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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

ABSTRACT: Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n?=?2021; p-additive?=?0.029) and African Americans (AAs) (n?=?177; p-additive?=?0.05), with a trend in European Americans (EAs) (n?=?512; p-additive?=?0.09), but not Germans (n?=?858; p-additive?=?0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n?=?3568; p-additive?=?0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n?=?2912) or EAs (n?=?1149); however, the T allele associated with higher BMI in the subset with BMI?30 kg/m(2) (n?=?568 EAs; p-additive?=?0.049, n?=?196 Japanese; p-additive?=?0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive?=?0.080) and 48 Hong Kong Chinese (p-additive?=?0.81) with BMI?30 kg/m(2) (n?=?1575; p-additive?=?0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive?=?0.018) and ACACB protein levels in the liver tissue (mixed model p-additive?=?0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

SUBMITTER: Ma L

PROVIDER: S-EPMC3584087 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

Ma Lijun L Murea Mariana M Snipes James A JA Marinelarena Alejandra A Krüger Jacqueline J Hicks Pamela J PJ Langberg Kurt A KA Bostrom Meredith A MA Cooke Jessica N JN Suzuki Daisuke D Babazono Tetsuya T Uzu Takashi T Tang Sydney C W SC Mondal Ashis K AK Sharma Neeraj K NK Kobes Sayuko S Antinozzi Peter A PA Davis Matthew M Das Swapan K SK Rasouli Neda N Kern Philip A PA Shores Nathan J NJ Rudel Lawrence L LL Blüher Matthias M Stumvoll Michael M Bowden Donald W DW Maeda Shiro S Parks John S JS Kovacs Peter P Hanson Robert L RL Baier Leslie J LJ Elbein Steven C SC Freedman Barry I BI

PloS one 20130227 2

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-addit ...[more]

PMID: 23460794

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Project description:BackgroundAlthough obesity has been hypothesized to worsen asthma, data from studies of subjects with well-characterized asthma are lacking.ObjectiveWe sought to evaluate the relationship between body mass index (BMI), asthma impairment, and response to therapy.MethodsBMI (in kilograms per meter squared) and asthma phenotypic and treatment response data were extracted from Asthma Clinical Research Network studies. The cross-sectional relationship between BMI and asthma impairment was analyzed, as was the longitudinal relationship between BMI and response to asthma controller therapies.ResultsOne thousand two hundred sixty-five subjects with mild-to-moderate persistent asthma were evaluated. Analyses of lean versus overweight/obese asthmatic subjects demonstrated small differences in FEV1 (3.05 vs 2.91 L, P = .001), FEV1/forced vital capacity ratio (mean, 83.5% vs 82.4%; P = .01), rescue albuterol use (1.1 vs 1.2 puffs per day, P = .03), and asthma-related quality of life (5.77 vs 5.59, P = .0004). Overweight/obese asthmatic subjects demonstrated a smaller improvement in exhaled nitric oxide levels with inhaled corticosteroid (ICS) treatment than did lean asthmatic subjects (3.6 vs 6.5 ppb, P = .04). With ICS/long-acting beta-agonist treatment, overweight/obese asthmatic subjects demonstrated smaller improvements in lung function than lean asthmatic subjects, with an 80 mL (P = .04) and 1.7% (P = .02) lesser improvement in FEV1 and FEV1/forced vital capacity ratio, respectively. Significant differences in therapeutic response to leukotriene modifiers between BMI categories were not observed.ConclusionsIncreased BMI is not associated with clinically significant worsening of impairment in subjects with mild-to-moderate persistent asthma. There is a modest association between increased BMI and reduced therapeutic effect of ICS-containing regimens in this patient population. Prospective studies evaluating the effect of being overweight or obese on treatment response in asthma are warranted.

Project description:The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.

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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

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