Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations.
Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations.
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评估英国种群中LPIN1变异在胰岛素抵抗，体重和人脂肪营养不良中的作用。
作者：
Fawcett KA;Grimsey N;Loos RJ;Wheeler E;Daly A;Soos M;Semple R;Syddall H;Cooper C;Siniossoglou S;O'Rahilly S;Wareham NJ;Barroso I
目的——脂蛋白1活性缺失在fld小鼠中导致脂肪代谢障碍和胰岛素抵抗，并且近期有人提出LPIN1表达及常见基因变异会影响人类的肥胖程度和胰岛素敏感性。我们旨在进行一项全面的关联研究，以阐明常见LPIN1变异对英国人群肥胖程度和胰岛素敏感性的影响，并检验LPIN1突变在胰岛素抵抗综合征中的作用。
研究设计与方法——对标记常见LPIN1变异的22个单核苷酸多态性在医学研究委员会（MRC）伊利（n = 1709）和赫特福德郡（n = 2901）基于人群的队列中进行基因分型。对158例特发性严重胰岛素抵抗患者（包括23例脂肪代谢障碍患者）和48例对照受试者的LPIN1外显子、外显子/内含子边界以及3′非翻译区进行测序。
结果——我们未发现LPIN1单核苷酸多态性与空腹胰岛素之间存在关联，但在对来自内部和公开研究的8504个样本进行的荟萃分析中，报告了rs13412852与体重指数（BMI）之间名义上的关联（P = 0.042）。在严重胰岛素抵抗患者中检测到3种罕见的非同义变异（A353T、R552K和G582R）。然而，这些变异在患病家族中与疾病并无共分离现象，并且携带变异的患者中脂蛋白1蛋白表达和磷酸化情况与对照受试者无差异。
结论——我们的数据不支持常见LPIN1变异对代谢特征有重大影响，并表明LPIN1突变并非人类脂肪代谢障碍的常见病因。英国队列中与BMI和其他代谢特征的名义关联需要在更大的队列中进行重复验证。
OBJECTIVE— Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes. RESEARCH DESIGN AND METHOD— Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3′ untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects. RESULTS— We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects. CONCLUSIONS— Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
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