

Hall D, Rahman T, Avery P, Keavney B . INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families. BMC Med Genet. 2006; 7:83. PMC: 1698479. DOI: 10.1186/1471-2350-7-83. View

Wang H, Zhang H, Zhang S, Pan Y, Ma J . Association of the common genetic variant upstream of INSIG2 gene with obesity related phenotypes in Chinese children and adolescents. Biomed Environ Sci. 2009; 21(6):528-36. DOI: 10.1016/S0895-3988(09)60013-1. View

Le Hellard S, Theisen F, Haberhausen M, Raeder M, Ferno J, Gebhardt S . Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?. Mol Psychiatry. 2008; 14(3):308-17. DOI: 10.1038/sj.mp.4002133. View

10.

Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, Hosono N . Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet. 2012; 44(3):302-6. PMC: 3838874. DOI: 10.1038/ng.1086. View

11.

Ji C . Report on childhood obesity in China (1)--body mass index reference for screening overweight and obesity in Chinese school-age children. Biomed Environ Sci. 2006; 18(6):390-400. View

12.

Grarup N, Stender-Petersen K, Andersson E, Jorgensen T, Borch-Johnsen K, Sandbaek A . Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects. Diabetes. 2008; 57(4):1136-42. DOI: 10.2337/db07-1534. View

13.

Smith A, Cooper J, Li L, Humphries S . INSIG2 gene polymorphism is not associated with obesity in Caucasian, Afro-Caribbean and Indian subjects. Int J Obes (Lond). 2007; 31(11):1753-5. DOI: 10.1038/sj.ijo.0803645. View

14.

Wang D, Ma J, Zhang S, Hinney A, Hebebrand J, Wang Y . Association of the MC4R V103I polymorphism with obesity: a Chinese case-control study and meta-analysis in 55,195 individuals. Obesity (Silver Spring). 2009; 18(3):573-9. DOI: 10.1038/oby.2009.268. View

15.

Mei H, Cuccaro M, Martin E . Multifactor dimensionality reduction-phenomics: a novel method to capture genetic heterogeneity with use of phenotypic variables. Am J Hum Genet. 2007; 81(6):1251-61. PMC: 2276344. DOI: 10.1086/522307. View

16.

Reinehr T, Hinney A, Toschke A, Hebebrand J . Aggravating effect of INSIG2 and FTO on overweight reduction in a one-year lifestyle intervention. Arch Dis Child. 2009; 94(12):965-7. DOI: 10.1136/adc.2008.147652. View

17.

Shimano H . SREBPs: physiology and pathophysiology of the SREBP family. FEBS J. 2009; 276(3):616-21. DOI: 10.1111/j.1742-4658.2008.06806.x. View

18.

Sakai J, Nohturfft A, Cheng D, Ho Y, Brown M, Goldstein J . Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J Biol Chem. 1997; 272(32):20213-21. DOI: 10.1074/jbc.272.32.20213. View

19.

Eberle D, Clement K, Meyre D, Sahbatou M, Vaxillaire M, Le Gall A . SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts. Diabetes. 2004; 53(8):2153-7. DOI: 10.2337/diabetes.53.8.2153. View

20.

Kumar J, Sunkishala R, Karthikeyan G, Sengupta S . The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population. Clin Genet. 2007; 71(5):415-8. DOI: 10.1111/j.1399-0004.2007.00795.x. View