Admixture Mapping of an Allele Affecting Interleukin 6 Soluble Receptor and Interleukin 6 Levels

• Published in: American journal of human genetics Vol. 80; no. 4; pp. 716 - 726
• Main Authors: Reich, David, Patterson, Nick, Ramesh, Vijaya, De Jager, Philip L., McDonald, Gavin J., Tandon, Arti, Choy, Edwin, Hu, Donglei, Tamraz, Bani, Pawlikowska, Ludmila, Wassel-Fyr, Christina, Huntsman, Scott, Waliszewska, Alicja, Rossin, Elizabeth, Li, Rongling, Garcia, Melissa, Reiner, Alexander, Ferrell, Robert, Cummings, Steve, Kwok, Pui-Yan, Harris, Tamara, Zmuda, Joseph M., Ziv, Elad
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-04-2007; University of Chicago Press; American Society of Human Genetics
• Subjects: African Americans - genetics; Aged; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 1 - genetics; Classical genetics, quantitative genetics, hybrids; European Continental Ancestry Group - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genomics - methods; Genotype; Human; Humans; Interleukin-6 - blood; Lod Score; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Polymorphism, Single Nucleotide - genetics; Receptors, Interleukin-6 - genetics; Software; Genetic mapping; Human; Interleukin 6; Cartography; Allele; Admixture; Genetics; Biological receptor
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/513206

Circulating levels of inflammatory markers can predict cardiovascular disease risk. To identify genes influencing the levels of these markers, we genotyped 1,343 single-nucleotide polymorphisms (SNPs) in 1,184 African Americans from the Health, Aging and Body Composition (Health ABC) Study. Using admixture mapping, we found a significant association of interleukin 6 soluble receptor (IL-6 SR) with European ancestry on chromosome 1 (LOD 4.59), in a region that includes the gene for this receptor (
IL-6R). Genotyping 19 SNPs showed that the effect is largely explained by an allele at 4% frequency in West Africans and at 35% frequency in European Americans, first described as associated with IL-6 SR in a Japanese cohort. We replicate this association (
P≪1.0×10
−12) and also demonstrate a new association with circulating levels of a different molecule, IL-6 (
P<3.4×10
−5). After replication in 1,674 European Americans from Health ABC, the combined result is even more significant:
P≪1.0×10
−12 for IL-6 SR, and
P<2.0×10
−9 for IL-6. These results also serve as an important proof of principle, showing that admixture mapping can not only coarsely localize but can also fine map a phenotypically important variant.