Association Analysis of the FTO Gene with Obesity in Children of Caucasian and African Ancestry Reveals a Common Tagging SNP

Abstract

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI≥95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r2 = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08–1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91–1.21; P = 0.49) and of 1.31 (95% CI 1.050–1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

“…The fat mass and obesity-associated gene (FTO) was recently identified as an obesity candidate gene by three largescale and independent genome-wide association studies, which strongly associated several single nucleotide polymorphisms (SNPs) of FTO with obesity-related traits, including body mass index, hip circumference and body weight. 1 --3 Significant associations between FTO and obesity were independently replicated in many other studies of different populations, including Korean, 4 Japanese, 5 Malay, 6 Chinese, 6,7 Belgian, 8 British, 9,10 Dutch, 11,12 German, 13 Finnish, 14 French, 15 Swedish, 16,17 Caucasian, 18 African 19 and American. 18,20 --22 In mice, FTO deficiency caused postnatal growth retardation and a significant reduction in adipose tissue and lean body mass, 23 and FTO deletion resulted in lesser postnatal growth and lower serum IGF-1 levels.…”

“…Several SNPs in intron 1 of chicken FTO (especially rs9939609) showed credible associations with obesity, similar to findings in various human populations. 7,17,18 In the pig, FTO SNPs are also related to intramuscular fat content and growth rate traits. 27,28 The associations of FTO SNPs with body weight, body composition and fatness traits in chickens supports the functional importance of FTO in birds, similar to that in mammals.…”

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents

“…A cluster of variants in the first intron of FTO show strong and highly significant association with obesity and obesity-related traits in three independent genome-wide association studies, [3][4][5] findings that have been replicated in several other studies. [15][16][17][18] In the present study, we identified three novel SNPs in the fourth intron, which are not in linkage disequilibrium with SNPs in the first intron, and examined the association between c.896 þ 223A4G and obesity as well as related phenotypes. Our study shows no increased risk of obesity for the novel variant and no significant differences in BMI or BMI SDS according to genotype among normal weight adolescents or among children and adolescents with severe FTO variants and insulin action in obese children and adolescents JA Jacobsson et al obesity.…”

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

“…26 The SNP is reported to have a high minor allele frequency in Caucasians (∼0.4) but very low in Asian population (∼0.1), whereas its association with obesity and type II diabetes has been confirmed in many populations but not in Chinese Han subjects. 11,[18][19][20][21][22][23][24][25][26][34][35][36][37][38] The six GWAS SNPs were found to be associated with type II diabetes and have been replicated for Chinese and Japanese populations only for association with type II diabetes. [27][28][29] However, these SNPs have not been previously studied with respect to obesity, and the Pakistani population represents an interesting ethnic group because of the many cultural and social restrictions and with an increasing rate of obesity and type II diabetes.…”

“…14,15 The association of common FTO variants, especially rs9939609, with obesity has been confirmed in Caucasians; however, the results in Asian populations are conflicting. [16][17][18][19][20][21][22][23][24][25] In Pakistan, there is limited research in the field of obesity genetics. A recent study in the Pakistani population indicated the association of this SNP with obesity in women and proposed that the SNP may play its role by affecting plasma glucose and leptin levels.…”