Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes

Abstract

Blood soluble E-selectin (sE-selectin) levels have been related to various conditions such as type 2 diabetes. We performed a genome-wide association study among women of European ancestry from the Nurses' Health Study, and identified genome-wide significant associations between a cluster of markers at the ABO locus (9q34) and plasma sE-selectin concentration. The strongest association was with rs651007, which explained approximately 9.71% of the variation in sE-selectin concentrations. SNP rs651007 was also nominally associated with soluble intracellular cell adhesion molecule-1 (sICAM-1) (P = 0.026) and TNF-R2 levels (P = 0.018), independent of sE-selectin. In addition, the genetic-inferred ABO blood group genotypes were associated with sE-selectin concentrations (P = 3.55 x 10(-47)). Moreover, we found that the genetic-inferred blood group B was associated with a decreased risk (OR = 0.44, 0.27-0.70) of type 2 diabetes compared with blood group O, adjusting for sE-selectin, sICAM-1, TNF-R2 and other covariates. Our findings indicate that the genetic variants at ABO locus affect plasma sE-selectin levels and diabetes risk. The genetic associations with diabetes risk were independent of sE-selectin levels.

Figure 1.

(A) Plot of the –log₁₀ P-values for the analysis for sE-selectin level GWA trend tests. The analysis was adjusted for age, BMI and diabetes status. Each point represents a SNP from the 704 409 SNPs remaining after quality control filters. Different bands are used to differentiate SNPs on consecutive autosomal and X chromosomes; (B) association signals at chromosome 9, across a region centering on ABO gene. The vertical axis representing the –log₁₀ P-values from the linear trend test. SNP rs651007 is shown in red, labeled with discovery stage P-values. Estimated recombination rates from HapMap are plotted to reflect the local LD structure. Genes were extracted from the HapMap Genome Browser.

Figure 2.

The levels of (A) sE-selectin, (B) sICAM-1 and (C) TNF-R2 by the genotypes of SNP rs651007. The P-values are from the trend test in linear regression model. The analyses were adjusted for age, BMI, fasting status, diabetes status and biomarkers (sICAM-1 and TNF-R2 for sE-selectin analysis; and sE-selectin for sICAM-1 and TNF-R2 analyses). Error bars denote standard deviation.

Figure 3.

Odds ratios of diabetes associated with the genetic-inferred ABO blood groups A, B and AB compared with blood group O. The analyses were adjusted for age, BMI, smoking, alcohol consumption, physical activity, family history of diabetes and menopausal status. Error bars denote 95 percent confidence intervals.