The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val→IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 × 10-12, replication cohort p = × 3 10 -14, combined cohort p = 9 × 10-24). We imputed 61 SNPs in CR1, and a ''possibly damaging'' SNP (rs2274567, His→Arg) in linkage disequilibrium (r2 = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 × 10-11, replication p = 7 × 10-17, and combined cohort p = 2 × 10-25). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions.
Bibliographical noteFunding Information:
The authors acknowledge Elizabeth Pugh for helpful discussions. The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI), with additional funding from National Institute of General Medical Sciences (NIGMS) through the following grants: U01-HG-04599 (Mayo Clinic), U01-HG-004610 (Group Health Cooperative), U01-HG-004608 (Marshfield Clinic), U01HG004609 (Northwestern University), and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center).