Glycerol as a correlate of impaired glucose tolerance:: Dissection of a complex system by use of a simple genetic trait

被引:51
作者
Gaudet, D [1 ]
Arsenault, S
Pérusse, L
Vohl, MC
St-Pierre, J
Bergeron, J
Després, JP
Dewar, K
Daly, MJ
Hudson, T
Rioux, JD
机构
[1] Chicoutimi Hosp, Lipid Clin, Lipid Res Grp, 305 St Vallier St, Chicoutimi, PQ, Canada
[2] Univ Laval, Phys Act Sci Lab, Quebec City, PQ G1K 7P4, Canada
[3] Univ Laval, Lipid Res Ctr, Quebec City, PQ G1K 7P4, Canada
[4] MIT, Whitehead Inst, Ctr Genome Res, Cambridge, MA 02139 USA
[5] McGill Univ, Montreal Gen Hosp, Inst Res, Montreal, PQ H3G 1A4, Canada
基金
英国医学研究理事会;
关键词
D O I
10.1086/302903
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism. Impaired glucose tolerance (IGT) and hypertriglyceridemia are associated with an increased risk of diabetes mellitus and cardiovascular disease. The relationship between glycerol and the risk of IGT, however, is poorly understood. We therefore undertook the study of fasting plasma glycerol levels in a cohort of 1,056 unrelated men and women of French-Canadian descent. Family screening in the initial cohort identified 18 men from five families with severe hyperglycerolemia (values above 2.0 mmol/liter) and demonstrated an X-linked pattern of inheritance. Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21.3 GK gene resulted in a peak LOD score of 3.46, centered around marker DXS8039. In addition, since all of the families originated in a population with a proven founder effect-the Saguenay Lac-St.-Jean region of Quebec-a common disease haplotype was sought. Indeed, a six-marker haplotype extending over a region of 5.5 cM was observed in all families. Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid. Although patients with the N288D mutation suffered from severe hyperglycerolemia, they were apparently otherwise healthy. The phenotypic analysis of the family members, however, showed that glycerol levels correlated with impaired glucose metabolism and body-fat distribution. We subsequently noted a substantial variation in glycerolemia in subjects of the initial cohort with normal plasma glycerol levels and demonstrated that this variance showed significant family resemblance. These results suggest a potentially important genetic connection between fasting glycerolemia and glucose homeostasis, not only in this X-linked deficiency but, potentially, in individuals within the "normal" range of plasma glycerol concentrations.
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页码:1558 / 1568
页数:11
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