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Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.
de Las Fuentes, L, Sung, YJ, Sitlani, CM, Avery, CL, Bartz, TM, Keyser, C, Evans, DS, Li, X, Musani, SK, Ruiter, R, et al
The pharmacogenomics journal. 2020;(3):482-493
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Abstract
Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.
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Genome-Wide Association Meta-Analysis of Individuals of European Ancestry Identifies Suggestive Loci for Sodium Intake, Potassium Intake, and Their Ratio Measured from 24-Hour or Half-Day Urine Samples.
Kho, M, Smith, JA, Verweij, N, Shang, L, Ryan, KA, Zhao, W, Ware, EB, Gansevoort, RT, Irvin, MR, Lee, JE, et al
The Journal of nutrition. 2020;(10):2635-2645
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Abstract
BACKGROUND Excess sodium intake and insufficient potassium intake are risk factors for hypertension, but there is limited knowledge regarding genetic factors that influence intake. Twenty-hour or half-day urine samples provide robust estimates of sodium and potassium intake, outperforming other measures such as spot urine samples and dietary self-reporting. OBJECTIVE The aim of this study was to investigate genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio measured from 24-h or half-day urine samples. METHODS Using samples of European ancestry (mean age: 54.2 y; 52.3% women), we conducted a meta-analysis of genome-wide association studies in 4 cohorts with 24-h or half-day urine samples (n = 6,519), followed by gene-based analysis. Suggestive loci (P < 10-6) were examined in additional European (n = 844), African (n = 1,246), and Asian (n = 2,475) ancestry samples. RESULTS We found suggestive loci (P < 10-6) for all 3 traits, including 7 for 24-h sodium excretion, 4 for 24-h potassium excretion, and 4 for sodium-to-potassium ratio. The most significant locus was rs77958157 near cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) , a gene involved in eating behavior and appetite regulation (P = 2.3 × 10-8 with sodium-to-potassium ratio). Two suggestive loci were replicated in additional samples: for sodium excretion, rs12094702 near zinc finger SWIM-type containing 5 (ZSWIM5) was replicated in the Asian ancestry sample reaching Bonferroni-corrected significance (P = 0.007), and for potassium excretion rs34473523 near sodium leak channel (NALCN) was associated at a nominal P value with potassium excretion both in European (P = 0.043) and African (P = 0.043) ancestry cohorts. Gene-based tests identified 1 significant gene for sodium excretion, CDC42 small effector 1 (CDC42SE1), which is associated with blood pressure regulation. CONCLUSIONS We identified multiple suggestive loci for sodium and potassium intake near genes associated with eating behavior, nervous system development and function, and blood pressure regulation in individuals of European ancestry. Further research is needed to replicate these findings and to provide insight into the underlying genetic mechanisms by which these genomic regions influence sodium and potassium intake.
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Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns.
Sliz, E, Kalaoja, M, Ahola-Olli, A, Raitakari, O, Perola, M, Salomaa, V, Lehtimäki, T, Karhu, T, Viinamäki, H, Salmi, M, et al
Journal of medical genetics. 2019;(9):607-616
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Abstract
BACKGROUND Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. OBJECTIVE To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. METHODS Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. RESULTS We identified seven novel and six previously reported genetic associations (p<3.1×10-9). Three loci were associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) level, one of which was the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Our findings suggest that the blood type B associates primarily with sVCAM-1 level, while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. The genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower circulating cholesterol levels and lower cardiovascular disease risk. CONCLUSION The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.
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Association of maternal iron deficiency anemia with the risk of gestational diabetes mellitus: a meta-analysis.
Tiongco, RE, Arceo, E, Clemente, B, Pineda-Cortel, MR
Archives of gynecology and obstetrics. 2019;(1):89-95
Abstract
PURPOSE The aim of the study was to conduct a meta-analysis investigating the association of maternal iron deficiency anemia (IDA) and risk of gestational diabetes mellitus (GDM). METHODS Literature search was conducted in various database websites such as PubMed, Cochrane Library, and Web of Science up to 17 June 2018 for related publications written in English. Selected data were extracted from the included studies and were subjected to statistical analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed, pooled, and interpreted. Subgroup analysis by ethnicity (Asians vs. Caucasians) was also performed. RESULTS Six studies with a total sample size of 15,157 from various countries were included in this meta-analysis. Pooled ORs of all publications included show that pregnant women with IDA have a reduced risk of developing GDM (OR 0.61; 95% CI 0.47-0.80; PA = 0.0003). Subgroup analysis, on the other hand, showed significant associations among Asians (OR 0.60; 95% CI 0.45-0.79; PA = 0.0003) than Caucasians (OR 0.76; 95% CI 0.32-1.76; PA = 0.52). CONCLUSION Results of this meta-analysis suggests that pregnant women with IDA are 39% less likely to develop GDM. However, more studies are needed to confirm the claims of our results.
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Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.
Irvin, MR, Sitlani, CM, Noordam, R, Avery, CL, Bis, JC, Floyd, JS, Li, J, Limdi, NA, Srinivasasainagendra, V, Stewart, J, et al
The pharmacogenomics journal. 2019;(1):97-108
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Abstract
We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
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THADA_rs13429458 Minor Allele Increases the Risk of Polycystic Ovary Syndrome in Asian, but Not in Caucasian Women: A Systematic Review and Meta-Analysis.
