title: Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing.
abstract: We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double-stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non-IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non-IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Rebecca W Y
authors.initials: RW
authors.lastname: Chan
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Peiyong
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Xianlu
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; and.
authors.forename: Lai-Shan
authors.initials: LS
authors.lastname: Tam
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Gary J W
authors.initials: GJ
authors.lastname: Liao
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; and.
authors.forename: Edmund K M
authors.initials: EK
authors.lastname: Li
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; and.
authors.forename: Priscilla C H
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: K C Allen
authors.initials: KC
authors.lastname: Chan
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China;
authors.forename: Rossa W K
authors.initials: RW
authors.lastname: Chiu
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China loym@cuhk.edu.hk.
authors.forename: Y M Dennis
authors.initials: YM
authors.lastname: Lo
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D002869:Chromosome Aberrations; D018899:CpG Islands; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D015723:Gene Library; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D017422:Sequence Analysis, DNA
chemical_list: D015415:Biomarkers; D007074:Immunoglobulin G; D004247:DNA
keywords: autoimmune disease; epigenetics; genomic representation; massively parallel sequencing; size profiling