title: Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate.
abstract: 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 (r(2) = 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.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. kullo.iftikhar@mayo.edu
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Khader
authors.initials: K
authors.lastname: Shameer
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Zi
authors.initials: Z
authors.lastname: Ye
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.forename: Rex L
authors.initials: RL
authors.lastname: Chisholm
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Chute
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D001799:Blood Sedimentation; D015331:Cohort Studies; D030541:Databases, Genetic; D057286:Electronic Health Records; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011951:Receptors, Complement / Q000235:genetics* / Q000378:metabolism*; D017463:Receptors, Complement 3b / Q000235:genetics* / Q000378:metabolism
chemical_list: C509991:CR1 protein, human; D011951:Receptors, Complement; D017463:Receptors, Complement 3b