A Common Haplotype in the G-Protein–Coupled Receptor Gene GPR74 Is Associated with Leanness and Increased Lipolysis Ingrid Dahlman, Andrea Dicker, Hong.

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A Common Haplotype in the G-Protein–Coupled Receptor Gene GPR74 Is Associated with Leanness and Increased Lipolysis Ingrid Dahlman, Andrea Dicker, Hong Jiao, Juha Kere, Lennart Blomqvist, Vanessa van Harmelen, Johan Hoffstedt, Knut Borch- Johnsen, Torben Jörgensen, Torben Hansen, Oluf Pedersen, Markku Laakso, Peter Arner The American Journal of Human Genetics Volume 80, Issue 6, Pages 1115-1124 (June 2007) DOI: 10.1086/518445 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic presentation of ascertainment schemes for samples 1–3. The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 GPR74 SNPs and haplotypes. Bold font indicates SNPs with a call rate >90% and a frequency >5% that were used for inferring the haplotypes. Allelic frequency of specific GPR74 haplotypes in obese case patients (n=611) and lean control subjects (n=402) in sample 1 analyzed with Haploview. Haplotype P = mean ± SD (lower value of range) of probabilities by which haplotypes have been assigned to individuals. P values were calculated by χ2 test for significance of the difference in haplotype frequency between cases and controls. An asterisk (*) indicates significant difference in ATAG haplotype frequency between cases and control s in joint analysis of samples 1 and 2; P=.0014. The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Linkage disequilibrium (D′) between GPR74 SNPs in sample 1, according to Haploview analysis The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 Association between carriage of GPR74 ATAG haplotype and waist circumference in men (A) and women (B). The blackened bar represents subjects carrying the ATAG haplotype; the unblackened bar represents subjects not carrying ATAG. The frequencies of haplotypes were as follows: in men in samples 1 and 2, ATAG = 19 and non-ATAG = 327; in men in sample 4, ATAG = 276 and non-ATAG = 3,615; in women in sample 1, ATAG = 55 and non-ATAG = 667; in women in sample 2, ATAG = 78 and non-ATAG = 995; in women in sample 4, ATAG = 262 and non-ATAG = 3,550. Samples 1 and 2 were analyzed by the Mann-Whitney U test, and sample 4 was analyzed using ANCOVA, with age as covariate. The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 A, Association between carriage of the ATAG haplotype and in vivo lipolysis measured as plasma glycerol corrected for body fat. The blackened bar represents the 124 subjects carrying ATAG; the unblackened bar represents the 1,771 subjects not carrying ATAG. B, Association between carriage of the ATAG haplotype and in vivo lipolysis measured as plasma free fatty acids corrected for body fat. The blackened bar represents the 100 subjects carrying ATAG; the unblackened bar represents the 1,494 subjects not carrying ATAG. C, Association between carriage of the ATAG haplotype and adipocyte lipolytic sensitivity (pD2) of different adrenergic agonists. The blackened bar represents the 14 subjects carrying ATAG; the unblackened bar represents the 136 subjects not carrying ATAG. Analyzed subjects came from samples 1 and 2. Groups were compared by ANCOVA, with age as covariate in panel A and with age and BMI as covariates in panel B. The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 6 A, Effect on human preadipocytes differentiated into adipocytes of the GPR74 agonist NPFF on lipolysis measured as plasma glycerol (five experiments). The white bar represents controls, the blackened bar represents NPFF for 3 h, and the striped bar represents NPFF for 48 h. B, Effect of siRNA against GPR74 on expression of GPR74 mRNA (four experiments). C, Effect of siRNA against GPR74 on lipolysis. The white bar represents no oligo, the gray shaded bar represents scrambled oligo, and the blackened bar represents GPR74 siRNA. Groups were compared by ANOVA. The American Journal of Human Genetics 2007 80, 1115-1124DOI: (10.1086/518445) Copyright © 2007 The American Society of Human Genetics Terms and Conditions