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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

Flow diagram of participant selection.
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pone-0017436-g001: Flow diagram of participant selection.

Mentions: Participants came from cohorts established in eight regions within five European countries (Italy, UK, the Netherlands, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study [12]. The cohorts were those in the EPIC that had a follow-up program including reassessment of anthropometry completed. Individuals were eligible if the following inclusion criteria were met: younger than 60 years of age at baseline and younger than 65 years at follow-up, blood sample available, had baseline information on diet, weight and height and follow-up information on weight, stable smoking habits, no cancer, cardiovascular diseases (CVD), and diabetes, and an annual weight change not more than 5 kg/year. Of the 146,543 participants who took part in the baseline examination during 1992–1998, a total of 50,293 men and women were eligible to participate in our study. Cases were defined as those individuals who had experienced the greatest degree of unexplained annual weight gain during follow-up (with an average duration of 6.8 years). They were identified by using the residuals from a regression model of annual weight change on baseline values of age, weight and height, smoking status (current/former/never smokers), and follow-up time. Regression models were run separately for each country and stratified by gender. For each of the five countries, except Italy, we randomly selected 600 male and 600 female cases. As the Italian cohort consisted of a general population-based sample and of a women-only sample (population-based breast cancer screening program), men were underrepresented (27%). Consistent with the sex-ratio in the Italian cohort, we selected 300 male and 900 female cases. The subcohort sample comprised a random sample of the total eligible cohort and was drawn in such a way that the total number of noncases equaled the number of cases (n = 1,200 in each country). This resulted in some cases also selected for the random subcohort. Therefore, oversampling of the random subcohort was performed, except in Denmark where overlap between cases and subcohort was negligible (n = 79). In total, 11,921 participants were included in the present genetic association study: 6,000 cases and a subcohort of 7,061 individuals, of which 5,921 were noncases. The flow chart of participant selection is shown in Figure 1. The demographic, anthropometric and dietary characteristics of cases, noncases and random subcohort are presented in Table 1.


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)

Flow diagram of participant selection.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017436-g001: Flow diagram of participant selection.
Mentions: Participants came from cohorts established in eight regions within five European countries (Italy, UK, the Netherlands, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study [12]. The cohorts were those in the EPIC that had a follow-up program including reassessment of anthropometry completed. Individuals were eligible if the following inclusion criteria were met: younger than 60 years of age at baseline and younger than 65 years at follow-up, blood sample available, had baseline information on diet, weight and height and follow-up information on weight, stable smoking habits, no cancer, cardiovascular diseases (CVD), and diabetes, and an annual weight change not more than 5 kg/year. Of the 146,543 participants who took part in the baseline examination during 1992–1998, a total of 50,293 men and women were eligible to participate in our study. Cases were defined as those individuals who had experienced the greatest degree of unexplained annual weight gain during follow-up (with an average duration of 6.8 years). They were identified by using the residuals from a regression model of annual weight change on baseline values of age, weight and height, smoking status (current/former/never smokers), and follow-up time. Regression models were run separately for each country and stratified by gender. For each of the five countries, except Italy, we randomly selected 600 male and 600 female cases. As the Italian cohort consisted of a general population-based sample and of a women-only sample (population-based breast cancer screening program), men were underrepresented (27%). Consistent with the sex-ratio in the Italian cohort, we selected 300 male and 900 female cases. The subcohort sample comprised a random sample of the total eligible cohort and was drawn in such a way that the total number of noncases equaled the number of cases (n = 1,200 in each country). This resulted in some cases also selected for the random subcohort. Therefore, oversampling of the random subcohort was performed, except in Denmark where overlap between cases and subcohort was negligible (n = 79). In total, 11,921 participants were included in the present genetic association study: 6,000 cases and a subcohort of 7,061 individuals, of which 5,921 were noncases. The flow chart of participant selection is shown in Figure 1. The demographic, anthropometric and dietary characteristics of cases, noncases and random subcohort are presented in Table 1.

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