In the genome-wide analyses, we confirmed that common variations near/within ABO gene and genetic-inferred ABO blood groups were associated with plasma concentrations of sE-selectin at a genome-wide significance level.
The human ABO
gene encodes a glycosyltransferase that catalyzes the transfer of carbohydrates to H antigen and form the antigenic structure of the ABO blood groups (15
). A and B antigens are formed by the action of glycosyltransferases encoded by functional alleles of the ABO
gene. The A allele encodes A transferase, which synthesizes the A antigen. Similarly, the B allele encodes B transferase, which synthesizes the B antigen. The O allele does not produce an active enzyme. Blood type A has variations in subgroups, of which A1 and A2 are the most important. Blood type A with a normal quantity of antigen is named A1, which comprises ~80% of blood type A in Europeans. Blood type A2 has a single base deletion near the carboxyl terminal, resulting in a loss of A2 transferase activity (16
). The A1 allele has 30–50-fold higher A transferase activity than A2 allele (17
Our results are highly consistent with the findings from a recent GWA analysis in type 1 diabetic patients and non-diabetic controls (11
), and also in line with previous report that human ABO blood groups were related to sE-selectin levels (18
). Although the mechanism underlying the associations between genetic variants at the ABO
locus and sE-selectin concentration is unknown, the high consistency in data from different studies provides solid evidence for ABO
locus as a major genetic determinant for plasma sE-selectin concentration.
In addition, we found the variations at ABO
locus and ABO blood groups were associated with sICAM-1 and/or TNF-R2 levels, independent of sE-selectin levels. These results are consistent with previous GWA studies in which SNPs in the same region were related to levels of sICAM-1 (12
) and TNF-alpha (13
). E-selectin is transcriptionally regulated by TNF-alpha (19
), and both sICAM-1 and/or TNF-R2 are positively correlated with sE-selectin levels. However, the associations of ABO variants with sICAM-1 and TNF-R2 were to the opposite direction to their associations with sE-selectin. The data suggest that ABO
variants may affect these markers through different mechanisms. Further investigations are warranted to understand the functional alterations contributing to the changes in these correlated markers.
Several previous studies have examined the relations between human ABO blood groups with the risk of type 2 diabetes. Although some studies suggested a link between ABO blood groups and diabetes (20
), the associations were not observed in others (23
). The controversial results from these studies were partly due to their retrospective design and small case numbers, and the variation in the genetic structure among different ethnic groups. We found that blood group B was associated with a decreased risk compared with blood group O. Although associated with even lower sE-selectin, the association between blood group A and diabetes risk was not significant, maybe partly explained by its associations with higher levels of sICAM-1 and TNF-R2, both are risk factors for type 2 diabetes (3
). In addition, data from some studies indicate that ABO
locus might also affect other biomarkers such as factor VIII and throumbomodulin (18
). Therefore, the associations between ABO blood groups and diabetes risk may reflect the combined effects of multiple risk factors. We did not find significant associations between individual SNPs at ABO
locus with diabetes risk. The results were in line with the failure in identifying genetic variants associated with diabetes in GWAS studies (26
). These data suggest that the combination of multiple alleles (haplotypes) at this locus, rather than individual genetic variant, may affect diabetes risk.
The major strengths of our study include high quality genotype data, careful quality control and minimal population stratification. We acknowledge several study limitations, including errors in biomarker measurements and genotyping. Nevertheless, we employed strict quality control criteria in genotyping, and these errors more likely bias the association toward null because the measurement errors for biomarker assays and genotyping are uncorrelated and, thus, random. The case–control sample may not represent a random sample from the general population. We have controlled the diabetes status in the analyses to avoid the potential sampling bias. In addition, we performed sensitivity analyses in the cases and controls separately. The associations with e-selectin levels from all the analyses were highly consistent. The study sample size is relatively small to identify the associations between blood groups and diabetes risk at genome-wide significance level. For example, given the effect size observed and the frequency for the genetic-inferred blood group B, we estimated a sample size of ~1700 (850 diabetes cases) is needed to reach genome-wide significance. Our study populations exclusively consisted of Caucasian women with European ancestry. Therefore, the findings may not be generalizable to men and other ethnicities.
In conclusion, by examining a GWA scan, we confirmed that the ABO locus was a major determinant for plasma sE-selectin levels. We found that the variants at ABO locus and the genetic-inferred ABO blood groups were associated with the risk of type 2 diabetes, independent of sE-selectin levels. We found that blood group B was associated with a decreased risk compared with blood group O. The mechanism underlying the observed association remains unknown and our findings warrant the need for further replications in other ethnic groups and functional investigations.