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Kaposi sarcoma‐associated herpesvirus (KSHV) is endemic in Xinjiang, China. Determinants of KSHV seropositivity among high‐risk groups are not well understood. We seek to identify genetic and environmental predisposing factors for KSHV infection among Uygurs in this endemic region. A cross‐sectional study was performed among the Uygur population in Xinjiang, China. KSHV‐antibodies were detected using immunofluorescence assay (IFA) and human leukocyte antigen (HLA) alleles were genotyped. Univariate and multivariate logistic regression analyses were applied to explore the environmental and genetic risk factors of KSHV seropositivity. Finally, a total of 721 participants were included. The seroprevalence of KSHV was 24.1% among this population. Sweet‐food preference (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.03–3.34), and coronary heart disease (OR 1.91, 95%CI 1.24–2.94) were statistically correlated with KSHV infection. HLA‐DQB1*06:09 were found to significantly increase the risk of KSHV infection under all 3 models (ORAllelic = 4.06; ORDominant = 3.27; and ORRecessive = 8.06). Six SNPs (SNP0260, SNP0361, SNP0797, SNP0852, SNP1159, and SNP1375) in the DQB1 and DRB1 region and haploid type GTCTAACTAATC in block 17 were statistically associated with KSHV infection. We demonstrated that genetic variations in HLA‐DQB1/DRB1 and environmental risk factors were strongly associated with KSHV infection among this population. Key Points/Highlights: Identifying potential predisposing factors of Kaposi sarcoma‐associated herpesvirus (KSHV) seropositivity in endemic settings, such as the Uygur population in Xinjiang, China, may be useful for the development of both therapeutic and preventive strategies of KSHV/KS to address this important public health concern.Susceptibility to KSHV infection might be caused by virus‐host‐environment interactions, HLA gene polymorphisms may play a crucial role in controlling the immune response to KSHV infection.Sweet‐food preference and coronary heart disease were significantly correlated with KSHV seropositivity. HLA‐DQB1*06:09, six SNPs, and haploid type GTCTAACTAATC in block 17 may be associated with KSHV infection.The first study to investigate the relationship between environmental risk factors, HLA gene polymorphisms, and KSHV susceptibility among Uygur ethnic population in Xinjiang, providing empirical data for further in‐depth and extensive studies. And the findings will contribute to an enhanced awareness of KSHV infection among high‐risk populations and benefit the prevention of KSHV in countries facing the same situations. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV) has become widely dispersed worldwide since it was first reported in 1994, but the seroprevalence of KSHV varies geographically. KSHV is relatively ubiquitous in Mediterranean areas and the Xinjiang Uygur Autonomous Region, China. The origin of KSHV has long been puzzling. In the present study, we collected and analysed 154 KSHV ORF-K1 sequences obtained from samples originating from Xinjiang, Italy, Greece, Iran and southern Siberia using Bayesian evolutionary analysis in BEAST to test the hypothesis that KSHV was introduced into Xinjiang via the ancient Silk Road. According to the phylogenetic analysis, 72 sequences were subtype A and 82 subtype C, with C2 (n = 56) being the predominant subtype. The times to the most recent common ancestors (tMRCAs) of KSHV were 29,872 years (95% highest probability density [HPD], 26,851-32,760 years) for all analysed sequences and 2037 years (95% HPD, 1843-2229 years) for Xinjiang sequences in particular. The tMRCA of Xinjiang KSHV was exactly matched with the time period of the ancient Silk Road approximately two thousand years ago. This route began in Chang'an, the capital of the Han dynasty of China, and crossed Central Asia, ending in the Roman Empire. The evolution rate of KSHV was slow, with 3.44 × 10 substitutions per site per year (95% HPD, 2.26 × 10 to 4.71 × 10), although 11 codons were discovered to be under positive selection pressure. The geographic distances from Italy to Iran and Xinjiang are more than 4000 and 7000 kilometres, respectively, but no explicit relationship between genetic distance and geographic distance was detected. [ABSTRACT FROM AUTHOR]