Association of hepatocyte growth factor promoter polymorphism with severity of interstitial lung disease in Japanese patients with systemic sclerosis

Abstract

Objective. To examine associations of singlenucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc).Methods. Four SNPs (HGF -1652 C/T, ؉44222 C/T, and ؉63555 G/T, and c-met -980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reactionbased assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA).Results. There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P ‫؍‬ 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease.Conclusion. A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.

Genetic associations for keratoconus: a systematic review and meta-analysis

“…One SNP in HGF , rs3735520 (c.−1652C > T), was reported to modulate the severity of interstitial lung disease in patients with systemic sclerosis by altering the transcriptional efficiency of the HGF gene 67 . Whether they are in linkage disequilibrium with other coding variants in the relevant genes remained to be elucidated by sequencing analyses.…”

Genome-Wide Association Study for Endothelial Growth Factors

“…In 78 control participants from the Cardiovascular Health Study, SNP rs3735520, which is located in the promoter region of the HGF gene, was statistically significantly associated with HFG levels, whereas SNP rs17501108 (likewise located in the promoter) was not. 21 However, SNP rs3735520 was not associated with HGF levels in 133 patients with systemic sclerosis, 22 although experimental data indicated that this variant was related to transcriptional activity. 22 In our dataset, both SNP rs3735520 (p=0.12) and SNP rs17501108 (p=0.39) were not associated with HGF concentrations.…”

“…21 However, SNP rs3735520 was not associated with HGF levels in 133 patients with systemic sclerosis, 22 although experimental data indicated that this variant was related to transcriptional activity. 22 In our dataset, both SNP rs3735520 (p=0.12) and SNP rs17501108 (p=0.39) were not associated with HGF concentrations. Thus far, there has been no genome-wide analysis regarding the genetic determinants of HGF levels.…”

Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients

“…SNP Rs3735520 was found to associate with end-stage lung disease in Japanese systemic sclerosis patients, and carriers of the HGF promoter with the HGF − 1652 TT allele had a relative inability to increase circulating HGF levels. By functional studies, the HGF promoter carrying the HGF − 1652 TT allele was reported to have lower transcriptional activity than the promoter carrying the CT or CC allele, possibly due to the binding of a negative transcriptional regulator [37]. In myeloma, the relevance of these SNPs, in particular Rs3735520, needs further clarification.…”