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Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study.

Du H, Vimaleswaran KS, Angquist L, Hansen RD, van der A DL, Holst C, Tjønneland A, Overvad K, Jakobsen MU, Boeing H, Meidtner K, Palli D, Masala G, Bouatia-Naji N, Saris WH, Feskens EJ, Wareham NJ, Sørensen TI, Loos RJ - PLoS ONE (2011)

Bottom Line: After accounting for multiple testing, none of the SNPs was significantly associated with weight change.Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB).We found no evidence of association between SNPs in the studied hypothalamic genes with weight change.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. huaidong.du@ctsu.ox.ac.uk

ABSTRACT

Background: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects.

Aim: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake.

Methods and findings: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷).

Conclusions: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.

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Related in: MedlinePlus

Linkage disequilibrium (LD) plot of the neuromedin β gene (NMB) 1.
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pone-0017436-g003: Linkage disequilibrium (LD) plot of the neuromedin β gene (NMB) 1.

Mentions: NMB is a decapeptide that belongs to the bombesin-like peptide family and is widely distributed in the human central nervous system, pancreas, adrenals, gastrointestinal tract and adipose tissue [23]. Evidence shows that NMB, when released in the gastrointestinal tract in response to food intake, represents a mediator between the gut and the brain and serves as a satiation signal to terminate meals [23]. NMB is also expressed in adipose tissue and can act as an adiposity signal reflecting nutritional status and regulating food intake over a longer term [23], [45]. Intravenous infusion of NMB has been shown to reduce meal size and meal duration in rats [32]. The rs7180849 is located at ∼2.7 kb upstream of the NMB (Figure 3) and is in complete LD (r2 = 1.0, D′ = 1.0 in CEU Hapmap) with SNP rs3809508 which is positioned in the intron region of the NMB. In a recent study among 1,144 European adolescents, the TT genotype (homozygous minor allele carriers) of the rs3809508 was associated with a higher risk of obesity and this association was stronger among those adolescents whose mothers had the lowest education level [46]. Given the close association between low education and unhealthy eating habits (i.e. a high GI diet), it might be possible that the influence of SNP rs3809508 on obesity risk was, at least partly, modified by dietary GI. In the Quebec Family Study, a missense mutation p.P73T in the NMB has been associated with eating behaviors associated with obesity and the amount of body fat gain during a 6-year follow-up [47]. The silent polymorphism g.G401A in the NMB has been significantly associated with body weight in children and adolescents [48]. However, there is no identified function of either rs7180849 or rs3809508 on NMB expression or function so far.


Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study.

Du H, Vimaleswaran KS, Angquist L, Hansen RD, van der A DL, Holst C, Tjønneland A, Overvad K, Jakobsen MU, Boeing H, Meidtner K, Palli D, Masala G, Bouatia-Naji N, Saris WH, Feskens EJ, Wareham NJ, Sørensen TI, Loos RJ - PLoS ONE (2011)

Linkage disequilibrium (LD) plot of the neuromedin β gene (NMB) 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044761&req=5

pone-0017436-g003: Linkage disequilibrium (LD) plot of the neuromedin β gene (NMB) 1.
Mentions: NMB is a decapeptide that belongs to the bombesin-like peptide family and is widely distributed in the human central nervous system, pancreas, adrenals, gastrointestinal tract and adipose tissue [23]. Evidence shows that NMB, when released in the gastrointestinal tract in response to food intake, represents a mediator between the gut and the brain and serves as a satiation signal to terminate meals [23]. NMB is also expressed in adipose tissue and can act as an adiposity signal reflecting nutritional status and regulating food intake over a longer term [23], [45]. Intravenous infusion of NMB has been shown to reduce meal size and meal duration in rats [32]. The rs7180849 is located at ∼2.7 kb upstream of the NMB (Figure 3) and is in complete LD (r2 = 1.0, D′ = 1.0 in CEU Hapmap) with SNP rs3809508 which is positioned in the intron region of the NMB. In a recent study among 1,144 European adolescents, the TT genotype (homozygous minor allele carriers) of the rs3809508 was associated with a higher risk of obesity and this association was stronger among those adolescents whose mothers had the lowest education level [46]. Given the close association between low education and unhealthy eating habits (i.e. a high GI diet), it might be possible that the influence of SNP rs3809508 on obesity risk was, at least partly, modified by dietary GI. In the Quebec Family Study, a missense mutation p.P73T in the NMB has been associated with eating behaviors associated with obesity and the amount of body fat gain during a 6-year follow-up [47]. The silent polymorphism g.G401A in the NMB has been significantly associated with body weight in children and adolescents [48]. However, there is no identified function of either rs7180849 or rs3809508 on NMB expression or function so far.

Bottom Line: After accounting for multiple testing, none of the SNPs was significantly associated with weight change.Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB).We found no evidence of association between SNPs in the studied hypothalamic genes with weight change.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. huaidong.du@ctsu.ox.ac.uk

ABSTRACT

Background: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects.

Aim: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake.

Methods and findings: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷).

Conclusions: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.

Show MeSH
Related in: MedlinePlus