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Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians

International Journal of Obesity volume 28, pages 442–446 (2004)Cite this article

Abstract

OBJECTIVE: To investigate whether genetic variation at the loci encoding the corticotropin-releasing factor receptors-1 and -2 (CRF-R1 and CRF-R2) contributes to human obesity.

DESIGN: The coding region of the CRF-R1 and CRF-R2 genes was screened in 51 severely obese children (body mass index (BMI)>4 kg/m2 standard deviations above the age-related mean) using denaturing high-performance liquid chromatography and direct nucleotide sequencing. Common polymorphisms that were identified were typed from a UK Caucasian population-based cohort by a PCR-based forced restriction digestion. A repeated measures analysis was used to determine associations between the C861T and G1047A genotypes and anthropometric and biochemical indices relevant to obesity.

RESULTS: In subjects with extreme early-onset obesity, four missense mutations were found, each in a single individual: CRF-R1 (Val161Met) and CRF-R2 (Glu220Asp, Val240Ile and Val411Met). However, none of these missense mutations clearly cosegregated with obesity in family studies. Two common single-nucleotide polymorphisms, C861T (Cys287Cys) in CRF-R1 and G1047A (Ser349Ser) in CRF-R2, were also detected. G1047A did not associate with any obesity-related phenotype. In contrast, carriers of the CRF-R1 polymorphism, C861T, had a significantly higher body mass index (BMI).

CONCLUSION: Mutations in the coding sequence of the CRF-R1 and CRF-R2 genes are unlikely to be a common monogenic cause of early-onset obesity. In an adult UK Caucasian population, the CRF-R1 C861T polymorphism is associated with increased BMI.

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Acknowledgements

This work was supported by the Wellcome Trust (NJW, ISF, SOR) and the MRC (SOR, NJW). We are grateful to all the physicians who have referred patients to the GOOS study, in particular, to Dr B Houston for help with clinical studies.

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Authors and Affiliations

  1. University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK

    B G Challis, J Keogh, I S Farooqi & S O'Rahilly

  2. Institute of Public Health, Addenbrooke's Hospital, Cambridge, UK

    J Luan & N J Wareham

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  1. B G Challis
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Correspondence to S O'Rahilly.

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Challis, B., Luan, J., Keogh, J. et al. Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians. Int J Obes 28, 442–446 (2004). https://doi.org/10.1038/sj.ijo.0802564

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