BMJ 1999;319:1337-1338 ( 20 November )

Papers

High penetrance, overweight, and glucocorticoid receptor variant: case-control study

Ruby C Y Lin, PhD student,  William Y S Wang, master of medicine student,  Brian J Morris, professor of physiology. 

Gene Laboratory, Department of Physiology and Institute for Biomedical Research, Building F13, University of Sydney, Sydney, NSW 2006, Australia

Correspondence to: B J Morris brianm{at}physiol.usyd.edu.au

A possible link between the glucocorticoid receptor gene (GRL, 5q31-q32) and overweight has been suggested in a study of 42 families with morbid obesity.1 Data from another small study---of pairs of siblings---although not significant, showed a trend towards similar body mass index (weight(kg)/(height(m)2); difference=2.4) for 20 pairs sharing similar alleles compared with 19 pairs having discordant alleles (difference=3.5).2 An Asn363Ser variant, caused by a single nucleotide difference (A1218G) in exon 2 of GRL has since shown an association with increased sensitivity to glucocorticoids.3 Because of the predisposition to a rise in body mass index that this increased sensitivity should cause, we tested this variant for association with overweight in two groups of non-diabetic white subjects of British descent.

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Methods and results
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All participants lived in or near Sydney and had responded to requests to take part in a study that involved DNA testing. Because of the interaction between obesity and hypertension we selected subjects on the basis of a positive or negative family history of hypertension and tested them separately. Group 1 was recruited from donors at the Sydney Blood Bank and comprised 195 subjects who were normotensive offspring of two normotensive parents. Group 2 comprised 124 subjects recruited by public advertising for people with essential hypertension whose parents also had hypertension. Mean body mass index was 26 (SD 4) in group 1 and 26 (SD 5) in group 2; mean age was 48 (SD 10) years and 52 (SD 12) years respectively; percentage of male participants was 57% and 49% respectively; and blood pressure was 120 (SD 11)/73 (SD 8) mm Hg and 173 (SD 24)/110 (SD 17) mm Hg respectively.

Each group was divided into two subgroups: lean (body mass index <= 25) and overweight (>25). Genotyping was performed on leucocyte DNA using polymerase chain reaction primers described previously4 and Tsp509I digestion of polymerase chain reaction products, which gave a band of 134 base pairs for the Asn363 variant and 153 base pairs for the Ser363 variant, together with a band of 95 base pairs for both.

The frequency of the Ser363 variant (number of Ser363 alleles divided by total number of alleles) in each group was similar (7.4% (95% confidence interval 4.8% to 10.0%) in group 1 v 6.0% (3.1% to 9.0%) in group 2), with 12.3% (7.7% to 16.9%) in group 1 being carriers (that is, they had one or two alleles) and 10.5% (5.1% to 15.9%) in group 2. In participants with body mass index <= 25 the Ser363 allele was rare (1.8% in group 1 and 0% in group 2). All Ser/Ser homozygotes were overweight, as were all Asn/Ser heterozygotes in group 2 and 80% of Asn/Ser heterozygotes in group 1 (table). Association with overweight was highly significant (table), with overall penetrance in participants with the Ser363 variant being 83% in group 1 and 100% in group 2. Consistent with this, the higher the body mass index, the more likely the subject was to have the Ser363 variant (table).


                              
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Association of Ser363 allele of GRL gene with overweight and body mass index



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Methods and results
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We found that the Ser363 variant of the glucocorticoid receptor confers a virtually absolute likelihood of being overweight---unlike most markers of overweight, which confer only a slight increase in likelihood. The allele is relatively common. Given the difference in response to various modalities of intervention according to genetic propensity to increased body mass index for a variant in another gene,5 our finding of almost complete penetrance of Ser363 genotypes to an overweight phenotype suggests that use of this marker could be important in clinical management.

    Acknowledgments

   Contributors: RCYL performed the genotyping, WYSW provided guidance with study design and performed statistical analyses, and BJM conceived the idea for the project and directed the research. All authors contributed to the drafting of the paper. BJM will act as guarantor.

    Footnotes

Funding: The study was supported by a grant from the National Health and Medical Research Council of Australia.

Competing interests: None declared.

    References
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Methods and results
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References

1. Clement K, Philippi A, Jury C, Pividal R, Hager J, Demenais F, et al. Candidate gene approach of familial morbid obesity: linkage analysis of the glucocorticoid receptor gene. Int J Obesity 1996; 20: 507-512[Medline].
2. Takami S, Wong ZYH, Stebbing M, Harrap SB. Linkage analysis of glucocorticoid and beta 2-adrenergic receptor genes with blood pressure and body mass index. Am J Physiol 1999; 276: H1379-H1384[Abstract/Free Full Text]
3. Huizenga NATM, Koper JW, deLange P, Pols HAP, Stolk RP, Burger H, et al. A polymorphism in the glucocorticoid receptor gene may be associated with increased sensitivity to glucocorticoids in vivo. J Clin Endocrin Metab 1998; 83: 144-151[Abstract/Free Full Text].
4. Koper JW, Stolk RP, de Lange P, Huizengo NATM, Molijn G-J, Pols HAP, et al. Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 1997; 99: 663-668[Medline].
5. Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. beta 2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet 1999; 353: 895-896[Medline].

(Accepted 30 July 1999)

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Glucocorticoid receptor variant and body mass index
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