De Luca Maria, Chambers Michelle Moses, Casazza Krista, Lok Kerry H, Hunter Gary R, Gower Barbara A, Fernández José R
Department of Nutrition Sciences, School of Health Professions, University of Alabama at Birmingham, 3rd Avenue South, Birmingham, AL 35294-3360, USA.
BMC Genet. 2008 Aug 11;9:52. doi: 10.1186/1471-2156-9-52.
The objective of the present study was to map candidate loci influencing naturally occurring variation in triacylglycerol (TAG) storage using quantitative complementation procedures in Drosophila melanogaster. Based on our results from Drosophila, we performed a human population-based association study to investigate the effect of natural variation in LAMA5 gene on body composition in humans.
We identified four candidate genes that contributed to differences in TAG storage between two strains of D. melanogaster, including Laminin A (LanA), which is a member of the alpha subfamily of laminin chains. We confirmed the effects of this gene using a viable LanA mutant and showed that female flies homozygous for the mutation had significantly lower TAG storage, body weight, and total protein content than control flies. Drosophila LanA is closely related to human LAMA5 gene, which maps to the well-replicated obesity-linkage region on chromosome 20q13.2-q13.3. We tested for association between three common single nucleotide polymorphisms (SNPs) in the human LAMA5 gene and variation in body composition and lipid profile traits in a cohort of unrelated women of European American (EA) and African American (AA) descent. In both ethnic groups, we found that SNP rs659822 was associated with weight (EA: P = 0.008; AA: P = 0.05) and lean mass (EA: P= 0.003; AA: P = 0.03). We also found this SNP to be associated with height (P = 0.01), total fat mass (P = 0.01), and HDL-cholesterol (P = 0.003) but only in EA women. Finally, significant associations of SNP rs944895 with serum TAG levels (P = 0.02) and HDL-cholesterol (P = 0.03) were observed in AA women.
Our results suggest an evolutionarily conserved role of a member of the laminin gene family in contributing to variation in weight and body composition.
本研究的目的是利用黑腹果蝇中的定量互补程序来定位影响三酰甘油（TAG）储存自然变异的候选基因座。基于我们在果蝇中的研究结果，我们进行了一项基于人群的关联研究，以调查LAMA5基因的自然变异对人体成分的影响。
我们鉴定出四个导致黑腹果蝇两个品系之间TAG储存差异的候选基因，包括层粘连蛋白A（LanA），它是层粘连蛋白链α亚家族的成员。我们使用一个可行的LanA突变体证实了该基因的作用，并表明该突变纯合的雌性果蝇的TAG储存、体重和总蛋白含量显著低于对照果蝇。果蝇LanA与人类LAMA5基因密切相关，该基因定位于20号染色体q13.2-q13.3上复制良好的肥胖连锁区域。我们在一组欧美（EA）和非裔美国（AA）血统的无关女性队列中，测试了人类LAMA5基因中的三个常见单核苷酸多态性（SNP）与身体成分和脂质谱特征变异之间的关联。在这两个种族群体中，我们发现SNP rs659822与体重（EA：P = 0.008；AA：P = 0.05）和瘦体重（EA：P = 0.003；AA：P = 0.03）相关。我们还发现该SNP与身高（P = 0.01）、总脂肪量（P = 0.01）和高密度脂蛋白胆固醇（P = 0.003）相关，但仅在EA女性中如此。最后，在AA女性中观察到SNP rs944895与血清TAG水平（P = 0.02）和高密度脂蛋白胆固醇（P = 0.03）有显著关联。
我们的结果表明，层粘连蛋白基因家族的一个成员在导致体重和身体成分变异方面具有进化保守的作用。
