FTO Risk Haplotype Among Early Onset and Severe Obesity Cases in a Population of Western Spain

Abstract

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...

Association of FTO Polymorphisms with Obesity and Obesity-Related Outcomes in Portuguese Children

“…Despite the similar genetic background between European populations, it is known that for several polymorphisms, frequencies can vary within different Caucasian populations [23], [24]. Moreover, a few studies failed to associate some FTO polymorphisms and obesity [25], [26], highlighting the need of more studies in different populations to better understand the role of FTO gene in obesity. The present study is the first to test whether common FTO gene SNPs are associated with obesity or to related anthropometric traits in children of Portuguese origin.…”

Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

“…For example, previous studies have shown that the degree of LD in a population with African ancestry is lower than that in European populations (32). Recent studies have reported that the genetic variability in the FTO gene that is in high LD are associated with a risk of obesity in Spanish (33) and African Americans (27). Our study showed novel patterns of LD in the FTO gene ancestry of Malaysian Malays.…”

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

“…One-hundred and seventy severely obese since childhood patients were selected from families screened as part of a study to detect cases of morbid obesity in Extremadura (western Spain; González et al, 2012) and whose pathogenesis can be attributed primarily to genetic alterations. All of them reached a weight greater than +3SD before 14 years of age; their overweight had been maintained and they exposed at least two other morbid obesity cases among first-or seconddegree relatives.…”