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Race disparity in blood sphingolipidomics associated with lupus cardiovascular comorbidity.

ABSTRACT: Systemic lupus erythematous (SLE) is a chronic multi-organ autoimmune disease. Genetic and environmental factors contribute to disease onset and severity. Sphingolipids are signaling molecules involved in regulating cell functions and have been associated with multiple genetic disease processes. African-Americans are more likely to suffer from SLE morbidity than Whites. The Medical University of South Carolina has banked plasma samples from a well-characterized lupus cohort that includes African-Americans and Whites. This study examined the influence of race on plasma sphingolipid profiles in SLE patients and association of sphingolipid levels with comorbid atherosclerosis and SLE disease activity. Mass spectrometry revealed that healthy African-Americans had higher sphingomyelin levels and lower lactosylcermide levels compared to healthy Whites. SLE patients, irrespective of race, had higher levels of ceramides, and sphingoid bases (sphingosine and dihydrosphingosine) and their phosphates compared to healthy subjects. Compared to African-American controls, African-American SLE patients had higher levels of ceramides, hexosylceramides, sphingosine and dihydrosphingosine 1-phosphate. Compared to White controls, White SLE patients exhibited higher levels of sphingoid bases and their phosphates, but lower ratios of C16:0 ceramide/sphingosine 1-phosphate and C24:1 ceramide/sphingosine 1-phosphate. White SLE patients with atherosclerosis exhibited lower levels of sphingoid bases compared to White SLE patients without atherosclerosis. In contrast, African-American SLE patients with atherosclerosis had higher levels of sphingoid bases and sphingomyelins compared to African-American SLE patients without atherosclerosis. Compared to White SLE patients with atherosclerosis, African-American SLE patients with atherosclerosis had higher levels of select sphingolipids. Plasma levels of sphingosine, C16:0 ceramide/sphingosine 1-phosphate ratio and C24:1 ceramide/sphingosine 1-phosphate ratio significantly correlated with SLEDAI in the African-American but not White SLE patients. The C16:0 ceramide/sphingosine 1-phosphate ratio in SLE patients, and levels of C18:1 and C26:1 lactosylcermides, C20:0 hexosylceramide, and sphingoid bases in SLE patients with atherosclerosis could be dependent on race. Further ethnic studies in SLE cohorts are necessary to verify use of sphingolipidomics as complementary diagnostic tool.

SUBMITTER: Hammad SM

PROVIDER: S-EPMC6867606 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Persistent racial/ethnic disparities in cardiovascular disease (CVD) mortality are partially explained by healthcare access and socioeconomic, demographic, and behavioral factors. Little is known about the association between race/ethnicity-specific CVD mortality and county-level factors. Methods and Results Using 2017 county-level data, we studied the association between race/ethnicity-specific CVD age-adjusted mortality rate (AAMR) and county-level factors (demographics, census region, socioeconomics, CVD risk factors, and healthcare access). Univariate and multivariable linear regressions were used to estimate the association between these factors; R2 values were used to assess the factors that accounted for the greatest variation in CVD AAMR by race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic/Latinx individuals). There were 659 740 CVD deaths among non-Hispanic White individuals in 2698 counties; 100 475 deaths among non-Hispanic Black individuals in 717 counties; and 49 493 deaths among Hispanic/Latinx individuals across 267 counties. Non-Hispanic Black individuals had the highest mean CVD AAMR (320.04 deaths per 100 000 individuals), whereas Hispanic/Latinx individuals had the lowest (168.42 deaths per 100 000 individuals). The highest CVD AAMRs across all racial/ethnic groups were observed in the South. In unadjusted analyses, the greatest variation (R2) in CVD AAMR was explained by physical inactivity for non-Hispanic White individuals (32.3%), median household income for non-Hispanic Black individuals (24.7%), and population size for Hispanic/Latinx individuals (28.4%). In multivariable regressions using county-level factor categories, the greatest variation in CVD AAMR was explained by CVD risk factors for non-Hispanic White individuals (35.3%), socioeconomic factors for non-Hispanic Black (25.8%), and demographic factors for Hispanic/Latinx individuals (34.9%). Conclusions The associations between race/ethnicity-specific age-adjusted CVD mortality and county-level factors differ significantly. Interventions to reduce disparities may benefit from being designed accordingly.

Project description:Background: Cardiovascular diseases are the leading causes of mortality worldwide. One reason behind this lethality lies in the fact that often cardiovascular illnesses develop into systemic failure due to the multiple connections to organismal metabolism. This in turn is associated with co-morbidities and multimorbidity. The prevalence of coexisting diseases and the relationship between the molecular origins adds to the complexity of the management of cardiovascular diseases and thus requires a profound knowledge of the genetic interaction of diseases. Objective: In order to develop a deeper understanding of this phenomenon, we examined the patterns of comorbidity as well as their genetic interaction of the diseases (or the lack of evidence of it) in a large set of cases diagnosed with cardiovascular conditions at the national reference hospital for cardiovascular diseases in Mexico. Methods: We performed a cross-sectional study of the National Institute of Cardiology. Socioeconomic information, principal diagnosis that led to the hospitalization and other conditions identified by an ICD-10 code were obtained for 34,099 discharged cases. With this information a cardiovascular comorbidity networks were built both for the full database and for ten 10-years age brackets. The associated cardiovascular comorbidities modules were found. Data mining was performed in the comprehensive ClinVar database with the disease names (as extracted from ICD-10 codes) to establish (when possible) connections between the genetic associations of the genetic interaction of diseases. The rationale is that some comorbidities may have a stronger genetic origin, whereas for others, the environment and other factors may be stronger. Results: We found that comorbidity networks are highly centralized in prevalent diseases, such as cardiac arrhythmias, heart failure, chronic kidney disease, hypertension, and ischemic diseases. Said comorbidity networks are actually modular on their connectivity. Modules recapitulate physiopathological commonalities, e.g., ischemic diseases clustering together. This is also the case of chronic systemic diseases, of congenital malformations and others. The genetic and environmental commonalities behind some of the relations in these modules were also found by resorting to clinical genetics databases and functional pathway enrichment studies. Conclusions: This methodology, hence may allow the clinician to look up for non-evident comorbidities whose knowledge will lead to improve therapeutically designs. By continued and consistent analysis of these types of patterns, we envisaged that it may be possible to acquire, strong clinical and basic insights that may further our advance toward a better understanding of cardiovascular diseases as a whole. Hopefully these may in turn lead to further development of better, integrated therapeutic strategies.

Project description:BackgroundBlood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden.MethodsWe studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients' characteristics.ResultsPatients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8-11.8%) than the control group 9.2% (7.4-11.2%), P < 0.001 by coefficient of variation. Additional measures of systolic blood pressure visit-to-visit variability (i.e. standard deviation, average real variation, successive variation and maximum measure-to-measure change) were also significantly higher in patients with SLE than in control subjects. In patients with SLE, blood pressure visit-to-visit variability correlated significantly with age, creatinine, CRP, triglyceride concentrations and the Charlson comorbidity score (all P < 0.05). Hydroxychloroquine use was associated with reduced blood pressure visit-to-visit variability (P < 0.001), whereas the use of antihypertensives, cyclophosphamide, mycophenolate mofetil and corticosteroids was associated with increased blood pressure visit-to-visit variability (P < 0.05).ConclusionPatients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Project description:Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.

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Race disparity in blood sphingolipidomics associated with lupus cardiovascular comorbidity.

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