Genetic Mapping of Vascular Calcified Plaque Loci on Chromosome 16p in European Americans from the Diabetes Heart Study

Authors

  • Allison B. Lehtinen,

    1. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    3. Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • Amanda J. Cox,

    1. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    3. Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • Julie T. Ziegler,

    1. Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • V. Saroja Voruganti,

    1. Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
    Search for more papers by this author
  • Jianzhao Xu,

    1. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • Barry I. Freedman,

    1. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • J. Jeffrey Carr,

    1. Department of Radiologic Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • Anthony G. Comuzzie,

    1. Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
    Search for more papers by this author
  • Carl D. Langefeld,

    1. Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author
  • Donald W. Bowden

    Corresponding author
    1. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    2. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    3. Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
    Search for more papers by this author

Corresponding author: DONALD BOWDEN, Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157. Tel.: 336-713-7500; Fax: 336-713-7566; E-mail: dbowden@wfubmc.edu

Summary

A linkage peak for carotid artery calcified plaque (CarCP) on chromosome 16p (LOD 4.39 at 8.4 cM) in families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined. Fine mapping encompassed 104 single-nucleotide polymorphisms (SNPs) in 937 subjects from 315 families; including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, CLEC16A). Linkage and association analyses using variance components analysis adjusting for age, gender, body mass index (BMI), and diabetes status refined the CarCP linkage into two distinct peaks (LODs: 3.89 at 6.9 cM and 4.86 at 16.0 cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19 cM) and a vascular calcification principle component (LOD: 3.71 at 16.0 cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 P= 0.005) with modest evidence of association with SNPs in CACNA1H (P= 0.010–0.033). Bayesian quantitative trait nucleotide (BQTN) analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium (LD) with a functional SNP. This study refined the 16p region contributing to vascular calcification. The causal variants remain to be identified, but results are consistent with a linkage peak that is due to multiple common variants, though rare variants cannot be excluded.

Ancillary