title: Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations.
abstract: Loss of function mutations in the small heterodimer partner (SHP) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies. Two common polymorphisms, G171A and -195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort, G171A and -195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated with higher BMI (P < 0.05) and waist circumference (P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load (P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.
authors.affiliation: University Departments of Medicine and Clinical Biochemistry, Cambridge Institute for Medical Research, Cambridge, U.K.
authors.forename: Chiao-Chien Connie
authors.initials: CC
authors.lastname: Hung
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Ken
authors.initials: K
authors.lastname: Ong
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Marcus
authors.initials: M
authors.lastname: Pembrey
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: David
authors.initials: D
authors.lastname: Dunger
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Stephen
authors.initials: S
authors.lastname: O' Rahilly
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology*; D001724:Birth Weight; D001824:Body Constitution; D002648:Child; D004252:DNA Mutational Analysis; D005215:Fasting; D005260:Female; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D009765:Obesity / Q000235:genetics; D011110:Polymorphism, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*
chemical_list: D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2