Elbein S C, Chu W, Ren Q, Wang H, Hemphill C, Hasstedt S J
Central Arkansas Veterans Healthcare System and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arizona, USA.
Diabetologia. 2002 Jul;45(7):1026-33. doi: 10.1007/s00125-002-0850-5. Epub 2002 May 8.
AIMS/HYPOTHESIS: We hypothesized that apolipoprotein A-II sequence variation was responsible for the observed linkage of Type II (non-insulin-dependent) diabetes mellitus to the apolipoprotein A-II region in Northern European families ascertained for multiple diabetic siblings, and might also influence insulin sensitivity and secretion, non-esterified fatty acids, and lipids.
We recruited 698 members of 63 families for pedigree studies and additional unrelated people providing 117 diabetic and 130 control subjects. We screened the apolipoprotein A-II gene by single strand conformation polymorphism analysis and fluorescent sequence analysis. Variants were typed by oligonucleotide ligation assay, restriction digest of amplification products, or radioactive fragment analysis for the microsatellite polymorphism. Association of each variant with Type II diabetes was tested in the case-control population by chi-square analysis, or using transmission disequilibrium test in families. Haplotypes were established in families using SIMWALK and tested for association with diabetes and quantitative traits.
No detected variant altered the coding sequence of the gene. Three single nucleotide polymorphisms showed modest evidence for an association, but no variant or haplotype was associated with diabetes in families. Similarly, we found no association with non-esterified fatty acid concentrations, HDL concentrations, or fasting insulin. In contrast, we found evidence for an association of some haplotypes and individual variants with 2-h post-challenge glucose and measures of insulin secretion.
CONCLUSION/INTERPRETATION: Apolipoprotein A-II is not likely to explain the observed linkage of Type II diabetes, but variation in this gene could alter insulin secretion and post-challenge glucose.
目的/假设：我们推测，在因多个糖尿病兄弟姐妹而被确定的北欧家庭中，载脂蛋白A-II序列变异是导致观察到的II型（非胰岛素依赖型）糖尿病与载脂蛋白A-II区域之间连锁关系的原因，并且可能还会影响胰岛素敏感性和分泌、非酯化脂肪酸以及脂质。
我们招募了63个家庭的698名成员进行系谱研究，并另外招募了无亲缘关系的人，提供了117名糖尿病患者和130名对照受试者。我们通过单链构象多态性分析和荧光序列分析对载脂蛋白A-II基因进行筛选。通过寡核苷酸连接测定、扩增产物的限制性消化或微卫星多态性的放射性片段分析对变异体进行分型。通过卡方分析在病例对照人群中测试每个变异体与II型糖尿病的关联，或在家庭中使用传递不平衡检验。使用SIMWALK在家庭中建立单倍型，并测试其与糖尿病和数量性状的关联。
未检测到的变异体改变该基因的编码序列。三个单核苷酸多态性显示出适度的关联证据，但在家庭中没有变异体或单倍型与糖尿病相关。同样，我们未发现与非酯化脂肪酸浓度、高密度脂蛋白浓度或空腹胰岛素有关联。相比之下，我们发现一些单倍型和个体变异体与激发后2小时血糖及胰岛素分泌指标之间存在关联证据。
结论/解读：载脂蛋白A-II不太可能解释观察到的II型糖尿病的连锁关系，但该基因的变异可能会改变胰岛素分泌和激发后血糖。
