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Association of single nucleotide polymorphisms with dyslipidemia in antiretroviral exposed HIV patients in a Ghanaian population: A case-control study.

ABSTRACT: Dyslipidemia is a potential complication of long-term usage of antiretroviral therapy (ART) and also known to be associated with genetic factors. The host genetic variants associated with dyslipidemia in HIV patients on ART in Ghana have not been fully explored. The study constituted a total of 289 HIV-infected patients on stable ART for at least a year. Fasting blood was collected into EDTA tube for lipids measurement. Lipid profiles were used to define dyslipidemia based on the NCEP-ATP III criteria. HIV-infected subjects were categorized into two groups; those with dyslipidemia (cases) (n = 90; 31.1%) and without dyslipidemia (controls)(n = 199; 68.9%). Four candidate single nucleotide polymorphism (SNP) genes (ABCA1-rs2066714, LDLR-rs6511720, APOA5-rs662799 and DSCAML1-rs10892151) were determined. Genotyping was performed on isolated genomic DNA of study participants using PCR followed by a multiplex ligation detection reaction (LDR). The percentage of the population who had the rare homozygote alleles for rs6511720 (T/T), rs2066714 (G/G), rs10892151 (T/T) and rs662799 (G/G) among case subjects were 5.5%, 14.4%, 6.6% and 10.0% whiles 2.0% 9.1%, 6.5% and 4.0% were observed among control subjects. There were statistically significant differences in the genotypic prevalence of APOA5 (p = 0.0357) and LDLR polymorphisms (p = 0.0387) between case and control subjects. Compared to the AA genotype of the APOA5 polymorphisms, individuals with the rare homozygote genotype [aOR = 2.38, 95%CI(1.06-6.54), p = 0.004] were significantly associated with an increased likelihood of developing dyslipidemia after controlling for age, gender, treatment duration, CD4 counts and BMI. Moreover, individuals with the rare homozygous genotype of ABCA1 (G/G) [aOR = 10.7(1.3-88.7), p = 0.0280] and LDLR (rs6511720) G>T [aOR = 61.2(7.6-493.4), p<0.0001) were more likely to have high levels of total cholesterol levels. Our data accentuate the presence of SNPs in four candidate genes and their association with dyslipidemia among HIV patients exposed to ART in the Ghanaian population, especially variants in APOA5-rs662799 and LDLR rs6511720 respectively. These findings provide baseline information that necessitates a pre-symptomatic strategy for monitoring dyslipidemia in ART-treated HIV patients. There is a need for longitudinal studies to validate a comprehensive number of SNPs and their associations with dyslipidemia.

SUBMITTER: Obirikorang C

PROVIDER: S-EPMC6957303 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:Highly active antiretroviral therapy (HAART) is known to cause lipid abnormalities such as dyslipidaemia in HIV-infected individuals. Yet, dyslipidaemia may not independently occur as it may be worsened by single nucleotide polymorphisms (SNPs) in lecithin cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL). This case-control study was conducted in three-selected hospitals in the Northern part of Ghana. The study constituted a total of 118 HIV-infected participants aged 19-71 years, who had been on HAART for 6-24 months. Dyslipidaemia was defined based on the NCEP-ATP III criteria. HIV-infected individuals on HAART with dyslipidaemia were classified as cases while those without dyslipidaemia were grouped as controls. Lipid profile was measured using an automatic clinical chemistry analyzer and genomic DNA was extracted for PCR (GeneAmp PCR System 2700). Overall, the prevalence of dyslipidaemia was 39.0% (46/118). High levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and reduced levels of high-density lipoprotein cholesterol (HDL-C) were observed in all cases. A total of 256 selected PCR amplicons comprising 137 LPL (exons 3, 5 and 6) and 119 LCAT (exons 1, 4, and 6) were sequenced in 46 samples (Inqaba Biotech). Six (6) clinically significant SNPs were identified in exons 1 and 4 for LCAT whereas 25 non-clinically significant SNPs were identified for LPL in exons 5 and 6. At position 97 for LCAT exon 1, there was a deletion of the nucleotide, 'A' in 32.5% (13/40) of the sampled population while 67.5% (27/40) of the sample population retained the nucleotide, 'A' which was significantly associated with dyslipidaemic outcomes in the study population (p?=?0.0004). A total of 25 SNPs were identified in exons 5 and 6 of LPL; 22 were substitutions, and 3 were insertions. However, none of the 25 SNPs identified in LPL exon 5 and 6 were statistically significant. SNPs in LCAT may independently contribute to dyslipidaemia among Ghanaian HIV-infected individuals on HAART, thus, allowing genetic and/or functional differential diagnosis of dyslipidaemia and creating an opportunity for potentially preventive options.

