We identified a childhood obesity locus on chromosome 6q16.3-q24.2 1 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity 1-8 . Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance 9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also with T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesityassociated A>G +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulinresistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions. Competing interests statementThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2007 October 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInitially, the phenotypic characteristics of 62 "6q-evidence" families (defined by an individual pedigree Zscore > 1.0 in the 2-LOD drop interval flanked by markers D6S434 and D6S1704) were compared with the remaining 35 families from our previously published genome scan for childhood obesity 1 . The "6q-evidence" obese children have a trend towards higher area under the glycemia curve after glucose administration and a significantly lower insulinogenic index (Supplementary Table 1). Compared to none of the other families, 3.1% of the "6q-evidence" obese children are glucose intolerant or diabetic and 13.8% of 6q linked obese children parents have type 2 diabetes mellitus (T2D) compared to 3.2% of parents in other families (p=0.018). Thus, the obesity susceptibility gene(s) on chromosome 6q may be also involved in glucose homeostasis.The "6q-evidence" 2-LOD drop interval 1 covers 41.4 Mb and includes 166 referenced genes. This was narrowed to a 2.4 Mb interval between markers D6S1656 and D6S270 using overlapping published linkage results on chromosome 6q16.1-q27 with either obesity 2 , insulin secretion 3,4 or T2D 5-8 . Within this interval, the best candidate was ectonucleotide pyrophosphatase phosphodiesterase ENPP1 (also known as the Plasma Cell glycoprotein-1 PC-1). ENPP1 is believed to directly inhibit insulin-induced conformational changes of the insulin receptor, thereby affecting its activation and downstream signaling 9,11 .The microsatellite marker D6S1656 in...

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.

OBJECTIVE-Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS-We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS-Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P ϭ 6.9 ϫ 10 Ϫ10 ). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged Ͼ52 years, 60% in 18-to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at Ͼ40 years).CONCLUSIONS-We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.

Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs ؊11,377C>G, ؊11,391G>A, ؉45T>G, and ؉276G>T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and ؊11,377C (odds ratio 1.23, P ‫؍‬ 0.001) and ؉276T (1.19, P ‫؍‬ 0.006). Surprisingly, alternative alleles ؊11,377G and ؉276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1 (C) -1 (G) -1 (T) -2 (T) including ؊11,377C and ؉276T in 634 obesity trios (P ‫؍‬ 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs ؊11,377C>G and ؉276G>T on ACDC functionality were not conclusive. In contrast, promoter SNP ؊11,391G>A was associated with higher adiponectin levels in obese children (P ‫؍‬ 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that ؊11,391A may increase ACDC activity. In summary, our study suggests that variations at the ACDC/adiponectin gene are associated with risk of severe forms of obesity. However, the mechanisms underlying these possible associations are not fully understood. Diabetes 55: [545][546][547][548][549][550] 2006 A diponectin is a potent insulin-sensitizing adipokine that acts on several peripheral tissues. In contrast to leptin, plasma adiponectin is reduced in obese children (1) and adults (2), and low adiponectin levels correlate with increased risk for type 2 diabetes (2). However, hypoadiponectinemia associates more with insulin resistance than with the degree of obesity (3). Associations between the adiponectin encoding gene (ACDC) variants and insulin resistance, type 2 diabetes, and/or cardiovascular diseases were reported in several but not all studies (4,5). The strongest associations are seen in two promoter single nucleotide polymorphisms (SNPs) Ϫ11,377CϾG and Ϫ11,391GϾA, the exon 2 synonymous SNP ϩ45TϾG, and the intronic SNP ϩ276GϾT. Alleles showing higher risk for type 2 diabetes associated with decreased adiponectin levels (6,7). Associations between ACDC SNPs and BMI have been previously described (8), but their contribution to risk for severe forms of obesity is not known. Here, we report genetic evidence for the role of ACDC SNPs in the risk for childhood and morbid adult obesity. We also provide functional data supporting the role for promoter SNP Ϫ11,391GϾA in the modulation of adiponectinemia. RESEARCH DESIGN AND METHODSWe genotyped 424 nuclear families including 634 obese children (defined as BMI Ͼ97th percentile for age and sex). Ninety-five unrelated obese children recruited in Toulouse were also genotyped (onli...

The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.