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Paraoxonase1 genetic polymorphisms in a mixed ancestry African population.

ABSTRACT: Paraoxonase 1 (PON1) activity is markedly influenced by coding polymorphisms, Q/R at position 192 and M/L at position 55 of the PON1 gene. We investigated the frequencies of these polymorphisms and their effects on PON1 and antioxidant activities in 844 South African mixed ancestry individuals. Genotyping was done using allele-specific TaqMan technology, PON1 activities were measured using paraoxon and phenylacetate, oxidative status was determined by measuring the antioxidant activities of ferric reducing antioxidant power and trolox equivalent antioxidant capacity, and lipid peroxidation markers included malondialdehyde and oxidized LDL. The frequencies of Q192R and L55M were 47.6% and 28.8%, respectively, and the most common corresponding alleles were 192R (60.4%) and 55M (82.6%). The Q192 was significantly associated with 5.8 units' increase in PON1 concentration and 15.4 units' decrease in PONase activity after adjustment for age, sex, BMI, and diabetes, with suggestion of differential effects by diabetes status. The PON1 L55 variant was associated with none of the measured indices. In conclusion, we have shown that the Q192R polymorphism is a determinant of both PON1 concentration and activity and this association appeared to be enhanced in subjects with diabetes.

SUBMITTER: Macharia M

PROVIDER: S-EPMC4248356 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Paraoxonase1 genetic polymorphisms in a mixed ancestry African population.

Macharia M M Kengne A P AP Blackhurst D M DM Erasmus R T RT Matsha T E TE

Mediators of inflammation 20141116

Paraoxonase 1 (PON1) activity is markedly influenced by coding polymorphisms, Q/R at position 192 and M/L at position 55 of the PON1 gene. We investigated the frequencies of these polymorphisms and their effects on PON1 and antioxidant activities in 844 South African mixed ancestry individuals. Genotyping was done using allele-specific TaqMan technology, PON1 activities were measured using paraoxon and phenylacetate, oxidative status was determined by measuring the antioxidant activities of ferr ...[more]

PMID: 25477710

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Project description:ObjectivesThe objectives were to characterise the haematological profile of screen-detected chronic kidney disease (CKD) participants and to correlate the complete blood count measures with the commonly advocated kidney function estimators.MethodsThe current cross-sectional study used data, collected between February 2015 and November 2016, of 1564 adults of mixed-ancestry, who participated in the Cape Town Vascular and Metabolic Health study. Kidney function was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. CKD was defined as estimated glomerular filtration rate (eGFR) <60?mL/min/1.73?m2, and anaemia as haemoglobin level <13.5?g/dL (men) and <12?g/dL (women).ResultsBased on the MDRD and CKD-EPI equations, the crude prevalence of CKD was 6% and 3%. Irrespective of the equation used, median red blood cell (RBC) indices were consistently lower in those with CKD compared with those without CKD (all p<0.0001). Despite not showing any significant difference in total white blood cell (WBC) count between the two groups, the number of lymphocytes were lower (p=0.0001?and p<0.0001 for MDRD and CKD-EPI, respectively) and neutrophil count (both p<0.0297) and the ratio of lymphocytes to neutrophil (both p<0.0001) higher in the CKD group compared with those without CKD; with the remaining WBC indices similar in the two groups. The platelet count was similar in both groups. Of the screen-detected CKD participants, 45.5% (MDRD) and 57.8% (CKD-EPI) were anaemic, with the prevalence increasing with increasing severity of CKD, from 37.2% (stage 3) to 82.4% (stages 4-5). Furthermore, CKD-EPI-estimated kidney function, but not MDRD, was positively associated with RBC indices.ConclusionThough it remains unclear whether common kidney function estimators provide accurate estimates of CKD in Africans, the correlation of their estimates with deteriorating RBC profile, suggests that advocated estimators, to some extent approximate kidney function in African populations.

Project description:Introduction: Human populations are often highly structured due to differences in genetic ancestry among groups, posing difficulties in associating genes with diseases. Ancestry-informative markers (AIMs) aid in the detection of population stratification and provide an alternative approach to map population-specific alleles to disease. Here, we identify and characterize a novel set of African AIMs that separate populations of African ancestry from other global populations including those of European ancestry. Methods: Using data from the 1000 Genomes Project, highly informative SNP markers from five African subpopulations were selected based on estimates of informativeness (In) and compared against the European population to generate a final set of 46,737 African ancestry-informative markers (AIMs). The AIMs identified were validated using an independent set and functionally annotated using tools like SIFT, PolyPhen. They were also investigated for representation of commonly used SNP arrays. Results: This set of African AIMs effectively separates populations of African ancestry from other global populations and further identifies substructure between populations of African ancestry. When a subset of these AIMs was studied in an independent dataset, they differentiated people who self-identify as African American or Black from those who identify their ancestry as primarily European. Most of the AIMs were found to be in their intergenic and intronic regions with only 0.6% in the coding regions of the genome. Most of the commonly used SNP array investigated contained less than 10% of the AIMs. Discussion: While several functional annotations of both coding and non-coding African AIMs are supported by the literature and linked these high-frequency African alleles to diseases in African populations, more effort is needed to map genes to diseases in these genetically diverse subpopulations. The relative dearth of these African AIMs on current genotyping platforms (the array with the highest fraction, llumina's Omni 5, harbors less than a quarter of AIMs), further demonstrates a greater need to better represent historically understudied populations.

Project description:The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6 × 10(-6)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.

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Paraoxonase1 genetic polymorphisms in a mixed ancestry African population.

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Paraoxonase1 genetic polymorphisms in a mixed ancestry African population.

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