Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles.
OBJECTIVE
Fewer than 5% of monozygotic (MZ) and dizygotic (DZ) twin pairs are clinically concordant for systemic sclerosis (SSc), yet the majority of MZ twins are concordant for antinuclear antibodies. To discover genetic versus nongenetic molecular pathways important to the pathogenesis of SSc, we compared global gene expression patterns in twins discordant for SSc.


METHODS
Total RNA from dermal fibroblasts of 15 discordant twin pairs (10 MZ and 5 DZ) and 5 normal controls were used in microarray analysis. Aberrantly expressed genes were confirmed using quantitative real-time reverse transcriptase-polymerase chain reaction.


RESULTS
Lesional and nonlesional fibroblasts from SSc patients showed no significant differences in gene expression, while SSc patients had gene profiles that were significantly different from those of unaffected DZ twins and normal controls. Unaffected MZ twins, however, were not significantly different from SSc patients. Unsupervised hierarchical clustering segregated the fibroblast samples as originating from 2 major groups. Group A contained 5 discordant MZ twin pairs, 3 affected MZ twins, and 3 affected DZ twins. Group B contained all 5 normal population controls, all 5 healthy DZ twins, 2 discordant MZ twins, and 2 discordant DZ twin pairs. Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts.


CONCLUSIONS
These results demonstrate that dermal fibroblasts from SSc patients and from 40-50% of their genetically identical but clinically unaffected MZ twins exhibit a similar gene expression pattern which can be induced in normal fibroblasts by sera from both. Thus, a stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts.
Zhou
Xiaodong
X
University of Texas Medical School at Houston, USA.
Tan
Filemon K
FK
Xiong
Momiao
M
Arnett
Frank C
FC
Feghali-Bostwick
Carol A
CA
D000328:Adult; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012595:Scleroderma, Systemic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*