Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study

Niina Siitonen, Leena Pulkkinen, Jaana Lindström, Marjukka Kolehmainen, Johan G Eriksson, Mika Venojärvi, Pirjo Ilanne-Parikka, Sirkka Keinänen-Kiukaanniemi, Jaakko Tuomilehto, Matti Uusitupa, Niina Siitonen, Leena Pulkkinen, Jaana Lindström, Marjukka Kolehmainen, Johan G Eriksson, Mika Venojärvi, Pirjo Ilanne-Parikka, Sirkka Keinänen-Kiukaanniemi, Jaakko Tuomilehto, Matti Uusitupa

Abstract

Background: Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits.

Methods: Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis.

Results: rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention.

Conclusions: These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM.

Trial registration number: ClinicalTrials.gov NCT00518167.

Figures

Figure 1
Figure 1
ADIPOQ gene, locations of the genotyped variants and their pairwise linkage disequilibrium (LD) patterns. Schematic presentation of the ADIPOQ, indicating the locations of the analysed variants, the two observed haploblocks and the pairwise LD measures D' (above) and r2 (below). Grey boxes, untranslated region; black boxes, coding region; MAF, minor allele frequency.
Figure 2
Figure 2
Body weight from baseline to year 4 according to rs3821799. Data are predicted geometric means and 95% CI. Additive (A) and dominant (B) inheritace models; p values are adjusted for age, sex, study group and the time; Correction for multiple hypothesis testing was performed with FDR, denoted as q-value.
Figure 3
Figure 3
Four year change in serum adiponectin levels according to rs16861205. Data are means ± SD. Dominant inheritance model for the whole DPS (A), for participants who lost weight (B), and for participants who gained weight during the first year (C). p/q value for GG genotype vs. A allele carriers, Kruskal-Wallis test; Correction for multiple hypothesis testing was performed with FDR, denoted as q-value.

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