Park, S, Liu, M, Zhang, T
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2019;(10):661-670
Abstract
Polycystic ovary syndrome (PCOS) is a highly prevalent disease in young women that also features increased insulin resistance. Genetic factors have a strong relationship with the etiology of PCOS. We assessed whether carrying THADA rs13429458 is associated with the development of PCOS by meta-analysis and whether the association is influenced by ethnicity. Articles were searched using PubMed, EMBASE, Cochrane Library, Korean scientific database, and Chinese and Indian medical databases to identify all eligible studies for evaluating the association of THADA rs13429458 and PCOS risk. The association was assessed in five genetic random effects models including the allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Subgroup analyses stratified by ethnicity (Asians and non-Asians) were assessed. Nine articles were selected and 1 association analysis of Korea PCOS study met Hardy-Weinberg equilibrium criteria. A set of 38 224 PCOS women and 120 173 healthy women were included. The AG and RG showed heterogeneity in the overall and Asian subjects, but the other genetic model did not exhibit heterogeneity in all subjects. AG, RG, DG, and HMG, but not HTG, exhibited publication bias in total subjects but there was no publication bias in all genetic models among Asians and non-Asians. The overall effect of THADA_rs13429458 on PCOS risk showed significant positive associations in pooling 10 studies. In sub-group analysis only Asians, but not non-Asians, had a positive association (AG: OR=1.24, p=0.001; RG: OR=1.32, p=0.002; DG: OR, 1.70, p<0.00001; HMG: OR, 1.71, p=0.002; HTG: OR=1.34, p=0,006). In conclusions, young Asian women with the minor allele (C) for THADA rs13429458 were at increased risk of PCOS.
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Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci.
Thio, CHL, Reznichenko, A, van der Most, PJ, Kamali, Z, Vaez, A, Smit, JH, Penninx, BWJH, Haller, T, Mihailov, E, Metspalu, A, et al
American journal of nephrology. 2019;(3):193-202
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Abstract
BACKGROUND Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.
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Vitamin D receptor ApaI, TaqI, BsmI, and FokI polymorphisms and psoriasis susceptibility: an updated meta-analysis.
Lee, YH
Clinical and experimental dermatology. 2019;(5):498-505
Abstract
BACKGROUND Vitamin D is considered a regulator of the immune system, and its polymorphisms have been associated with psoriasis in some but not all reports. AIM: To explore whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to psoriasis. METHODS Meta-analyses were conducted to determine the associations between psoriasis and the VDR ApaI, TaqI, BsmI and FokI polymorphisms in all participants, and stratified by ethnic group. RESULTS In total, 16 studies on VDR polymorphisms and psoriasis were included in this meta-analysis, which involved 2086 patients and 2182 controls. The meta-analysis indicated an association between psoriasis and the VDR TaqI TT genotype in Caucasian (OR = 1.29, 95% CI = 1.00-1.66, P < 0.05), but not in Asian (OR = 1.32, 95% CI = 0.89-1.96, P = 0.16) populations. However, no association was found between psoriasis and the VDR TaqI polymorphism using dominant, allele contrast or homozygous contrast models. No association was found between psoriasis and either the VDR ApaI, BsmI or FokI polymorphisms by meta-analyses of the allele contrast, recessive, or dominant models or homozygous contrast models in the overall, Caucasian or Asian populations. CONCLUSION This meta-analysis showed that polymorphisms in VDR ApaI, BsmI and FokI are not associated with psoriasis susceptibility in overall, Caucasian or Asian populations. However, the VDR TaqI polymorphism is associated with psoriasis susceptibility in Caucasian populations.
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Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.
Suri, P, Palmer, MR, Tsepilov, YA, Freidin, MB, Boer, CG, Yau, MS, Evans, DS, Gelemanovic, A, Bartz, TM, Nethander, M, et al
PLoS genetics. 2018;(9):e1007601
Abstract
Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
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Vitamin D receptor rs2228570 polymorphism and susceptibility to ovarian cancer: An updated meta-analysis.
Chen, H, Zhu, J
The journal of obstetrics and gynaecology research. 2018;(3):556-565
Abstract
AIM: The FokI polymorphism (C>T, rs2228570) of the vitamin D receptor gene is a coding nonsynonymous single nucleotide polymorphism in the translational initiation codon reported to have functional significance. Although the role of rs2228570 in the risk of ovarian cancer has been widely researched, the association is still unclear. We performed an updated meta-analysis to clarify this issue. METHODS Eligible studies were retrieved from electronic databases for the period 2007-2016. The association was measured by unadjusted odds ratio combined with 95% confidence intervals (CIs). Random-effect or fixed-effect models were used according to the heterogeneity of the studies. We further appreciated the strength of evidence according to Venice guidance. RESULTS Fourteen studies (4448 cases and 7242 controls) were included in the meta-analysis. Studies were predominantly conducted in Caucasian populations (4152 cases and 6693 controls). A dominant genetic model was determined to be the most appropriate genetic model. Overall meta-analysis showed a fixed-effect odds ratio of 1.14 (95% CI 1.05-1.23) under a dominant model. The fixed-effect odds ratios were 1.12 (95% CI 1.03-1.21) and 1.49 (95% CI 1.06-2.09) in Caucasian and Asian populations, respectively. The strength of the evidence was moderate. CONCLUSION The rs2228570 polymorphism increased the risk of ovarian cancer in Caucasian populations in a dominant genetic model. The role of this polymorphism in the risk of ovarian cancer in Asian populations should be further studied.