Osteoarthritis

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Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family

  1. Hsiang-Cheng Chen1,3,†,
  2. Virginia Byers Kraus2,†,*,
  3. Yi-Ju Li2,
  4. Sarah Nelson2,
  5. Carol Haynes2,
  6. Jessica Johnson2,
  7. Thomas Stabler2,
  8. Elizabeth R. Hauser2,
  9. Simon G. Gregory2,
  10. William E. Kraus2,
  11. Svati H. Shah2

Article first published online: 25 FEB 2010

DOI: 10.1002/art.27288

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 62, Issue 3, pages 781–790, March 2010

Additional Information

How to Cite

Chen, H.-C., Kraus, V. B., Li, Y.-J., Nelson, S., Haynes, C., Johnson, J., Stabler, T., Hauser, E. R., Gregory, S. G., Kraus, W. E. and Shah, S. H. (2010), Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family. Arthritis & Rheumatism, 62: 781–790. doi: 10.1002/art.27288

Author Information

  1. 1

    Duke University Medical Center, Durham, North Carolina

  2. 2

    Duke University Medical Center, Durham, North Carolina

  3. 3

    Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

  1. †

    Drs. Chen and V. Kraus contributed equally to this work.

*Box 3416, Duke University Medical Center, Durham, NC 27710

Publication History

  1. Issue published online: 25 FEB 2010
  2. Article first published online: 25 FEB 2010
  3. Manuscript Accepted: 17 NOV 2009
  4. Manuscript Received: 2 MAY 2009

Funded by

  • Claude D. Pepper Older Americans Independence Centers of the NIH/National Institute on Aging. Grant Numbers: 2P60-AG-11268, 1P30-AG-028716
  • Mary Duke Biddle Foundation
  • Trent Foundation
  • Taiwanese government

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Abstract

Objective

The genetic contributions to the multifactorial disorder osteoarthritis (OA) have been increasingly recognized. The goal of the current study was to use OA-related biomarkers of severity and disease burden as quantitative traits to identify genetic susceptibility loci for OA.

Methods

In a large multigenerational extended family (n = 350), we measured 5 OA-related biomarkers: hyaluronan (HA), cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA collagen (PIIANP), C-propeptide of type II procollagen (CPII), and type II collagen neoepitope (C2C). Single-nucleotide polymorphism markers (n = 6,090) covering the whole genome were genotyped using the Illumina HumanLinkage-12 BeadChip. Variance components analysis, as implemented in the Sequential Oligogenic Linkage Analysis Routines, was used to estimate heritabilities of the quantitative traits and to calculate 2-point and multipoint logarithm of odds (LOD) scores using a polygenic model.

Results

After adjusting for age and sex, we found that 4 of the 5 biomarkers exhibited significant heritability (PIIANP 0.57, HA 0.49, COMP 0.43, C2C 0.30; P ≤ 0.01 for all). Fourteen of the 19 loci that had multipoint LOD scores of >1.5 were near to or overlapped with previously reported OA susceptibility loci. Four of these loci were identified by more than 1 biomarker. The maximum multipoint LOD scores for the heritable quantitative biomarker traits were 4.3 for PIIANP (chromosome 8p23.2), 3.2 for COMP (chromosome 8q11.1), 2.0 for HA (chromosome 6q16.3), and 2.0 for C2C (chromosome 5q31.2).

Conclusion

Herein, we report the first evidence of genetic susceptibility loci identified by OA-related biomarkers in an extended family. Our results demonstrate that serum concentrations of PIIANP, HA, COMP, and C2C have substantial heritable components, and using these biomarkers, several genetic loci potentially contributing to the genetic diversity of OA were identified.

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