scholarly journals Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression

2018 ◽  
Vol 29 (7) ◽  
pp. 1939-1947 ◽  
Author(s):  
Adrienne Tin ◽  
Girish Nadkarni ◽  
Anne M. Evans ◽  
Cheryl A. Winkler ◽  
Erwin Bottinger ◽  
...  
Keyword(s):  
African American ◽  
Risk Factor ◽  
Genetic Variants ◽  
Clinical Characteristics ◽  
Molecular Signature ◽  
American Study ◽  
Ckd Progression ◽  
Significance Threshold ◽  
Risk Alleles ◽  
Untargeted Profiling

Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles—genetic variants associated with CKD risk commonly present in persons of African descent—may reveal novel markers of CKD progression relevant to other populations.Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (n=588; Bonferroni significance threshold P<6.5×10−5) and replicated findings in 678 black participants with CKD in BioMe, an electronic medical record–linked biobank. We tested the metabolite association with CKD progression in AASK, BioMe, and the Modification of Diet in Renal Disease (MDRD) Study.Results One metabolite, 6-bromotryptophan, was significant in AASK (P=4.7×10−5) and replicated in BioMe (P=5.7×10−3) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and BioMe participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; BioMe, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers.Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.

scholarly journals Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK)

2013 ◽  
Vol 304 (4) ◽  
pp. F348-F355 ◽  
Author(s):  
Jamison Chang ◽  
Jennie Z. Ma ◽  
Qing Zeng ◽  
Sylvia Cechova ◽  
Adam Gantz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
African American ◽  
Kidney Disease ◽  
Disease Progression ◽  
Genetic Variants ◽  
Null Allele ◽  
African American Study ◽  
Null Alleles ◽  
American Study ◽  
Kidney Disease Progression

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis ( P = 0.04) and in the time to GFR event, dialysis, or death ( P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

Has the time come to integrate genetic risk scores into clinical practice?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F.V Moniz Mendonca ◽  
M.I Mendonca ◽  
A Pereira ◽  
J Monteiro ◽  
J Sousa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Practice ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Risk Scores ◽  
Cumulative Number ◽  
Genetic Risk Scores ◽  
Risk Alleles ◽  
Cad Risk

Abstract Background The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice. Aim The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice. Methods A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated. Results A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p&lt;0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002). Conclusion Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting. Funding Acknowledgement Type of funding source: None

scholarly journals FRI0443 CLINICAL CHARACTERISTICS AND RELATED FACTORS OF COMMON RHEUMATIC DISEASES COMPLICATED WITH TUBERCULOSIS INFECTION

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 819.1-819
Author(s):  
L. Long ◽  
G. Tang ◽  
Y. Han ◽  
Q. Peng ◽  
J. Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Weight Loss ◽  
Risk Factor ◽  
High Risk ◽  
Rheumatic Diseases ◽  
Clinical Characteristics ◽  
Control Group ◽  
Average Dose ◽  
Systemic Lupus ◽  
Infection Group

Background:Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and syndrome(SS) are common rheumatic diseases with high incidence. Patients with those rheumatic diseases are at high risk of tuberculosis (TB) infection. However, manifestations can be atypical and easily confused with those of rheumatic disease itself. For those patients, diagnosis is usually much more difficult and further make treatment delayed. Sometimes it may lead to mistreatment. Therefore, it is important to recognize the clinical characteristics of those patients.Objectives:To explore the clinical characteristics and high risk factors of common systemic rheumatism complicated with tuberculosis infection.Methods:A total of 3,906 cases of RA, SLE, and SS common systemic rheumatism diagnosed in the People’s Hospital of Sichuan Province from January 2007 to January 2017 were collected with carefully exclusion with other infectious diseases and neoplastic disease. One hundred and five patients with TB were included as infection group, including 42 cases of RA, 41 cases of SLE, and 22 cases of SS. In the control group, 84 patients with RA, 82 patients with SLE, and 44 patients with SS were randomly selected from the corresponding rheumatoid non-infected patients hospitalized during the same period.Results:Fever was the most common symptom among 42 cases of RA, 41 cases of SLE, and 22 cases of SS with TB, accounting for 83.3%, 92.7%, and 68.2%, respectively. Cough, weight loss or fatigue was less common. For 41 cases of SLE and 22 cases of SS with TB, the proportion of pulmonary was 46.3%, 59.01%, respectively.In TB infection group, 27 cases of RA, 21 cases of SLE, and 13 cases of SS with TB had two or more chest CT findings, accounting for 59%, 57%, 62%, respectively. Lesions located in the posterior or posterior segment which TB usually affected were 9 cases(33.3%),9cases(42.9%),6cases(27.2%),respectively.The daily average dose of hormones within 1 year in TB infection group was higher than that in the control group (P<0.05). For SLE patients, lower counts of CD4+TL were found in TB infection group (P<0.05), while no such differences were found in RA and SS group.Conclusion:Patients with RA who have TB infection are mainly pulmonary TB. For SLE and SS patients, the chance of pulmonary tuberculosis and extra-pulmonary tuberculosis is similar.Symptoms of RA, SLE, SS with TB, such as fever, cough, weight loss, fatigue, are similar with the primary disease or other infection. Chest imaging is diversity. It is difficult to diagnose.Daily average dose of hormone within one year may be a common risk factor for RA, SLE and SS patients with TB. Decreased CD4+TL may also be a risk factor for SLE patients with TB.References:[1]Cantini F, Nannini C, Niccoli L, et al. Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics[J]. Mediators of Inflammation, 2017, 2017(6):1-15.[2]Ruangnapa K, Dissaneewate P, Vachvanichsanong P. Tuberculosis in SLE patients: rare diagnosis, risky treatment.[J]. Clinical & Experimental Medicine, 2015, 15(3):429-432.[3]Manuela D F, Bruno L, Martina S, et al. Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections[J]. International Journal of Molecular Sciences, 2017, 18(2):293-315.[4]Disseminated tuberculosis masquerading as a presentation of systemic lupus erythematosus.Li JC, Fong W, Wijaya L, Leung YY.Int J Rheum Dis. 2017 Oct 2. doi: 10.1111/1756-185X.13195.[5]Handa R, Upadhyaya S, Kapoor S, et al. Tuberculosis and biologics in rheumatology: India – A special situation[J]. International Journal of Rheumatic Diseases, 2017, 51(2):115.Disclosure of Interests:None declared

Recruitment experience in the African American Study of Kidney disease and hypertension (AASK) pilot study

1996 ◽  
Vol 17 (4) ◽  
pp. S17-S33 ◽  
Author(s):  
Paul K. Whelton ◽  
Jeannette Y. Lee ◽  
John W. Kusek ◽  
Jeanne Charleston ◽  
Jennifer DeBruge ◽  
...  
Keyword(s):  
African American ◽  
Pilot Study ◽  
Kidney Disease ◽  
African American Study ◽  
American Study
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