Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: Results of genome-wide association analyses including 4659 European individuals

Abstract

Objective

Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women.

Methods

We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 × 10⁻⁴ for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin.

Results

The ADIPOQ locus showed genome-wide significant p-values in the combined (p = 4.3 × 10⁻²⁴) as well as in both women- and men-specific analyses (p = 8.7 × 10⁻¹⁷ and p = 2.5 × 10⁻¹¹, respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p > 0.01).

Conclusions

We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin.

Introduction

Plasma adiponectin is a quantitative parameter, which has a strong role in modulating insulin sensitivity and glucose homeostasis. It has been found to be decreased in humans with type 2 diabetes and cardiovascular disease (CVD) [1], [2] and decreased plasma adiponectin was found to be associated with deteriorated levels of virtually all parameters of the metabolic syndrome [3], [4], [5]. Experiments in mice transgenic or deficient for the adiponectin gene have underscored the functional role of adiponectin on various components of the metabolic syndrome and diabetes mellitus [3], [6], [7].

Concerning CVD outcomes the observations on adiponectin are heterogeneous as recently reviewed extensively [8]: experimental data demonstrate that adiponectin stimulates the production of nitric oxide, positively affects inflammatory mechanisms, has anti-apoptotic properties and is involved in vascular remodeling. Clinical data are diverse depending mainly on the disease stage when investigated. Low levels seem to be associated with worse outcomes when measured in healthy conditions. However, there is accumulating data that in diseased states such as chronic heart failure or existing CVD high rather than low levels predict CVD and non-CVD mortality. Knowing the genes which affect plasma adiponectin might be helpful to disentangle adiponectin as cause or consequence of disease states using a Mendelian randomization approach [9].

Plasma adiponectin shows pronounced differences between men and women with about 1.5 times higher concentrations in women [10]. An explanation for these differences is lacking as plasma adiponectin is only moderately influenced by nutritional behavior, physical activity or other environmental components [5], [8], [11]. However, there is clear evidence for a high heritability of about 50% [4], [12], [13], [14] which one study even suggested to be sex-dependent [14]. In-line with lower plasma adiponectin in men, higher prevalences of type 2 diabetes and impaired fasting glucose were also reported in men [15].

Recent genome-wide association (GWA) scans have highlighted the potential of genetic factors with differential sex effects on concentrations of uric acid [16], [17], [18] and lipids [19], waist circumference [20] or schizophrenia [21]. Many of these phenotypes show pronounced sex-specific differences in plasma concentrations or prevalence. A sex-differential SNP association with a quantitative phenotype can even mask a real association if data are analyzed without stratification. One example is a SNP near the LYPLAL1 gene which recently showed a strong association with waist–hip ratio in women but not in men and would have been missed in the sex-combined analysis [20]. To our knowledge, sex-specific differences for genetic effects on plasma adiponectin have not been investigated so far.

In the study at hand, we aimed to identify not only novel genes modulating plasma adiponectin but also whether genetic effects are differential between men and women. We combined this meta-analysis with a candidate gene approach considering all genes which have recently been associated with singular components of the metabolic syndrome in GWA studies.