Genetic Determinants of Major Blood Lipids in Pakistanis Compared With Europeans

“…17,18 The CX3CR1 variant V249I met significance after correction for all SNPs tested, but neither CX3CR1 T280M nor CCR2 V64I were significant in adjusted analyses (Table 2). In interrogation of all 181 low-frequency and common SNPs in CCR2 , CCR5, and CX3CR1, five additional non-coding variants in CX3CR1 were significantly associated with MI after Bonferroni correction (Table 2, Supplemental table 3).…”

Section: Resultsmentioning

confidence: 99%

“…17,18 Samples were genotyped on the Illumina 660 and Illumina 770 arrays and imputed using the 1000 genomes phase I integrated reference panel (March, 2012). 3 Individual tests for association were performed on variants with a MAF > 1% adjusting for the first four principal components.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Common and Rare Genetic Variation in CCR2 , CCR5 , or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits

Golbus

Stitziel²,

Zhao

et al. 2016

Circ Cardiovasc Genet

Self Cite

View full text Add to dashboard Cite

Background The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms (SNPs) in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. Methods and Results We interrogated the CARDIoGRAMplusC4D (60,801 cases, 123,504 controls), the MIGen and CARDIoGRAM Exome consortia (42,335 cases, 78,240 controls), and ESP EOMI (4,703 cases, 5,090 controls) datasets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low frequency variation in South Asians through PROMIS (9,058 cases, 8,379 controls), identifying six variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed DIAGRAM, GLGC, GIANT and MAGIC datasets revealed no association with glucometabolic traits though three SNPs in PROMIS were associated with type II diabetes mellitus (DM). Conclusions No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified SNP associations with MI and type II DM but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.

show abstract

“…Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans. 13 …”

Section: Genetic Determinants Of Major Blood Lipids In Pakistanis Commentioning

confidence: 99%

Genetic Epidemiology in Circulation and the Circulation Subspecialty Journals

2012

Circulation

View full text Add to dashboard Cite

The following articles are being highlighted as part of Circulation's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the articles related to genetic epidemiology that were published in Circulation and its subspecialty journals in and 2011 . (Circulation. 2012125:e443-e455.) Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms Summary: The inverse relationship between high-density lipoprotein cholesterol and risk of coronary heart disease suggests that therapeutic elevation of high-density lipoprotein cholesterol may provide an effective means of prevention of coronary heart disease. Pharmacological inhibition of cholesteryl ester transfer protein (CETP) leads to elevation in high-density lipoprotein cholesterol, but torcetrapib (the first-in-class CETP inhibitor) increased the risk of cardiovascular events in the ILLUMINATE trial (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events), which may have resulted from an unexpected blood pressureelevating effect of this agent. We used common genetic polymorphisms in the CETP gene to distinguish whether the hypertensive action of torcetrapib was mechanism based or off target, because a genetic study of these variants can be considered to be a type of natural randomized trial of a "clean" low-dose CETP inhibitor with no off-target actions. Common CETP gene polymorphisms and torcetrapib treatment had concordant effects on 8 lipid and lipoprotein markers, including high-density lipoprotein cholesterol, but CETP gene variants had no effect on blood pressure. The blood pressure-elevating effect of torcetrapib appears to be an off-target action that is unlikely to be shared by chemically dissimilar CETP inhibitors. Genetic studies could be used in drug-development programs as a new source of randomized evidence for drug-target validation in humans.Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans. 1

show abstract

Genetic Determinants of Major Blood Lipids in Pakistanis Compared With Europeans

Cited by 26 publications

References 47 publications

Effect of Long-Term Exposure to Lower Low-Densilipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease. A Mendelian Randomization Analysis

Effect of Long-Term Exposure to Lower Low-Densilipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease. A Mendelian Randomization Analysis

Common and Rare Genetic Variation in CCR2 , CCR5 , or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits

Genetic Epidemiology in Circulation and the Circulation Subspecialty Journals

Contact Info

Product

Resources

About