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1.
Genome-wide association analysis of common genetic variants of resistant hypertension.
El Rouby, N, McDonough, CW, Gong, Y, McClure, LA, Mitchell, BD, Horenstein, RB, Talbert, RL, Crawford, DC, , , Gitzendanner, MA, et al
The pharmacogenomics journal. 2019;(3):295-304
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Abstract
Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10-4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10-5) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10-5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10-8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10-5) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10-3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10-5) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10-15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.
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Triacylglycerol-Lowering Effect of Docosahexaenoic Acid Is Not Influenced by Single-Nucleotide Polymorphisms Involved in Lipid Metabolism in Humans.
AbuMweis, SS, Panchal, SK, Jones, PJH
Lipids. 2018;(9):897-908
Abstract
The triacylglycerol (TAG)-lowering effects of long-chain n-3 fatty acids, and in particular docosahexaenoic acid (DHA), are well documented, although these effects manifest large interindividual variability. The objective of this secondary analysis is to investigate whether common single-nucleotide polymorphisms (SNP) in genes involved in DHA synthesis and TAG metabolism are associated with the responsiveness of blood lipids, lipoprotein, and apolipoprotein concentration to dietary treatment by DHA supplied in high-oleic canola oil (HOCO). In a randomized, crossover-controlled feeding trial, 129 subjects with metabolic syndrome received high-oleic canola oil (HOCO) and high-oleic canola oil supplemented with DHA (HOCO-DHA), each for 4 weeks. During the HOCO-DHA phase, the intake of DHA ranged from 1 to 2.5 g/day. The subjects were genotyped for apolipoprotein E (APOE) isoforms, and SNP including FADS1-rs174561, FADS2-rs174583, ELOVL2-rs953413, ELOVL5-rs2397142, CETP-rs5882, SCD1-rs2234970, PPARA-rs6008259, and LIPF-rs814628 were selected as important genes controlling fatty acid metabolism. Overall, consumption of HOCO-DHA oil reduced blood concentrations of TAG by 24% compared to HOCO oil. The reduction in TAG was independent of genetic variations in the studied genes. Similarly, no treatment-by-gene interactions were evident in the response to other lipids, lipoproteins, or apolipoproteins to DHA supplementation. Nevertheless, a lower interindividual variation in the TAG response to DHA supplementation compared to other studies was observed in this analysis. The TAG-lowering effect of a supplemental body-weight-based dose of DHA was not influenced by genetic variations in APOE, FADS1, FADS2, ELOVL2, ELOVL5, CETP, SCD1, PPARA, and LIPF.
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Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients.
Mbatchi, LC, Robert, J, Ychou, M, Boyer, JC, Del Rio, M, Gassiot, M, Thomas, F, Tubiana, N, Evrard, A
Clinical pharmacokinetics. 2016;(9):1145-57
Abstract
BACKGROUND AND OBJECTIVES Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug-drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens. PATIENTS AND METHODS In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites. RESULTS After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively). CONCLUSION Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan.
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Association of the MTHFR Gene C677T Polymorphism with Breast Cancer in a Turkish Population.
Kaya, EF, Karakus, N, Ulusoy, AN, Özaslan, C, Kara, N
Oncology research and treatment. 2016;(9):534-8
Abstract
BACKGROUND Breast cancer is the most common cancer among women. 1 in every 8 women in the United States have a lifetime risk of getting breast cancer. MTHFR is a key enzyme that regulates the folate metabolism which has an important role in DNA synthesis, repair, and methylation. The aim of the current study was to analyze the association between the MTHFR gene C677T (Ala222Val, rs1801133) polymorphism and breast cancer. PATIENTS AND METHODS 199 breast cancer patients and 195 healthy controls were included in this study. The MTHFR gene C677T polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods. A meta-analysis including 707 breast cancer patients and 880 controls from Turkish populations was also carried out. Statistical analyses were performed using the χ2 test. RESULTS No statistically significant differences in allele and genotype frequencies were observed between patients and controls (p > 0.05). Although not statistically significant, TT homozygous variants were encountered more frequently in patients than in controls. A statistically significant association was observed between the MTHFR gene C677T polymorphism and the tumor histology of breast cancer patients (p = 0.038). The results of the meta-analysis suggested that there was a high association between breast cancer and the MTHFR gene C677T polymorphism in Turkish populations (p < 0.0001). CONCLUSION In our study, we did not find any association between the MTHFR gene C677T polymorphism and breast cancer. However, a meta-analysis of the 6 association studies carried out in Turkish populations with 707 patients and 880 controls showed a significant association between breast cancer and the MTHFR gene C677T polymorphism.
