Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, P.O. Box 285, Cambridge, CB5 8QD, United Kingdom.
Eur J Pharmacol. 2011 Jun 11;660(1):156-64. doi: 10.1016/j.ejphar.2011.01.033. Epub 2011 Feb 2.
While rare MC4R mutations are the commonest cause of monogenic forms of extreme, early-onset obesity, growing evidence shows that common MC4R variants contribute to obesity in the general population. Candidate gene studies have focussed on the V103I and I251L MC4R variants that both affect MC(4) receptor function in vitro. Individual association studies, which are typically small and underpowered, have found no association between V103I (frequency of 103I-allele: ~4%) or I251L (251L-allele: ~2%) and the risk of obesity in the general population. However, large-scale meta-analyses have confirmed that both variants reduce the risk of obesity by -21% in 103I-allele carriers (P<10(-4)) and by -50% in 251L-allele carriers (P<10(-4)). Recently, genome-wide association studies have identified a common variant (minor allele frequency: ~27%) at ~188kb downstream of MC4R showing robust association (P<5×10(-8)) with BMI and obesity in adults and children. Each additional minor allele increases BMI by 0.20kg/m(2), body weight by 700-1000g, and obesity risk by 14% in adults. Interestingly, this variant also showed association with increased height, consistent with the phenotype seen for rare MC4R mutations. Although MC4R is the nearest gene and phenotypic associations are consistent with those of MC4R mutations, it has not yet been established whether this variant indeed reflects MC(4) receptor function. Taken together, common MC4R variants contribute to variation in BMI and obesity risk in the general population. Of particular interest is the finding from genome-wide association studies that suggests that the region downstream of MC4R contributes to its regulation.
虽然罕见的 MC4R 突变是导致单基因形式的极端早发性肥胖的最常见原因，但越来越多的证据表明，常见的 MC4R 变体在普通人群中也与肥胖有关。候选基因研究集中在 V103I 和 I251L MC4R 变体上，这两种变体都在体外影响 MC(4)受体功能。个体关联研究通常规模较小且效力不足，没有发现 V103I（103I-等位基因频率：4%）或 I251L（251L-等位基因频率：2%）与普通人群肥胖风险之间存在关联。然而，大规模荟萃分析证实，这两种变体都使 103I-等位基因携带者的肥胖风险降低了-21%（P<10(-4)），使 251L-等位基因携带者的肥胖风险降低了-50%（P<10(-4)）。最近，全基因组关联研究在 MC4R 下游约 188kb 处发现了一个常见变体（次要等位基因频率：~27%），与成人和儿童的 BMI 和肥胖具有显著关联（P<5×10(-8)）。每个额外的次要等位基因使 BMI 增加 0.20kg/m(2)，体重增加 700-1000g，使成人肥胖风险增加 14%。有趣的是，该变体还与身高增加有关，这与罕见的 MC4R 突变的表型一致。虽然 MC4R 是最近的基因，表型关联与 MC4R 突变一致，但尚未确定该变体是否确实反映了 MC(4)受体功能。总之，常见的 MC4R 变体导致普通人群 BMI 和肥胖风险的变化。特别有趣的是，全基因组关联研究的结果表明，MC4R 下游区域有助于其调节。
