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Higher Increase in Plasma DHA in Females Compared to Males Following EPA Supplementation May Be Influenced by a Polymorphism in ELOVL2: An Exploratory Study.
Metherel, AH, Irfan, M, Klingel, SL, Mutch, DM, Bazinet, RP
Lipids. 2021;(2):211-228
Abstract
Young adult females have higher blood docosahexaenoic acid (DHA), 22:6n-3 levels than males, and this is believed to be due to higher DHA synthesis rates, although DHA may also accumulate due to a longer half-life or a combination of both. However, sex differences in blood fatty acid responses to eicosapentaenoic acid (EPA), 20:5n-3 or DHA supplementation have not been fully investigated. In this exploratory analysis, females and males (n = 14-15 per group) were supplemented with 3 g/day EPA, 3 g/day DHA, or olive oil control for 12 weeks. Plasma was analyzed for sex effects at baseline and changes following 12 weeks' supplementation for fatty acid levels and carbon-13 signature (δ13 C). Following EPA supplementation, the increase in plasma DHA in females (+23.8 ± 11.8, nmol/mL ± SEM) was higher than males (-13.8 ± 9.2, p < 0.01). The increase in plasma δ13 C-DHA of females (+2.79 ± 0.31, milliUrey (mUr ± SEM) compared with males (+1.88 ± 0.44) did not reach statistical significance (p = 0.10). The sex effect appears driven largely by increased plasma DHA in the AA genotype of females (+58.8 ± 11.5, nmol/mL ± SEM, n = 5) compared to GA + GG in females (+4.34 ± 13.5, n = 9) and AA in males (-29.1 ± 17.2, n = 6) for rs953413 in the ELOVL2 gene (p < 0.001). In conclusion, EPA supplementation increases plasma DHA levels in females compared to males, which may be dependent on the AA genotype for rs953413 in ELOVL2.
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Assessment of the association between ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility: a meta-analysis.
Shi, J, Li, W, Ding, X
The International journal of biological markers. 2017;(1):e96-e101
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Abstract
BACKGROUND The protein encoded by ZBTB20 is a member of the POK family, whose members function as transcriptional repressors through interactions mediated by their conserved C2H2 Krüppel-type zinc finger and BTB/POZ domains. Polymorphisms in ZBTB20 appeared to be associated with gastric and esophageal cancer susceptibility in biological models, but the results of these studies were inconclusive. Therefore, we conducted a meta-analysis by pooling all available data to assess the exact association between the ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility. METHOD The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The pooled odds ratios (ORs) with the corresponding confidence intervals (CIs) were calculated. Moreover, the data were analyzed using the Stata 12.0 software(StataCorp). RESULT A total of 8 independent case-control studies comprising 9,994 cases and 10,258 controls were included. We found a significant association between the rs9841504 polymorphism and decreased gastric cancer susceptibility in the allelic, homozygous, dominant and recessive models (B vs. A:OR = 0.797, 95% CI 0.644-0.986, p = 0.036; BB vs. AA:OR = 0.601, 95% CI 0.366-0.988, p = 0.045; BA + BB vs. AA:OR = 0.789, 95% CI 0.627-0.992, p = 0.043; BB vs. BA + AA:OR = 0.635, 95% CI 0.405-0.997, p = 0.049). Conversely, no association between the rs9841504 polymorphism and esophageal cancer susceptibility was found. In subgroup analysis by ethnicity, we observed a significantly decreased susceptibility to gastric cancer in Asian populations in the allele contrast, homozygous and recessive models (B vs. A:OR = 0.791, 95% CI 0.628-0.996, p = 0.046; BB vs. AA:OR = 0.559, 95% CI 0.323-0.966, p = 0.037; BB vs. BA + AA:OR = 0.593, 95% CI 0.361-0.972, p = 0.038). CONCLUSIONS In summary, our work suggests that the ZBTB20 rs9841504 polymorphism is a protective factor for gastric cancer rather than esophageal cancer.
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Effects of Genetic and Nongenetic Factors on Total and Bioavailable 25(OH)D Responses to Vitamin D Supplementation.
Yao, P, Sun, L, Lu, L, Ding, H, Chen, X, Tang, L, Xu, X, Liu, G, Hu, Y, Ma, Y, et al
The Journal of clinical endocrinology and metabolism. 2017;(1):100-110
Abstract
CONTEXT Little is known about how genetic and nongenetic factors modify responses of vitamin D supplementation in nonwhite populations. OBJECTIVE To investigate factors modifying 25-hydroxyvitamin D [25(OH)D] and bioavailable 25(OH)D [25(OH)DBio] responses after vitamin D3 supplementation. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION In this 20-week, randomized, double-blinded, placebo-controlled trial, 448 Chinese with vitamin D deficiency received 2000 IU/d vitamin D3 or placebo. MAIN OUTCOME MEASURES Serum 25(OH)D, vitamin D-binding protein (VDBP), parathyroid hormone (PTH) and calcium were measured, and 25(OH)DBio was calculated based on VDBP levels. Six common polymorphisms in vitamin D metabolism genes were genotyped. RESULTS Between-arm net changes were +30.6 ± 1.7 nmol/L for 25(OH)D, +2.7 ± 0.2 nmol/L for 25(OH)DBio, and -5.2 ± 1.2 pg/mL for PTH, corresponding to 70% [95% confidence interval (CI), 62.8% to 77.2%] net reversion rate for vitamin D deficiency at week 20 (P < 0.001). Only 25(OH)DBio change was positively associated with calcium change (P < 0.001). Genetic factors (GC-rs4588/GC-rs7041, VDR-rs2228570, and CYP2R1-rs10741657; P ≤ 0.04) showed stronger influences on 25(OH)D or 25(OH)DBio responses than nongenetic factors, including baseline value, body mass index, and sex. An inverse association of PTH-25(OH)D was demonstrated only at 25(OH)D of <50.8 (95% CI, 43.6 to 59.0) nmol/L. CONCLUSIONS Supplemented 2000 IU/d vitamin D3 raised 25(OH)D and 25(OH)DBio but was unable to correct deficiency in 25% of Chinese participants, which might be partially attributed to the effect of genetic modification. More studies are needed to elucidate appropriate vitamin D recommendations for Asians and the potential clinical implications of 25(OH)DBio.