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Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.
Schoeler, NE, Leu, C, White, J, Plagnol, V, Ellard, S, Matarin, M, Yellen, G, Thiele, EA, Mackay, M, McMahon, JM, et al
Epilepsy research. 2015;:22-8
Abstract
In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: ≥ 50% seizure reduction and seizure-freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF<0.01 was evaluated. 303 Individuals had KCNJ11 and 246 individuals had BAD sequencing data and diet response data. Six SNPs in KCNJ11 and two in BAD had MAF>0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAF<0.01. No significant results were obtained from association analyses, with either KDT response phenotype. P-values were similar when accounting for ethnicity using a stratified Cochran-Mantel-Haenszel test. There did not seem to be a consistent effect of rare variants on response to KDT, although the cohort size was too small to assess significance. Common variants in KCNJ11 and BAD do not predict response to KDT for epilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes.
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Association between maternal micronutrient status, oxidative stress, and common genetic variants in antioxidant enzymes at 15 weeks׳ gestation in nulliparous women who subsequently develop preeclampsia.
Mistry, HD, Gill, CA, Kurlak, LO, Seed, PT, Hesketh, JE, Méplan, C, Schomburg, L, Chappell, LC, Morgan, L, Poston, L, et al
Free radical biology & medicine. 2015;:147-55
Abstract
Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia.
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Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort.
Chen, R, Wang, J, Tang, S, Zhang, Y, Lv, X, Wu, S, Xia, Y, Deng, P, Ma, Y, Tu, D, et al
Tuberculosis (Edinburgh, Scotland). 2015;(1):68-74
Abstract
This study investigated the association between genetic variants in two hepatic uptake transporter genes (SLCO1B1 and SLC10A1) and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) in a Chinese cohort. The frequencies and distributions of single nucleotide polymorphisms (SNPs) and haplotypes of these genes were compared among 89 incident ATDH cases and 356 matched ATDH-free controls using a multivariate conditional logistic regression analysis. After correction for potential confounding factors, significant differences were found in polymorphism of rs4149014 under an addictive model (P = 0.008) and a recessive model (P = 0.016). The result of haplotype analysis suggested that patients carrying at least one SLCO1B1*15 haplotype had a higher risk of ATDH (odds ratio (OR) = 1.74, 95% confidence intervals (CI): 1.04-2.90, P = 0.034) in comparison with those carrying SLCO1B1*1a or SLCO1B1*1b haplotypes. These findings indicate that genetic variants of SLCO1B1 are associated with the development of ATDH in Chinese population.
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Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.
Espinosa-Parrilla, Y, Muñoz, X, Bonet, C, Garcia, N, Venceslá, A, Yiannakouris, N, Naccarati, A, Sieri, S, Panico, S, Huerta, JM, et al
International journal of cancer. 2014;(9):2065-76
Abstract
MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.
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Genetic variants associated with VLDL, LDL and HDL particle size differ with race/ethnicity.
Frazier-Wood, AC, Manichaikul, A, Aslibekyan, S, Borecki, IB, Goff, DC, Hopkins, PN, Lai, CQ, Ordovas, JM, Post, WS, Rich, SS, et al
Human genetics. 2013;(4):405-13
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Abstract
Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial/ethnic groups on lipoprotein profile. Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P < 1.97 × 10(-05) (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N = 2,430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N = 1,594), Chinese (N = 758), and Hispanic (N = 1,422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only. Our findings suggest that the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race/ethnicity.
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H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis.
van Rheenen, W, Diekstra, FP, van Doormaal, PT, Seelen, M, Kenna, K, McLaughlin, R, Shatunov, A, Czell, D, van Es, MA, van Vught, PW, et al
Neurobiology of aging. 2013;(5):1517.e5-7
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Abstract
The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival.