Program on Genomics and Nutrition, Department of Epidemiology, University of California, Los Angeles, California, USA.
Obesity (Silver Spring). 2010 Sep;18(9):1812-20. doi: 10.1038/oby.2009.496. Epub 2010 Jan 28.
Adipocypte fatty acid-binding protein-4 (FABP4/adipocyte P2) may play a central role in energy metabolism and inflammation. In animal models, defects of the aP2 gene (aP2(-/-)) partially protected against the development of obesity-related insulin resistance, dyslipidemia, and atherosclerosis. However, it is unclear whether common genetic variation in FABP4 gene contributes to risk of type 2 diabetes (T2D) or diabetes-related metabolic traits in humans. We comprehensively assess the genetic associations of variants in the FABP4 gene with T2D risk and diabetes-associated biomarkers in a prospective study of 1,529 cases and 2,147 controls among postmenopausal women aged 50-79 years who enrolled in the Women's Health Initiative Observational Study (WHI-OS). We selected and genotyped a total of 11 haplotype-tagging single-nucleotide polymorphisms (tSNPs) spanning 41.3 kb across FABP4 in all samples. None of the SNPs and their derived haplotypes showed significant association with T2D risk. There were no significant associations between SNPs and plasma levels of inflammatory and endothelial biomarkers, including C-reactive protein, tumor necrosis factor (TNF), interleukin-6 (IL-6), E-selectin, and intercellular adhesion molecule (ICAM-1). Among African-American women, several SNPs were significantly associated with lower levels of vascular cell adhesion molecule-1 (VCAM-1), especially among those with incident T2D. On average, plasma levels of VCAM-1 were significantly lower among carriers of each minor allele at rs1486004(C/T; -1.08 ng/ml, P = 0.01), rs7017115(A/G; -1.07 ng/ml, P = 0.02), and rs2290201(C/T; -1.12 ng/ml, P = 0.002) as compared with the homozygotes of the common allele, respectively. After adjusting for multiple testing, carriers of the rs2290201 minor allele remained significantly associated with decreasing levels of plasma VCAM-1 in these women (P = 0.02). In conclusion, our finding from a multiethnic cohort of postmenopausal women did not support the notion that common genetic variants in the FABP4 gene may trigger increased risk of T2D. The observed significant association between reduced VCAM-1 levels and FABP4 genotypes in African-American women warrant further confirmation.
脂肪细胞脂肪酸结合蛋白-4（FABP4/脂肪细胞 P2）可能在能量代谢和炎症中发挥核心作用。在动物模型中，aP2 基因缺陷（aP2(-/-)）部分保护了肥胖相关的胰岛素抵抗、血脂异常和动脉粥样硬化的发展。然而，常见的 FABP4 基因突变是否导致 2 型糖尿病（T2D）或人类糖尿病相关代谢特征尚不清楚。我们在一项前瞻性研究中综合评估了 FABP4 基因变异与 T2D 风险和糖尿病相关生物标志物之间的遗传关联，该研究纳入了年龄在 50-79 岁的绝经后女性 1529 例病例和 2147 例对照，这些女性参加了妇女健康倡议观察研究（WHI-OS）。我们在所有样本中选择并对横跨 FABP4 的 41.3kb 范围内的 11 个单倍型标签单核苷酸多态性（tSNP）进行了基因分型。没有发现 SNP 及其衍生的单倍型与 T2D 风险显著相关。SNP 与炎症和内皮生物标志物（包括 C 反应蛋白、肿瘤坏死因子（TNF）、白细胞介素 6（IL-6）、E-选择素和细胞间黏附分子（ICAM-1））的血浆水平之间没有显著关联。在非裔美国女性中，几个 SNP 与血管细胞黏附分子-1（VCAM-1）水平降低显著相关，尤其是在那些新发 T2D 的女性中。平均而言，与常见等位基因 rs1486004(C/T)、rs7017115(A/G)和 rs2290201(C/T)的每个次要等位基因携带者相比，血浆 VCAM-1 水平分别显著降低 1.08ng/ml（P=0.01）、1.07ng/ml（P=0.02）和 1.12ng/ml（P=0.002）。在调整了多重检验后，这些女性携带 rs2290201 次要等位基因的个体仍与血浆 VCAM-1 水平降低显著相关（P=0.02）。总之，我们在一个多民族绝经后女性队列中的发现并不支持常见的 FABP4 基因突变可能会增加 T2D 风险的观点。在非裔美国女性中观察到的 VCAM-1 水平降低与 FABP4 基因型之间的显著关联需要进一步证实。
