The strongest risk factor for childhood and adolescent obesity is parental obesity, and studies show that the strong predictive value of parental BMI results mainly from genetic rather than environmental factors (1,2). Therefore, the study of obese subjects from families with a high occurrence of obesity might reflect a stronger heritable component and prove helpful to increase the potential for detecting genetic associations. Several genome-wide association studies in European populations have identified that genetic variants located in the fat mass and obesity associated (FTO) gene are associated with increased risk of developing obesity (3). In an attempt to finely map the region where the initial signals were described, >100 common single nucleotide polymorphisms (SNPs) across the associated region where the FTO gene lies have been genotyped in populations of different ancestry. The principal signal is found for rs9939609, an SNP which lies in a cluster of highly correlated variants located in a linkage disequilibrium (LD) block of about 47 kb that encompasses parts of the first two introns and exon 2 of the FTO gene (4-6).The aim of this work was to investigate the LD block structure of a 448.4-kb region surrounding the candidate rs9939609 SNP and perform haplotype analyses in order to identify the best SNP combination that could explain the susceptibility to severe early onset obesity. Methods and Procedures Patients and controlsWe selected probandi who reached a weight greater than (mean + 3 s.d.) before 14 years of age and who referred at least two other morbid obesity cases among first-or second-degree relatives. We consider the existence of grade 3 overweight (commonly called morbid obesity) to be a BMI ≥40 kg/m 2 ; in children this corresponds to a BMI greater than the 95th percentile for age-and sex-matched control subjects from our population data.After their completion of an informed consent form, 202 patients were selected for study of their genetic risk profiles of polygenic/nonsyndromic Childhood and adult obesity have been widely associated with FTO genetic variability in different populations. This study aimed to investigate the linkage disequilibrium (LD) block structure of a region surrounding the candidate rs9939609 SNP and determine the best single nucleotide polymorphism (SNP) combination that explains the higher proportion of variability observed in children with severe obesity, including obese subjects from families with a very high occurrence of obesity. A sliding window approach pointed to a block containing the rs1477196/rs17817449/ rs9939609 haplotype (P value 3.1 × 10 −8 ). Carriers of the GGA combination had an increased risk of obesity (odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41-3.04, P = 2.0 × 10 −4 ) with respect to those individuals with the reference ATT haplotype. A further SNP, rs9921255, also showed association with obesity (P = 8.3 × 10 −4 , OR 1.77; 95% CI 1.15-2.74 and OR 5.78; 95% CI 1.22-27.49 for heterozygotes and homozygotes, respectively) and did not s...

The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility.

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