Contribution of Variants in the Small Heterodimer Partner Gene to Birthweight, Adiposity, and Insulin Levels Mutational Analysis and Association Studies in Multiple Populations Chiao-Chien Connie Hung 1 , I. Sadaf Farooqi 1 , Ken Ong 2 , Jian’an Luan 3 , Julia M. Keogh 1 , Marcus Pembrey 4 , Giles S.H. Yeo 1 , David Dunger 2 , Nicholas J. Wareham 3 and Stephen O’ Rahilly 1 1 University Departments of Medicine and Clinical Biochemistry, Cambridge Institute for Medical Research, Cambridge, U.K 2 Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, U.K 3 Department of Public Health and Epidemiology, Addenbrooke’s Hospital, Cambridge, U.K 4 Unit of Perinatal and Paediatric Epidemiology, University of Bristol, Bristol, U.K 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. Footnotes Address correspondence and reprint requests to Stephen O’Rahilly, University Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, U.K. E-mail: sorahill{at}hgmp.mrc.ac.uk . Received for publication 15 November 2002 and accepted in revised form 30 January 2003. C.C.H. and I.S.F. contributed equally to this work. Additional information can be found in an online appendix at http://diabetes.diabetesjournals.org . ALSPAC, Avon Longitudinal Study of Parents and Children; DHPLC, denaturing high-performance liquid chromatography; GOOS, Genetics Of Obesity Study; HNF-4α, hepatocyte nuclear factor-4α; MODY, maturity onset diabetes of the young; SDS, standard deviation score; SHP, small heterodimer partner. DIABETES