Abstract
BackgroundThe aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time.MethodsData were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-α (TNFα), and peroxisome proliferative activated receptor-γ and -δ (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes.ResultsThe results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFα rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101).ConclusionFindings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.
Highlights
The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality
Individual behaviors, such as physical activity and eating habits, are known to play important roles in the development of obesity [7]. It has been hypothesized, and observed in some studies, that genetic factors may be involved. These genetic factors include single nucleotide polymorphisms (SNPs) in genes that encode proteins involved in biological processes influencing body composition, including fat metabolism and adipocyte differentiation (peroxisome proliferator activated receptor γ (PPARG)) [8], hydrolyzation of triglycerides in both chylomicrons and very-low density lipoproteins (lipoprotein lipase (LPL)) [9], regulation of leptin, a protein involved in body weight regulation (leptin receptor (LEPR)) [10], prevention of low-density lipoprotein oxidation (paraoxonase 1 (PON1) and 2 (PON2)) [11], and regulation of monoamine levels (monoamine oxidase A (MAOA)) [12]
The following SNPs were in strong linkage disequilibrium (D' > 90): paraoxonase 2 (PON2) Ser299Cys and PON2 Ala136Gly (D' = 99), LEPR rs7602 and LEPR rs1045895 (D' = 99), tumor necrosis factor-α (TNFα) rs1799964 and TNFα rs1799724 (D' = 98), and PPARG rs709158 and PPARG rs1175543 (D' = 97)
Summary
The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. The biological plausibility of this association is well established, as it is known that excess body fat can lead to cardiovascular disease, type 2 diabetes mellitus, and cancer [7]. Individual behaviors, such as physical activity and eating habits, are known to play important roles in the development of obesity [7]. A recent review by Yang et al [13] reported that there are over 400 studies examining SNPs in these types of genes and obesity, with 22 of these genes found to be associated with obesity in at least five studies [13,14] While these genes may be associated with obesity, little is known as to whether these genes influence mortality
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