Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Abstract

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

“…20 There are several other loci reported to be associated with CAD in European populations including those on chromosomes 2q33, 6q24, 12q24 and 21q22. 10,11 We have not tested them in this study, because the minor allele frequency of each SNP was less than 5% in the HapMap data for the Japanese (JPT) or Han Chinese (CHB) populations (Supplementary Table 1) and therefore the statistical power was too low to obtain a definite conclusion from our study design. The association of the BRAP SNP with CAD was replicated in two East Asian populations, Japanese and Korean.…”

“…3 Several large-scale association studies using a large number of genetic variations, including single nucleotide polymorphisms (SNPs), have recently identified the susceptibility genes and loci for CAD. [4][5][6][7][8][9][10][11][12] However, not all of the reported associations could be replicated in other studies even if middle-to large-sized samples were investigated in the original reports, suggesting that the contribution of genetic factors was not large enough to be replicated in some cases. 13 Validation studies for the association in other populations are, therefore, crucial to establish the role of diseaserelated genes.…”

“…7 In a recent study, three other loci were reported to be associated with early-onset MI 10 (loci on chromosomes 2q33, 6q24 and 21q22). In addition, Gudbjartsson et al 11 reported that an SNP on chromosome 12q24 was significantly associated with MI. All these studies were conducted in European populations.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…The variant rs3184504 tagging the SH2B3 gene is associated with CAD (Gudbjartsson et al , 2009; CARDIoGRAMplusC4D Consortium, 2013). The interpretation of this association is complicated by the fact that this particular variant also represents an eSNP for a neighbour gene, ATXN2 (Braenne et al , 2015).…”

“…Besides the platelet phenotypes (Soranzo et al , 2009; Takizawa et al , 2010) and the also known association with blood pressure (Levy et al , 2009; Newton‐Cheh et al , 2009), SH2B3 seems to mainly influence inflammatory processes. From a genetic point of view, this is already noticeable from the associations of the locus with different inflammatory diseases, for example coeliac disease (Hunt et al , 2008), type 1 diabetes (Barrett et al , 2009; Concannon et al , 2009) and high eosinophil numbers (Gudbjartsson et al , 2009). An experimental study revealed that Sh2b3/Lnk influences the activation of dendritic cells, thereby modulating the immune response, that is dendritic cells from Lnk −/− mice are hyper‐responsive to IL‐15, resulting in an excessive production of IFN‐γ (Mori et al , 2014).…”