Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate |
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| Authors: | Kullo Iftikhar J Ding Keyue Shameer Khader McCarty Catherine A Jarvik Gail P Denny Joshua C Ritchie Marylyn D Ye Zi Crosslin David R Chisholm Rex L Manolio Teri A Chute Christopher G |
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| Institution: | 1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA;2Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA;3Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA 98195, USA;4Departments of Medicine and Biomedical Informatics, Vanderbilt University, Nashville, TN 37232, USA;5Center for Human Genetics, Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37231, USA;6Department of Biostatistics, University of Washington, Seattle, WA 98195, USA;7Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA;8Office of Population Genomics, National Human Genome Research Institute (NHGRI), Bethesda, MD 20892, USA;9Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA |
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| 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. |
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