Effects of environment and genetic interactions on chronic metabolic diseases

Transcription

1 Chinese Bulletin of Life Sciences Vol. 22, No. 1 Jan., (2010) ( ) R151; R589; R587.1; R A Effects of environment and genetic interactions on chronic metabolic diseases LIN Xu (Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai , China) Abstract Owing to rapid economic development and nutrition transition, obesity and type 2 diabetes epidemics have become one of major health challenges in China. Compared with western populations, Asian people are known to have higher genetic predisposition for type 2 diabetes, which may link to commonly observed metabolically obese phenotype and also encounter unhealthy diet and lifestyle associated obesogenic environment. It has been well established that these metabolic diseases are caused by a complex interplay of multiple genetic variants and environmental factors. With recent success of genome-wide association studies (GWAS), approximately 20 loci have been discovered to be associated with the predisposition of obesity and type 2 diabetes. Although there are ethical differences regarding gene frequency and genetic effective size, which could not fully explain differences in the disease susceptibility. Therefore, lifestyle factors including dietary pattern, nutrients and physical activity are still considered as major determinants in the pathogenesis of type 2 diabetes and other metabolic diseases. In post GWAS era, the international trends in this research area will put more emphases on the interactions of gene-gene, gene-diet, and gene-phenotype. Existing studies have xlin@sibs.ac.cn

2 2 suggested that the genetic variants, inflammatory cytokines and adipocytokines could be used as predictive biomarkers in early diagnosis of chronic metabolic diseases. Meanwhile diet and lifestyle interventions have been internationally recoginized as the most effective strategy in controlling metabolic diseases. However, few large-scale prospective studies have been conducted in Chinese population to systematically investigate the effects of gene variants, environmental factors and their interaction on pathogenesis of chronic metabolic diseases. The evidence from these studies however would provide a solid scientific basis for establishing effective strategies which could be used in early diagnosis and disease prevention corresponding to Chinese genotype and phenotype. Key words: obesity; type 2 diabetes; metabolic diseases; gene environment interaction [1] (1) (2) 2 (BMI) (3) BMI (4) β (5) [1] (Nurses Health Study) BMI 2 2 [2] 2 2 (1) BMI 2 (2) (obesogenic environment) 2 (3) (4) [1] FTO CDKAL1 SLC30A FTO 2 β β [3-8] 2 2 TCF7L2 (SNP) rs rs

3 3 2 rs kb rs [9,10 ] FTO 2 (MAF) (Haplotype) (LD) FTO [11] 2 β 2 [12] ( D) [13 ] 2 (JAMA) 2005 Appel [14] (48% 27% 25% ) (48% 37% 15% ) (58% 27% 15% ) 2007 Atkins (45%~55% 18%~35% ) Ornish (21%~30% 52%~63% ) [15] Shai [16] 2008 (40% 40% ) (30% 50% ) Ornish (dietary reference intakes DRIs) 20%~30% %~35% 1~2 Atkins ( ) Atkins 2 ( 59%~75%) (95% 1.09~1.50) ( 200 g/d 300 g/d) (95% 1.48~2.15) [3]

4 4 [17] 2 4 PPARG Pro12Ala 2 SNP SNP Pro12Pro 2 Ala Hum Mol Genet Pro12Ala BMI [18] Pro12Pro BMI Ala12 BMI Ala12 BMI Pro12Pro FTO FTO SNP rs A BMI (Diabetes) FTO BMI A [19] 2009 (American Journal of Clinical Nutrition) Frank Hu CDKAL1 IGF2BP ( =12) 2 ( <10) 2.75 (NIH) (Genes, Environment, and Health Initiative, GEI) (Genetic Program) (Exposure Biology Program) (genome-wide association study, GWAS) PPARG Pro12Ala CAPN10 43G>A 44T>C SNP 2 [20] CRP IL6 BMI 2 [21] CRP [22]

5 5 2 (CDKAL1 CDKN2A/B IGF2BP2 SLC30A8 GCKR KCNQ1) (CRP IL6) (Adiponectin RBP4 Resistin) CRP CRP CRP CRP [23] 2 80% 2 40% (DPP) 3 (Metformin) 2 58% 31% TCF7L2 rs TT CC 2 [24] % [25] ( ) 2 (1) (2) (3) (4) (5)

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