The purpose of this study was to evaluate whether ADIPOQ
SNPs were associated with plasma adiponectin levels as well as glucose homeostasis and adiposity measures. There is an abundant literature investigating the association between adiponectin variants and glucose homeostasis and adiposity measures [10
]. Much of this literature has been inconclusive, but if adiponectin actively participates in metabolic disease, we would hypothesize that variants that alter circulating adiponectin levels should be associated with metabolic measures. Overall, our results were not consistent with this hypothesis: no consistent pattern of association was observed between SNPs, adiponectin levels, and metabolic traits. The few nominal associations, e.g. rs17300539 and rs822387, that followed from adiponectin levels into metabolic traits are less convincing when strict corrections for multiple comparisons (for Hispanic Americans, 40 SNPs; P≤0.0013 and for African Americans, 42 SNPs; P≤0.0012) were made.
Recently Hivert et al
] observed association with two ADIPOQ
promoter SNPs, rs17300539 and rs822387, with plasma adiponectin levels in the Framingham Offspring Study, a study which is comprised almost exclusively of individuals of European descent. We observed similar association with plasma adiponectin levels in the IRASFS Hispanic-American cohort with p-values of 0.0079 (rs17300539) and 0.021 (rs822387) for the two correlated SNPs (r2
=0.69). In addition, in the IRASFS African-American cohort, rs17300539 was also associated with plasma adiponectin levels (P=0.0018), while rs822387 was not associated (P=0.23) potentially due to decreased correlation among the variants (r2
=0.06). Interestingly, Hivert et al
did not find association with glucose homeostasis and adiposity measures with either of these variants whereas in the IRASFS, there was association of rs17300539 and rs822387 with SI
in the Hispanic- American cohort (P=0.0067 and 0.013, respectively) and association of rs17300539 with fasting glucose in the African-American cohort (P=0.042). The association of rs17300539 and rs822387 with SI
did not result in dramatic differences in SI
in individuals with zero (2.16 ± 1.86 × 10−5
; 2.14 ± 0.84 × 10−5
), one (2.08 ± 1.85 × 10−5
; 2.26 ± 2.11 × 10−5
), and two (1.94 × 10−5
; 1.94 × 10−5
) copies of the minor allele, respectively (Appendix Table 1
). The association of rs17300539 with fasting glucose in the African Americans yielded similar modest differences in the genotypic means for 0 (94.77 ± 9.74 mg/dL) and 1 (91.91 ± 8.38 mg/dL) copy of the minor allele. We explored the rs17300539 SNP further. Although the SNP was associated with fasting glucose in the independent African-American and Hispanic-American cohorts, the beta coefficients were in the opposite direction and in a meta-analysis there was no evidence for association (P=0.51, data not shown). Hivert et al
was able to find association between the coding variant rs17366743 and fasting glucose (P=0.0004) and diabetes risk (P=0.01) [10
]. However, in the IRASFS Hispanic- and African-American cohorts, there was no evidence of association of rs17366743 with glucose homeostasis or adiposity measures. Dastani et al
] recently reported evidence for nominal association (P=0.003–0.048) between T2D and a collection of adiponectin-associated variants across the genome in a large European sample, however, the promoter SNP, rs17300539, was not found to be associated with T2D, only associated with high molecular weight adiponectin in the Cardiovascular Health Study (P=3.0 × 10−16
In addition to common variants we evaluated multiple low frequency coding variants. Similar to the G45R mutation which we have previously described [25
], the R55C coding variant in African Americans corresponds to very low adiponectin levels and no evidence of association with the glucose homeostasis and adiposity phenotypes studied here ( and ). The frequency of the R55C is low (1.0%) which limits power to assess association, but one would suspect that a mutation that reduces the amount of circulating adiponectin 80–85% would result in a difference in metabolic measures. It is noteworthy that in a cross-ethnic (Hispanic American and African American) analysis, cross-SNP (R55C and G45R) meta-analysis of these high impact variants, there was no evidence of association with any of the metabolic and adiposity traits evaluated here (data not shown).
While there are reports of association between SI
and plasma adiponectin levels [36
], it is difficult to discern the exact relationship between the two due to a lack of consistent association between variants associated with plasma adiponectin levels and SI
. Within the IRASFS, there were only two SNPs that were associated with both plasma adiponectin and SI
in the Hispanic-American cohort, and none within the African-American cohort. There are also some mixed reports of association between fasting glucose and plasma adiponectin levels [4
]. These inconclusive findings across ancestries could be attributed to reduced power in the IRASFS African American cohort in comparison to the Hispanic American cohort as a result of sample size differences (Appendix Table 2
) and compounded by LD differences between the two ethnicities. Therefore, it is not possible to draw firm conclusions based on these results, but we hypothesize that if adiponectin and fasting glucose are associated with one another, there may be factors other than ADIPOQ
variants that drive the association.
As an adipocytokine, adiponectin has been reported to be associated with adiposity phenotypes [3
]. In the IRASFS Hispanic-American cohort, there were several SNPs associated with adiposity phenotypes such as BMI, visceral and subcutaneous adipose tissue, and waist circumference. However, none of the variants were concomitantly associated with plasma adiponectin levels. This finding leads us to speculate that variants associated with plasma adiponectin levels are not similarly related to adipose tissue distribution or overall body mass, unlike many other reports. Interestingly, in the African-American cohort of the IRASFS, there were no ADIPOQ
variants associated with adiposity phenotypes.
Within the IRASFS Hanley et al
] previously reported strong correlations between plasma adiponectin levels and SI
, fasting glucose, fasting insulin, BMI, waist circumference, and visceral adipose tissue. The current study failed to find consistent association between variants associated with plasma adiponectin and glucose homeostasis and adiposity phenotypes. One of the greatest strengths of the IRASFS is a unique study design with well phenotyped and comprehensively genotyped samples of African and Hispanic Americans. These results are limited in the number of individuals available within the sample, 1183 Hispanic and 566 African Americans. Due to the high quality phenotyping performed in the IRASFS, this also limits replication samples since this type of phenotyping is unavailable in most other cohorts. In spite of this, this study performed a comprehensive tagging of the ADIPOQ
gene to assess the association of adiponectin variants with glucose homeostasis and adiposity phenotypes.