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


METHODS
The coding region of the CRF-R1 and CRF-R2 genes was screened in 51 severely obese children (body mass index (BMI)>4 kg/m(2) 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).


CONCLUSIONS
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.
Challis
B G
BG
University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK. sorahill@hgmp.mrc.ac.uk
Luan
J
J
Keogh
J
J
Wareham
N J
NJ
Farooqi
I S
IS
O'Rahilly
S
S
D017668:Age of Onset; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D000099052:CRF Receptor, Type 1
C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1