Hixson J E, Almasy L, Cole S, Birnbaum S, Mitchell B D, Mahaney M C, Stern M P, MacCluer J W, Blangero J, Comuzzie A G
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245, USA.
J Clin Endocrinol Metab. 1999 Sep;84(9):3187-91. doi: 10.1210/jcem.84.9.5951.
We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.
我们之前报道过，我们的基因组扫描计划在墨西哥裔美国家庭中检测到2号染色体上的一个数量性状位点（QTL）与瘦素水平之间存在高度显著的连锁关系（对数优势比 = 4.95；P = 9×10⁻⁷）。我们现在在该区域对更多微卫星标记进行了分型，将这个对数优势比分数提高到了7.46（P = 2×10⁻⁹）。2号染色体的这个区域包含一个强有力的位置候选基因，即阿黑皮素原（POMC）基因。POMC基因编码POMC，α-促黑素（αMSH）、促肾上腺皮质激素（ACTH）和β-内啡肽均由该前体激素衍生而来。其他研究表明，POMC衍生产物参与食欲和肥胖的调节。我们利用POMC中的多态性来确定其在QTL连锁信号峰值的95%置信区间内的位置。我们还利用这些多态性构建了POMC单倍型，并发现其与瘦素水平的正常变异存在显著关联（P = 0.001）。我们得出结论，POMC的变异与血清瘦素水平的正常变异相关，这进一步证明POMC可能是之前在墨西哥裔美国家庭中鉴定出的瘦素QTL。
