Association Study Of PDGF-B Polymorphisms With Susceptibility Of Severe Fever With Thrombocytopenia Syndrome

BackgroundSevere fever with thrombocytopenia syndrome(SFTS) is an emerging hemorrhagic fever that was first reported in rural areas of China and recently, has been reported in Japan, Korea, and Dubai. The causative agent is SFTS bunyavirus(SFTSV), a novel member of the Phlebovirus species in the family Bunyaviridae.The SFTSV infected patients had wide clinical spectrum, with some experiencing self-limiting clinical course, while approximately 12% might develop fatal disease. The iceberg phenomenon of SFTS is obvious that a seroprevalence of 0.84-6.37% was found among the healthy population residing in endemic areas. Research on person to person transmission events disclosed a higher tendency of having clinical disease and severe disease outcome in the inheritable related individuals, providing further evidence that human genetic background might play roles in the disease development and modulation of disease severity.Among all the immune dyregulation, the cytokine mediated inflammatory response, characterized by cytokine/chemokine production imbalance, and was found to be responsible for SFTSV infection and disease progression.For the PDGF-B gene, the population based association studies have been focused on two single nucleotide polymorphisms(SNPs), rs1800818 located in the 5′-UTR and rs1800817 in first intron.The role of the PDGF-B polymorphisms in SFTS, however, has never been investigated. In the present study, we examined whether these two important PDGF-B polymorphisms has any bearing on the risk or severity of SFTS in Chinese populations. MethodsPart one:The study was performed in an SFTS-designated hospital(The 154 Hospital) in Xinyang. From 2011 to 2013.For subjects who had blood drawn for routine test, we kept the residues of the serum samples in a-80°C refrigerator until enzyme-linked immunosorbent assay(ELISA) detection.Part two:An initially small-scale case-control association study guided the selection of platelet derived growth factor-B(PDGF-B) rs1800818 in 1020 SFTS patients and 1353 controls.Part three:To compare the expression patterns of PDGF-BB, acute SFTS patients and age matched controls were selected to measure the PDGF-BB levels by using PDGF-BB ELISA assay(Gen Way Biotech, USA). The SFTS patients who were successfully followed up and sampled during the convalescence were also tested for the PDGF-BB evaluation. All measurements were performed in duplicate. ResultsPart one:From July of 2011 to December of 2013, altogether, 5,245 subjects were recruited and tested. A seropositive rate of 6.59% was determined in the highly endemic region for severe fever with thrombocytopenia syndrome. Annual seropositive rates were comparable among three sampling years(7.72% in 2011, 5.35% in 2012, and 6.77% in2013). The year-to-year variance of seropositive rates was in significant for each month(P = 0.120). The median age of the positive patients was 49 years old(interquartile range = 35–61 years old). No significant association between positive antibodies response rates and antibody magnitude was observed for gender. The SFTSV seroprevalence increased significantly with age(Ptrend = 0.022). The seroprevalence of 6.12% corresponded to the low incidence rate of 0.17 per 1,000,000 in the low-risk region, where as the seroprevalence of 8.36% corresponded to the high incidence rate of 22.52 per 1,000,000 in the high-risk region.Part two:In all of the 1020 SFTS patients and 1353 controls, rs1800818 G allele was significantly overrepresented in SFTS patients than controls(9% vs. 5.6%, P < 0.001). After adjustment for age, sex, and underlying medical conditions, the genotypes containing G allele(AG + GG genotypes) were significantly associated with increased susceptibility to SFTS(OR = 1.66, 95% CI = 1.28-2.16; P < 0.001).Part three:By using the ELISA assay, we observed that PDGF-BB concentration was significantly reduced in acute phase of patients than in the controls(P < 0.001) and recovered patients at 6 month(P = 0.007) and 12 month(P = 0.003). The rs1800818 G allele was associated with decreased serum PDGF-BB levels in SFTS patients at their early infection(P = 0.015). PDGF-B rs1800818 conferred no susceptibility to severe or fatal outcome in SFTS patients. ConclusionsSeroprevalence was comparable in the last 3 years, indicating a stable and ongoing circulation of the infection. Our findings also suggest that the PDGF-B rs1800818 polymorphism might play a role in mediating the susceptibility to SFTS.