Candidate gene approach of familial morbid obesity: linkage analysis of the glucocorticoid receptor gene

Abstract

Background: Morbid obesity is a multifactorial disease, with a strong but almost unknown genetic component. Familial linkage studies using the candidate gene approach have been shown to be powerful tools for identifying susceptibility genes for inherited diseases.

Aim of the study: We have investigated the role of the Glucocorticoid Receptor gene (GRL) in morbid obesity.

Subjects: Eighty obese families were recruited through a multimedia campaign (42 families, sample 1) or from the department of nutrition of the Hotel Dieu hospital in Paris (38 families, sample 2).

Methods: A multipoint linkage analysis with markers on chromosome 5q placed the GRL gene between D5S658 and D5S436 at genetic distances of 3.5 and 5 centimorgans, respectively. Using this map, we have chosen seven polymorphic microsatellite markers located in the vicinity of the GRL gene locus for sib pair linkage analysis. In addition to the obesity status, different quantitative phenotypes associated with obesity and insulin resistance were used for analysis.

Results: In sample 1, the results show a tendency towards linkage between three markers (one bc/1 intragenic RFLP and two microsatellite markers) in the GRL region and obesity characterised by a BMI > 27. However, using this phenotype, we failed to replicate the results in the second set of families. When using a more precise phenotype (the individual coefficient of variation of the BMI compared to a sex and age matched French reference population (pop) defined as the Zscore (indBMI-popBMI/SD of popBMI), a tendency for linkage was found for one marker in sample 2 as well as in the whole sample. No linkage was found when using quantitative traits associated with obesity.

Conclusion: The GRL locus does not appear to be a major locus for obesity, but we cannot exclude that this gene or gene located nearby may have some minor effects on the obese phenotype or may be involved in some subtypes of obesity. Larger cohorts of families are probably necessary to improve the power of such linkage analysis in this heterogeneous disease.