Abstract
Autoimmune diseases (AD) are responsible for a substantial amount of disability and morbidity worldwide. Research generally focuses on a single disease, although autoimmune phenotypes could represent pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms. This report examined the effect and importance of the homozygosity status, using genome-wide interspersed markers, in individuals and multiplex families affected with AD. This study presented two approaches: (I) a case-control comparison and evaluation on the effect of homozygosity at the genome-wide level and per marker, including 453 unrelated individuals (121 late-, 79 early-onset AD, 40 polyautoimmunity (PolyA), 30 multiple autoimmune syndrome (MAS) and 183 healthy control individuals); and (II) a model-free affected pair linkage approach which included 35 MAS, 49 polyA, 104 late-, and 83 early-onset multiplex families. A total of 372 genome-wide markers were used in the analysis. The standardized observed homozygosity (SOH) was calculated and the association of the homozygosity status and the autoimmune trait was evaluated. The multipoint model-free linkage analysis was applied by using RELPAL from S.A.G.E v6.3. Results for the SOH showed significant differences between controls and early-onset individuals, where early-onset affected individuals showed lower homozygosity relative to controls. No differences were observed relative to controls for MAS, polyA and late-onset disease at the genome-wide level. The local marker homozygosity effect showed share and specific risk and/or protective effects for 24 markers. The model-free affected pair linkage approach lacked any suggestive linkage signals, but marginal signals displayed excess allele sharing for extreme phenotypes in autoimmunity. This study presumed autoimmunity as a trait rather than a clinical phenotype and tried to approach AD as a continuous trait presenting extreme phenotypes. Future approaches would be expected to dwell on the data presented here to corroborate and expand on sample size, marker coverage and their effects.
Highlights
Human genetic markers reflect the differences in DNA sequence within the genome of individuals within populations
Type 1 diabetes (T1D) cases were categorized as individuals with early-onset Autoimmune diseases (AD) while any other affected AD individual was categorized as late-onset AD; and (ii) polyautoimmunity and/or multiple autoimmune syndrome (MAS)
This study assumed autoimmunity as a trait rather than a clinical phenotype and tried to approach AD as a continuous phenotype presented with extreme phenotypes
Summary
Human genetic markers reflect the differences in DNA sequence within the genome of individuals within populations These markers can take many forms, including single nucleotide variants (i.e., SNPSingle nucleotide polymorphisms), short tandem repeats (STRs) (i.e., microsatellites and/or variable number of tandem repeats), small indels (i.e., insertions and deletions of a short DNA sequence) and duplications or deletions that change the copy number of a larger segment [1]. STRs have been the workhorse of human genetic analysis since the late 1980s. Their polymorphism is due to variations in the number of tandem repeats of short sequence units typically ranging from two to four nucleotides in size [2]. STR variations convey high information content due to their rapid mutation and multi-allelic spectra, making this type of variants key for population genetics pilot and or proof of principle studies, when applied in a wide-range of methods to find signatures of selection, to elucidate mutation patterns in nearby SNPs, in DNA forensics and in genetic genealogy [5,6]
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