Variants in genes related to inflammation and endothelial function can increase the risk for carotid atherosclerosis in southwestern China

Abstract

AimTo investigate the potential association between polymorphisms in genes involved in endothelial function, inflammation and carotid atherosclerosis.MethodsThis was a three-center, population-based sectional survey conducted in Sichuan province of southwestern China. We randomly selected 8 different communities in Sichuan, and the residents in each community volunteered to participate in the survey by face-to-face questionnaire. A total of 2,377 residents with high stroke risk population in the 8 communities were included. Carotid atherosclerosis was evaluated by carotid ultrasound, and the 19 single nucleotide polymorphisms (SNPs) in 10 endothelial function as well as inflammation relevant genes were measured in the high stroke risk population. Carotid atherosclerosis was defined by the presence of carotid plaque or any carotid stenosis ≥15% or mean intima-media thickness (IMT) > 0.9 mm. Generalized multifactor dimensionality reduction (GMDR) approach was used to analyze gene–gene interactions among the 19 SNPs.ResultsAmong the 2,377 subjects with high stroke risk, 1,028 subjects had carotid atherosclerosis (43.2%), of which 852 (35.8%) cases had carotid plaque, 295 (12.4%) cases had ≥15% carotid stenosis, whereas 445 (18.7%) had mean IMT > 0.9 mm. Multivariate logistic regression revealed that IL1A rs1609682 TT and HABP2 rs7923349 TT served as independent risk factors for carotid atherosclerosis (OR, 1.45, 95% CI: 1.034–2.032, p = 0.031, and OR, 1.829, 95% CI: 1.228–2.723, p = 0.003). GMDR analysis indicated that there was a significant gene–gene interaction found among IL1A rs1609682, ITGA2 rs1991013, and HABP2 rs7923349. After adjusting the covariates, the high-risk interactive genotypes in the 3 variants were significantly associated with a significantly higher risk for carotid atherosclerosis (OR, 2.08, 95% CI: 1.257–5.98, p < 0.001).ConclusionThe prevalence of carotid atherosclerosis was observed to be extremely high in the high-risk stroke population in southwestern China. There were associations observed between the specific variants in inflammation and endothelial function relevant genes and carotid atherosclerosis. The high-risk interactive genotypes among IL1A rs1609682, ITGA2 rs1991013, and HABP2 rs7923349 significantly increased the risk of carotid atherosclerosis. These results are expected to provide novel strategies for the prevention of carotid atherosclerosis. The gene–gene interactive analysis used in this study may be very helpful to elucidate complex genetic risk factors for carotid atherosclerosis.

Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population

“…For instance, Gardener et al (13) evaluated the associations between carotid plaque and 197 variants in 43 genes implicated in inflammation and endothelial function and demonstrated that the variants in 10 genes (IL6R, TNF, NOS2A, IL1A, TNFSF4, ITGA2, PPARA, TLR4, HABP2, and VCAM1) were associated with carotid plaque in the Northern Manhattan population. Similarly, our previous studies have also shown that specific single nucleotide polymorphisms (SNPs) in genes related to inflammation and endothelial function and high-risk interaction among HABP2 rs7923349, ITGA2 rs1991013, IL1A rs1609682, and NOS2A rs8081248, the interaction between ITGA2 rs4865756 and HABP2 rs7923349, and interaction among ITGA2 rs1991013, IL1A rs1609682, and HABP2 rs7923349 were associated with carotid plaque vulnerability (10), carotid stenosis and IMT (14,15), and increased risk of carotid atherosclerosis (16), respectively. However, Gardener et al and our previous studies did not prospectively investigate the association of these variants and carotid atherosclerosis with subsequent stroke and other vascular events.…”

“…Based on our previous community-based cross-sectional survey (16), we undertook this multicenter prospective cohort study in Sichuan, southwestern China, from May 2015 to January 2020. This study is a part of the CNSSS, and the study protocol was approved by the Ethics Committee of the Affiliated Hospital of Southwest Medical University, Suining Central Hospital, and the People's Hospital of Deyang City.…”

“…The community-based cross-sectional survey was carried out in eight communities of Sichuan between May 2015 and September 2015. The detailed procedures relating to recruitment of participants, evaluation of risk factors, and definition of high-risk stroke population were described in our previous articles (10,(14)(15)(16). Briefly, the eight communities were selected using the cluster randomization method.…”

“…Atherosclerosis is a chronic inflammatory disease where the activation of various inflammatory cells, smooth muscle cell proliferation, and endothelial cell damage play key roles in the pathological mechanisms of atherosclerosis (11,12). Many studies have revealed that variants in genes related to inflammation and endothelial function are associated with carotid atherosclerosis (10,(13)(14)(15)(16). For instance, Gardener et al (13) evaluated the associations between carotid plaque and 197 variants in 43 genes implicated in inflammation and endothelial function and demonstrated that the variants in 10 genes (IL6R, TNF, NOS2A, IL1A, TNFSF4, ITGA2, PPARA, TLR4, HABP2, and VCAM1) were associated with carotid plaque in the Northern Manhattan population.…”

“…According to the China National Stroke Screening Survey (CNSSS) program (3), we carried out a multicenter community-based sectional survey among the high-risk stroke population to evaluate the associations between the variants in genes related to inflammation and endothelial function with carotid atherosclerosis in Sichuan, southwestern China (16). Based on the survey, we undertook this prospective cohort study to investigate (1) the incidence of new stroke and other vascular events during follow-up in the high-risk stroke population; (2) the associations between 19 SNPs in genes related to inflammation and endothelial function, as well as carotid atherosclerosis, and their potential impact on subsequent stroke and other vascular events.…”