Project description:In this report, we describe a case control study in a Chinese population aimed at identifying possible associations between susceptibility to cervical cancer and single nucleotide polymorphisms in XRCC1 194C>T, XRCC1 280G>A, XRCC1 399G>A, ERCC2 751A>C, ERCC2 156C>A, ERCC1 118C>T, PARP1 762T>C, RAD51 135G>C and HER2 655A>G. The cases comprised 154 patients: 80 cervical squamous cell carcinomas (SCCs), 2 adenocarcinomas and 72 cervical intraepithelial neoplasias (CINs). A total of 177 healthy women were recruited as the controls. A significant association was found between ERCC1 118C>T and SCC in the additive genetic model [odds ratio (OR)=1.711; 95% confidence interval (CI), 1.089-2.880; p=0.021] and the dominant genetic model (OR=1.947; 95% CI, 1.056-3.590; p=0.033). Among women with a smoking family member, ERCC1 118C>T increased SCC risk in the additive model (OR=2.800; 95% CI, 1.314-5.968; p=0.008). For women who had first intercourse before 22 years of age, XRCC1 280G>A was found to act as a protective factor for SCC under the additive model (OR=0.228; 95% CI, 0.058-0.900; p=0.035), while RAD51 135G>C was a risk factor for CIN (OR=4.246; 95% CI, 1.335-13.502; p=0.014). For women who had first intercourse after 22 years of age, the additive genetic model showed RAD51 135G>C (OR=0.359; 95% CI, 0.138-0.934; p=0.036) and HER2 655A>G (OR=0.309; 95% CI, 0.098-0.972; p=0.045) to be protective factors for SCC. XRCC1 399G>A increased CIN risk among women who first gave birth before the age of 22 in the additive genetic model (OR=4.459; 95% CI, 1.139-17.453; p=0.032). For those who first gave birth after age 22, ERCC1 118C>T was found to be a risk factor for SCC in the additive genetic model (OR=1.884; 95% CI, 1.088-3.264; p=0.024). A significant interaction was observed between RAD51 135G>C and age at first intercourse (p(interaction)=0.033 for SCC, p(interaction)=0.021 for CIN), as well with sexual partner number (p(interaction)=0.001 for SCC). The interaction between HER2 655A>G and age at first intercourse, ERCC2 156C>A and family smoking status and XRCC1 280G>A and alcohol consumption were significant, with p(interaction)=0.023 for SCC, p(interaction)=0.021 for CIN and p(interaction)=0.025 for SCC, respectively.

Project description:Abstract Background HIV-1 set-point viral load (SPVL) is predictive of disease progression and shows variability across HIV-1-positive (HIV+) persons. Various factors may influence SPVL including viral features, environmental exposure and host genetics. To identify single nucleotide polymorphisms (SNPs) associated with SPVL, we performed a genome-wide association study (GWAS) on a subset of participants from the Strategic Timing of AntiRetroviral Treatment (START) study covering a demographically diverse population. Methods. Consenting participants were antiretroviral therapy (ART)-naïve and SPVL was taken as log10(HIV RNA) at study entry. Genotypic data were generated on a custom content Affymetrix Axiom SNP array covering 770,558 probes. The Ensembl Gene database, assembly GRCh37.p13, was used for annotation. Principal component analysis (PCA) was used to identify population structures, and analysis of variance (ANOVA) was performed to detect associations between SNPs and SPVL. SNPs with zero variance or minor allele frequency (MAF) ?0.05 were removed. Results. Among the 2,544 participants, PCA showed distinct population structures with strong separation between black (n = 578) and nonblack (n = 1,966) participants, Figure 1. ANOVA was performed independently on both subsets. Two SNPs located in the Major Histocompatibility Complex (MHC) class I region of chromosome six reached genome-wide significance (P < 5 × 10–8) in the non-black population: rs4418214 (P = 1.74 × 10-10), and rs57989216 (P = 3.96 × 10–8), Figure 2. Two additional SNPs, rs9264942 (P = 5.99 × 10–8) and rs7356880 (P = 9.69 × 10–8), in the same region approached significance. The minor alleles of all four SNPs were associated with lower SPVL, Figure 3. While no SNPs reached genome-wide significance in the black group, we observed similar trends toward lower SPVL for both rs4418214 and rs57989216. Conclusion. In this study we confirm the association of a previously reported SNP (rs4418214) and identify a novel candidate SNP (rs57989216) associated with lower SPVL in a population of nonblack, ART-naïve HIV+ persons. Current findings suggest that the effects of these SNPs are consistent across race groups, but further studies are required to confirm this. Our results support previous findings that variation in the MHC class I region is a major host determinant of HIV-1 control. Disclosures D. D. Murray, Centre of Excellence for Health, Immunity and Infectious diseases (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark: Employee, Salary. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee.

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Association of single nucleotide polymorphisms with dyslipidemia in antiretroviral exposed HIV patients in a Ghanaian population: A case-control study.

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