Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD

Fairoozy, Roaa Hani; White, Jon; Palmen, Jutta; Kalea, Anastasia Z.; Humphries, Steve E.

doi:10.1371/journal.pone.0167676

Cited by 30 publications

(25 citation statements)

References 60 publications

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“…Similar low frequencies in APOA5 and LDLR homozygotes mutant genes were reported by Lazzaretti et al [15] in a cross-sectional study among HIV-infected patients on ART in the Brazilians population. Genome-wide associations studies have identified LDL-R SNP rs6511720 (G>T), which is located in intron-1 of the gene, to be associated with lower plasma levels of LDL-C and a lower risk of CHD [35]. Data from the GLGC consortium suggested that LDLR rs6511720 minor allele is prevalent in about 10% of the population and have established that the allele is protective, being associated with lower levels of LDL-C [46].…”

Section: Discussionmentioning

confidence: 99%

“…The four candidate SNPs (rs2066714, rs6511720, rs662799, and rs10892151) selected for this study have been shown in previous studies to be significantly associated with lipid serum abnormalities following a review of GWAS and PubMed reports of SNPs associated with dyslipidemia among HIV-infected individuals [24,[33][34][35]. Genomic DNA was isolated from EDTA-collected whole blood samples of study participants using the Qiagen midi kit prep as per manufacturer's protocol.…”

Section: Single Nucleotide Polymorphisms Selection and Genotypingmentioning

confidence: 99%

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

et al. 2020

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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

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Section: Discussionmentioning

confidence: 99%

Section: Single Nucleotide Polymorphisms Selection and Genotypingmentioning

confidence: 99%

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

et al. 2020

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“…Concerning unaffected individuals with high GRS in quartile IV (II-16 and III-10 in family HC126, III-1 in family HC218, and II-3 in family HC806), the presence of an unknown factor can reduce the effect of the high GRS and explain the normal LDL-C levels. It can be: (1) an LDL-C-lowering variant in the APOB gene which abolish the hypercholesterolemia phenotype since we have not sequenced the whole gene [21], (2) the combined impact of several LDL-C-lowering SNPs such as rs6511720 and rs57217136 located in intron 1 of the LDLR [22] and rs11591147 (p.(Arg46Leu)) in PCSK9 [23] that have been reported to be associated with lower levels of LDL-C, (3) loss-of-function mutations in ANGPTL3 [21], or (4) environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?

Ghaleb¹,

Elbitar²,

Khoury³

et al. 2018

Eur J Hum Genet

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Familial hypercholesterolemia (FH) is caused by mutations in LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), or APOE (apolipoprotein E) genes in approximately 80% of the cases. Polygenic forms of hypercholesterolemia may be present among patients clinically diagnosed with FH but with no identified mutation (FH mutation-negative (FH/M-)). To address whether polygenic forms may explain phenocopies in FH families, we calculated a 6-single-nucleotide polymorphism (SNP) genetic risk score (GRS) in all members from five French FH families where a mutation was identified (FH/M+) as well as some phenocopies (FH/M-). In two families, three FH/M- patients present a high GRS suggesting a polygenic hypercholesterolemia for these phenocopies. However, a high GRS is also observed in nine FH/M+ patients and in four unaffected relatives from three families. These observations indicate that the GRS does not seem to be a good diagnostic tool at the individual level. Nevertheless, the GRS seems to be a contributor of the severity of hypercholesterolemia since patients who cumulate a mutation and a high GRS exhibit higher low-density lipoprotein cholesterol levels when compared to patients with only FH (p = 0.054) or only polygenic hypercholesterolemia (p = 0.0039). In conclusion, the GRS can be used as a marker of the severity of hypercholesterolemia but does not seem to be a reliable tool to distinguish phenocopies within FH families.

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“…The SNP is in complete linkage disequilibrium with three intron-1 SNPs (rs141787760, rs60173709, rs57217136), so only one or more than one of these variants may be the functional SNP at this locus. Using luciferase reporter assays in the hepatoma cell line Huh7 cells we showed [51] that the rare alleles of both rs6511720 and rs57217136 (but not rs60173709) caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively).…”

Section: Five Year Viewmentioning

confidence: 95%

How close are we to implementing a genetic risk score for coronary heart disease?

Beaney

Drenos

Humphries

2017

Expert Review of Molecular Diagnostics

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Genome-wide association meta-analysis have now identified more than 150 loci where common variants (SNPs) are significantly associated with coronary heart disease (CHD) and CHD end points. Areas covered: The authors review publications from their own laboratory and published recently where identified CHD risk SNPs are used in combination, and 'scaled' by their effect size, to create a 'weighted' Genetic risk Score (GRS), which, in combination with an individual's classical CHD risk factors, can be used to identify those at overall low, intermediate and high future risk. Those at highest risk can be offered life-style and therapeutic options to reduce their risk and those at intermediate levels can be monitored. Expert commentary: The authors discuss the selection of the best variants to be included in the GRS, and the potential utility of such scores in different clinical settings. The limitations of the current data sets and the way forward in the next 5 years is discussed.

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Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD

Cited by 30 publications

References 60 publications

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

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

Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?

How close are we to implementing a genetic risk score for coronary heart disease?

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