Structural Analysis Of Candidate Genes For NIDDM/Obesity

一个基因被认为是皮马印第安人2型糖尿病的候选基因，如果1）它在与2型糖尿病/肥胖症相关的途径中具有已知的生理功能，或2）它与另一个人群或动物模型中的糖尿病/肥胖症相关。过去一年分析的候选基因包括：PPARg 2、PGC-1、IRS-1、IRS-2、FOXC 2和MCR 4。在所有这些基因中鉴定多态性并分析关联。例如，黑皮质素4受体（MC 4 R）已被鉴定为人类和啮齿动物中罕见形式的单基因肥胖症的原因。MCR 4中的杂合编码突变与1 - 6%的早发性或重度成人肥胖有关。作为我们在皮马印第安人中鉴定肥胖易感基因座的努力的一部分，我们筛选了MCR 4作为候选基因。在96名严重肥胖的Pima受试者中对MCR 4进行测序，发现了两种罕见的编码区变体和一种常见的启动子变体。一种编码变体预测在密码子165处精氨酸到赖氨酸的取代（R165 Q），而第二种编码变体是单碱基插入（A），其预测在密码子37处的过早终止（TGA）。R165 Q之前已经在其他人群中被发现，功能研究表明它显著降低了MCR 4的活性。相比之下，在核苷酸100处的单碱基插入尚未报道。在一个大的队列的皮马印第安人的共同启动子变异的基因分型表明，这种变异是高度相关的肥胖在一般皮马人口。我们目前正在对该基因进行功能研究。

A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. Candidate genes analyzed in the past year include: PPARg2, PGC-1, IRS-1, IRS-2, FOXC2, and MCR4. Poymorphisms were identified in all of these genes and analyzed for association. As an example, the melanocortin 4 receptor (MC4R), has been identified as the cause of rare forms of monogenic obesity in both humans and rodents. Heterozygous coding mutations in MCR4 are implicated in 1 to 6% of early onset or severe adult obesity. As part of our efforts to identify obesity susceptibility loci in the Pima Indians, we screened MCR4 as a candidate gene. Sequencing of MCR4 in 96 severely obese Pima subjects identified two rare coding region variants and one common promoter variant. One coding variant predicts an arginine to lysine substitution at codon 165 (R165Q), while the second coding variant is a single base insertion (A) which predicts a premature STOP (TGA) at codon 37. The R165Q has been previously identified in other populations, and functional studies have shown that it dramatically reduces the activity of MCR4. In contrast, the single base insertion at nucleotide 100 has not yet been reported. Genotyping of the common promoter variant in a large cohort of Pima Indians indicates that this variant is highly associated with obesity in the general Pima population. We are currently pursuing functional studies on this gene.