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  • In a meta analysis of genome wide association studies a

    2022-08-09

    In a meta-analysis of genome-wide association studies, a variant (rs10423928) in the GIPR gene has been found to be associated with elevated postprandial glucose and insulin (Saxena et al., 2010) as well as lean body composition including decreased BMI, lean mass and waist circumference (Lyssenko et al., 2011), hence its selection for this study. Only one study however has investigated GIPR variation in relation to BMD; reporting that a functional SNP in linkage disequilibrium with rs10423928 was associated with low BMD in early postmenopausal women (Torekov et al., 2014). To date there have been no population-based studies investigating association of variants in the GIP gene with bone phenotypes. The primary aim of our study was to investigate the association of SNPs in the GIP and GIPR GSK2126458 sale with skeletal phenotypes beyond bone density (BMC, bone microarchitecture, fracture), body composition and serum GIP level. Since menopausal (estrogen) status may influence the association, the study was performed in two population-based cohorts consisting of 75year and 25year old women.
    Materials and methods
    Results The characteristics of the women from the two differently aged cohorts have been published previously (Gerdhem et al., 2004, McGuigan et al., 2007). Briefly, elderly women from the OPRA cohort, as expected, had higher BMI and fat mass and lower lean mass and bone mineral density than the young women from PEAK-25 cohort (Supplementary Table 1). Both fat and lean mass were strongly positively associated with BMD and QUS (Callreus et al., 2012, Garg et al., 2014, Gerdhem et al., 2003). Mean serum GIP level in the OPRA cohort at 10year follow-up was 58.5pg/ml [SD 33.8]. There was no association between GIP level and any of the bone phenotypes measured at 10y follow-up, although femoral neck BMD and BMC were lower in the highest GIP tertile compared to the lowest (BMD: 0.693 vs 0.684, p=0.87; BMC: 3.564 vs 3.517, p=0.94). Similarly, body composition phenotypes were not associated with serum GIP despite fat and lean mass showing a tendency towards being higher in the highest GIP tertile (TB-fat: 24.2 vs 25.4, p=0. 57; TB-lean: 35.7 vs 36.1, p=0.39). The GIP polymorphism was not associated with serum GIP. However, as previously reported (Lyssenko et al., 2011), the variant ‘A’ allele of the GIPR polymorphism was associated with lower serum GIP in a dose dependent fashion (TT: 54.8 vs TA: 46.1 vs AA: 41.9; p=0.019) even after adjustment for fat mass (β=−6.93 (SE 3.19); padj=0.03). In the elderly women, GIP genotype was associated with lower BMD at the femoral neck (padj=0.016), BMC at total body (padj=0.020) and femoral neck (padj=0.030), as well as lower QUS_SoS values (padj=0.021) at baseline (Table 2) and at 10year follow-up (data not shown). Conversely, in the young women neither BMD nor BMC were associated with this SNP. Neither did bone properties reflecting microarchitecture (i.e. QUS at the calcaneus and TBS at the spine), differ between genotypes (Table 2). Variation in GIPR was not associated with BMD or BMC in either cohort (Table 3). In PEAK-25, although trabecular bone score did not differ with genotype, women carrying the minor allele had lower calcaneus QUS values, but only BUA and SI reached nominal significance and remained after adjustment for fat mass (BUA β=−1.63 (SE 0.59), padj=0.006; SI β=−1.86 (SE 0.83), padj=0.026). The results remained similar after further adjustment for femoral neck BMD. Conversely, although non-significant, the trend was towards higher QUS values in the elderly women (Table 3). In PEAK-25, a general trend for association between weight, BMI, fat and lean mass was observed with the GIP polymorphism (Table 2). Nominal significance was reached for weight and total body fat mass after adjustment for smoking (padj=0.031 and 0.026) (Table 2). There was no association with body composition in OPRA. Variation in GIPR was not associated with body composition in either cohort.