Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus
Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus
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DOI：
10.1210/jc.82.10.3373
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发表时间：
1997-10-01
影响因子：
5.8
通讯作者：
Zinman, B
中科院分区：
文献类型：
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作者：
Hegele, RA;Connelly, PW;Zinman, B
确定NIDDM的遗传决定因素需要来自几种互补方法的证据，包括使用离散表型和中间数量性状的连锁和关联分析。我们在一个Oji-Cree样本中测试了位于染色体7q21-q22的三个基因的常见基因组变异与与NIDDM相关的数量性状之间的关联。我们发现对氧磷酶-2基因第148密码子(丙氨酸或甘氨酸)的常见基因组变异与空腹血糖的变异显著相关(P<；0.0001)。此外，我们发现空腹血糖的变化和由PON2148密码子遗传变异和非胰岛素依赖型糖尿病(NIDDM；P<；0.0001)的存在组成的相互作用项之间存在显著的关联。然后，我们根据PON2基因和NIDDM状态对受试者进行分析。在NIDDM患者中，PON2148G/G纯合子的平均空腹血糖显著高于其他两种基因型的受试者(P<；0.0001)。然而，在非NIDDM受试者中，任何一种基因型的平均空腹血糖没有差异。在该样本中，PON2型与NIDDM本身、糖耐量受损或其他与NIDDM相关的数量性状没有关联。这些发现表明，1)PON2G148基因变异会加重NIDDM患者的血糖；2)确定PON2基因产物的生理作用是值得的；3)遗传因素可以改变NIDDM患者的临床表型严重程度。
Defining the genetic determinants of NIDDM requires evidence from several complementary approaches, including both linkage and association analyses using both discrete phenotypes and intermediate quantitative traits. We tested for association between common genomic variation in three genes that map to chromosome 7q21-q22 and quantitative traits related to NIDDM in a sample of Oji-Cree. We found that a common genomic variation in codon 148 (alanine or glycine) of the paraoxonase-2 gene (PON2) demonstrated a significant association with a variation in fasting plasma glucose (P < 0.0001). Furthermore, we found a significant association between a variation in fasting plasma glucose and the interaction term comprised of a PON2 codon 148 genetic variation and the presence of noninsulin-dependent diabetes mellitus (NIDDM; P < 0.0001). We then analyzed subjects according to PON2 genotype and NIDDM status. In subjects with NIDDM, the PON2 codon 148 G/G homozygotes had significantly higher mean fasting plasma glucose than subjects with the other two genotypes (P < 0.0001). However, in non-NIDDM subjects, there was no difference in mean fasting plasma glucose among any of the genotypes. There was no association of the PON2 genotype with NIDDM itself, with impaired glucose tolerance, or with other quantitative traits related to NIDDM in this sample. These findings suggest that 1) the PON2 G148 gene variant worsens glycemia in subjects with NIDDM; 2) defining the physiological role of the PON2 gene product would be worthwhile; and 3) genetic factors can modify the severity of clinical phenotypes in subjects with NIDDM.