Dataset Information

Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

ABSTRACT: Previous studies have replicated the association of variants within FTO (fat mass- and obesity-associated) intron 1 with obesity and adiposity quantitative traits in populations of European ancestry. Non-European populations, however, have not been so intensively studied. The goal of this investigation was to examine the association of FTO single-nucleotide polymorphisms (SNPs), prominent in the literature in a multiethnic sample of non-Hispanic White American (n=458), Hispanic American (n=373) and African American (n=288) subjects from the Insulin Resistance Atherosclerosis Study (IRAS). This cohort provides the unique ability to evaluate how variation within FTO influences measures of adiposity and glucose homeostasis in three different ethnicities, which were ascertained and examined using a common protocol.A total of 26 FTO SNPs were genotyped, including those consistently associated in the literature (rs9939609, rs8050136, rs1121980, rs1421085, rs17817449 and rs3751812), and tested for association with adiposity and glucose homeostasis traits.For the adiposity phenotypes, these and other SNPs were associated with body mass index (BMI) in both non-Hispanic Whites (P-values ranging from 0.015 to 0.048) and Hispanic Americans (P-values ranging from 7.1 × 10(-6) to 0.027). In Hispanic Americans, four other SNPs (rs8047395, rs10852521, rs8057044 and rs8044769) still showed evidence of association after multiple comparisons adjustment (P-values ranging from 5.0 × 10(-5) to 5.2 × 10(-4)). The historically associated BMI SNPs were not associated in the African Americans, but rs1108102 was associated with BMI (P-value of 5.4 × 10(-4)) after accounting for multiple comparisons. For glucose homeostasis traits, associations were seen with acute insulin response in non-Hispanic Whites and African Americans. However, all associations with glucose homeostasis measures were no longer significant after adjusting for multiple comparisons.These results replicate the association of FTO intron 1 variants with BMI in non-Hispanic Whites and Hispanic Americans but show little evidence of association in African Americans, suggesting that the effect of FTO variants on adiposity phenotypes shows genetic heterogeneity dependent on ethnicity.

SUBMITTER: Wing MR

PROVIDER: S-EPMC4068260 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

Wing M R MR Ziegler J M JM Langefeld C D CD Roh B H BH Palmer N D ND Mayer-Davis E J EJ Rewers M J MJ Haffner S M SM Wagenknecht L E LE Bowden D W DW

International journal of obesity (2005) 20101123 9

<h4>Objective</h4>Previous studies have replicated the association of variants within FTO (fat mass- and obesity-associated) intron 1 with obesity and adiposity quantitative traits in populations of European ancestry. Non-European populations, however, have not been so intensively studied. The goal of this investigation was to examine the association of FTO single-nucleotide polymorphisms (SNPs), prominent in the literature in a multiethnic sample of non-Hispanic White American (n=458), Hispanic ...[more]

PMID: 21102551

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Project description:ContextMetabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes.ObjectiveSurvey metabolites associated with dynamic and basal measures of glucose homeostasis.DesignAnalysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study.SettingCommunity based.ParticipantsOne thousand one hundred eleven Mexican Americans.Main outcomeDynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and β-cell function.ResultsInsulin sensitivity was associated with 99 metabolites (P < 6.82 × 10-5) explaining 28% of the variance (R2adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 × 10-18 to 1.70 × 10-5, R2adj = 8.1%) and phospholipids (P = 3.51 × 10-17 to 3.00 × 10-5, R2adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.49 × 10-23 to 4.14 × 10-7, R2adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 × 10-16). Homeostatic model assessment of β-cell function had significant signatures from the urea cycle (P = 9.64 × 10-14 to 7.27 × 10-6, R2adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 × 10-13 to 6.70 × 10-5, R2adj = 10%) and LCFAs (P = 9.06 × 10-15 to 3.93 × 10-7, R2adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55 × 10-12 to 5.81 × 10-6; R2adj = 3.8%) beyond that of its component measures.ConclusionsMetabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.

Project description:The SOCS3 gene product participates in the feedback inhibition of a range of cytokine signals. Most notably, SOCS3 inhibits the functioning of leptin and downstream steps in insulin signaling after being expressed by terminal transcription factors, such as STAT3 and c-fos. The SOCS3 gene is located in the chromosome region 17q24-17q25, previously linked to body mass index (BMI), visceral adipose tissue (VAT), and waist circumference (WAIST) in Hispanic families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A high density map of 1,536 single nucleotide polymorphisms (SNPs) was constructed to cover a portion of the 17q linkage interval in 1,425 Hispanic subjects from 90 extended families in IRASFS. Analysis of this dense SNP map data revealed evidence of association of rs9914220 (located 10 kb 5' of the SOCS3 gene) with BMI, VAT, and WAIST (P-value ranging from 0.003 to 0.017). Using a tagging SNP approach, rs9914220 and 22 additional SOCS3 SNPs were genotyped for genetic association analysis with measures of adiposity and glucose homeostasis. The adiposity phenotypes utilized in association analyses included BMI, WAIST, waist to hip ratio (WHR), subcutaneous adipose tissue, VAT, and visceral to subcutaneous ratio (VSR). Linkage disequilibrium calculations revealed three haplotype blocks near SOCS3. Haplotype Block 3 (5' of SOCS3) contained SNPs consistently associated with BMI, WAIST, WHR, and VAT (P-values ranging from 2.00 x 10(-4) to 0.036). Haplotype Block 1 contained single-SNPs that were associated with most adiposity traits except for VSR (P-values ranging from 0.002 to 0.047). When trait associated SNPs were included in linkage analyses as covariates, a reduction of VAT LOD score from 1.26 to 0.76 above the SOCS3 locus (110 cM) was observed. Multi-SNP haplotype testing using the quantitative pedigree disequilibrium test was broadly consistent with the single-SNP associations. In conclusion, these results support a role for SOCS3 genetic variants in human obesity.

Dataset Information

Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

Publications

Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

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