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Polymorphisms of the FTO and MTHFR genes and vascular, inflammatory and metabolic marker levels in postmenopausal women.
Chedraui, P, Pérez-López, FR, Escobar, GS, Espinoza-Caicedo, JA, Montt-Guevara, M, Genazzani, AR, Simoncini, T, ,
Journal of endocrinological investigation. 2016;(8):885-90
Abstract
OBJECTIVE To determine the prevalence of three single nucleotide polymorphisms (SNPs) in postmenopausal women with and without the metabolic syndrome (METS) and to explore levels of circulating biomarkers of inflammation, vascular and metabolic dysfunction according to SNP genotypes. METHODS DNA was extracted from the whole blood of 192 natural postmenopausal women (40 to 65 years) screened for the METS and tested for three gene SNPs related to obesity: the fat mass obesity (FTO: rs9939609) and the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C). Blood levels of angiopoietin, IL-8, sFASL, IL-6, TNF-α, sCD40L, PAI-1, u-PA, leptin, adiponectin, resistin, ghrelin, visfatin, adipsin and insulin were measured in a subgroup, with and without the METS, using multiplex technology (n = 100) and compared according to SNP genotypes. RESULTS Genotype frequency of the three studied SNPs did not differ in relation to the presence of the METS. However, genotypes CT+TT (C677T) and AT (rs9939609) were more prevalent in women with high triglyceride levels. Pooled sub-analysis (n = 100) found that median sCD40L and visfatin levels were higher in women with genotypes AT+TT (rs9939609) as compared to AA (1178 vs. 937.0 pg/mL and 0.93 vs. 0.43 ng/mL, respectively, p < 0.05). CONCLUSION Two SNP genotypes related to obesity were more prevalent in women with abnormal triglyceride levels and two vascular and inflammatory serum markers were higher in relation to the rs9939609 SNP.
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Genetic Variations in the Vitamin D Receptor Predict Type 2 Diabetes and Myocardial Infarction in a Community-Based Population: The Tromsø Study.
Zostautiene, I, Jorde, R, Schirmer, H, Mathiesen, EB, Njølstad, I, Løchen, ML, Wilsgaard, T, Joakimsen, RM, Kamycheva, E
PloS one. 2015;(12):e0145359
Abstract
BACKGROUND Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population. METHODS AND FINDINGS Measurements and DNA were obtained from the participants in the Tromsø Study in 1994-1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05-1.49) for T2D and 1.14 (1.02-1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints. CONCLUSIONS The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed.
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Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses.
Hammer, C, Begemann, M, McLaren, PJ, Bartha, I, Michel, A, Klose, B, Schmitt, C, Waterboer, T, Pawlita, M, Schulz, TF, et al
American journal of human genetics. 2015;(5):738-43
Abstract
The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.
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Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.
Nimptsch, K, Aleksandrova, K, Boeing, H, Janke, J, Lee, YA, Jenab, M, Bueno-de-Mesquita, HB, Jansen, EH, Tsilidis, KK, Trichopoulou, A, et al
International journal of cancer. 2015;(5):1181-92
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Abstract
High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP-score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.
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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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VEGFA, FLT1, KDR and colorectal cancer: assessment of disease risk, tumor molecular phenotype, and survival.
Slattery, ML, Lundgreen, A, Wolff, RK
Molecular carcinogenesis. 2014;:E140-50
Abstract
Angiogenesis is essential for tumor progression. Vascular endothelial growth factor (VEGFA) and its receptors 1 (FLT1) and 2 (KDR), have been identified as major mediators of this process. We hypothesized that genetic variation in FLT1 (38 SNPs), KDR (22 SNPS), and VEGFA (11 SNPs) would be associated with colon and rectal cancer development and survival. Data from a case-control study of 1555 colon cancer cases and 1956 controls and 754 rectal cancer cases and 959 controls were used. An adaptive rank truncation product (ARTP), based on 10,000 permutations, was used to determine the statistical significance of the candidate genes and angiogenesis pathway. Based on ARTP results, FLT1 was significantly associated with risk of colon cancer (P(ARTP) = 0.045) and VEGFA was significantly associated with rectal cancer (P(ARTP) = 0.036). After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFA rs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors. FLT1 rs2296189 and rs600640 were associated with CIMP+ rectal tumors and FLT1 rs7983774 was associated with TP53-mutated rectal tumors. Four SNPs in FLT1 were associated with colon cancer survival while three SNPs in KDR were associated with survival after diagnosis with rectal cancer. Aspirin/NSAID use, smoking cigarettes, and BMI modified the associations. These findings suggest the importance of inflammation and angiogenesis in the etiology of colorectal cancer and that genetic and lifestyle factors may be targets for modulating disease risk.
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Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci.
Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, OʼLeary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, et al
Inflammatory bowel diseases. 2014;(10):1784-93
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BACKGROUND As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. METHODS The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. RESULTS We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10(-7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10(-15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10(-6), n = 99). CONCLUSIONS We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.