-
1.
Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease.
Martínez-Montoro, JI, Cornejo-Pareja, I, Gómez-Pérez, AM, Tinahones, FJ
Nutrients. 2021;(11)
Abstract
In the last decades, the global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions with derived major health and socioeconomic consequences; this tendency is expected to be further aggravated in the coming years. Obesity, insulin resistance/type 2 diabetes mellitus, sedentary lifestyle, increased caloric intake and genetic predisposition constitute the main risk factors associated with the development and progression of the disease. Importantly, the interaction between the inherited genetic background and some unhealthy dietary patterns has been postulated to have an essential role in the pathogenesis of NAFLD. Weight loss through lifestyle modifications is considered the cornerstone of the treatment for NAFLD and the inter-individual variability in the response to some dietary approaches may be conditioned by the presence of different single nucleotide polymorphisms. In this review, we summarize the current evidence on the influence of the association between genetic susceptibility and dietary habits in NAFLD pathophysiology, as well as the role of gene polymorphism in the response to lifestyle interventions and the potential interaction between nutritional genomics and other emerging therapies for NAFLD, such as bariatric surgery and several pharmacologic agents.
-
2.
Associations between common ion channel single nucleotide polymorphisms and sudden cardiac death in adults: A MOOSE-compliant meta-analysis.
Liu, X, Shi, J, Xiao, P
Medicine. 2018;(38):e12428
-
-
Free full text
-
Abstract
BACKGROUND We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings. METHODS This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD. RESULTS We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67-0.85; P < .001). Subgroup analysis showed that rs11720524 in SCN5A protected against SCD in Europeans and Caucasians but not in Koreans. The allelic model indicated that rs12296050 in KCNQ1 also had significant protective effects against SCD (OR: 0.85; 95% CI: 0.76-0.96; P = .007). Moreover, this model demonstrated that rs2283222 in KCNQ1 had a significant negative relationship with SCD (OR: 0.73; 95% CI: 0.62-0.85; P < .001). Rs12296050 in KCNQ1 protected against SCD in Koreans and Americans. Our results also showed that rs790896 in RYR2 was negatively associated with SCD in a dominant model (OR: 0.66; 95% CI: 0.45-0.97; P = .033). CONCLUSIONS Rs11720524 in SCN5A is negatively related to SCD in Europeans and Caucasians, and rs12296050 and rs2283222 in KCNQ1 and rs790896 in RYR2 clearly have protective effects against SCD.
-
3.
Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis.
Luo, Z, Lu, Z, Muhammad, I, Chen, Y, Chen, Q, Zhang, J, Song, Y
Lipids in health and disease. 2018;(1):191
Abstract
BACKGROUND The associations of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) rs1801133 polymorphism with coronary artery disease (CAD) and plasma lipid levels have been widely investigated, but the results were inconsistent and inconclusive. This meta-analysis aimed to clarify the relationships of the rs1801133 polymorphism with CAD and plasma lipid levels. METHODS By searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases, 123 studies (87,020 subjects) and 65 studies (85,554 subjects) were identified for the CAD association analysis and the lipid association analysis, respectively. Odds ratio (OR) and standardized mean difference (SMD) were used to determine the effects of the rs1801133 polymorphism on CAD risk and lipid levels, respectively. RESULTS The variant T allele of the rs1801133 polymorphism was associated with increased risk of CAD under allelic model [OR = 1.11, 95% confidence interval (CI) = 1.06-1.17, P < 0.01], additive model (OR = 1.25, 95% CI = 1.14-1.37, P < 0.01), dominant model (OR = 1.11, 95% CI = 1.04-1.17, P < 0.01), and recessive model (OR = 1.22, 95% CI = 1.12-1.32, P < 0.01). The T carriers had higher levels of total cholesterol (TC) (SMD = 0.04, 95% CI = 0.01-0.07, P = 0.02) and low-density lipoprotein cholesterol (LDL-C) (SMD = 0.07, 95% CI = 0.01-0.12, P = 0.01) than the non-carriers. CONCLUSIONS The meta-analysis suggested that the T allele of the rs1801133 polymorphism is a risk factor for CAD, which is possibly and partly mediated by abnormal lipid levels.
-
4.
Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.
Harrison, SC, Holmes, MV, Burgess, S, Asselbergs, FW, Jones, GT, Baas, AF, van 't Hof, FN, de Bakker, PIW, Blankensteijn, JD, Powell, JT, et al
JAMA cardiology. 2018;(1):26-33
-
-
Free full text
-
Abstract
IMPORTANCE Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. OBJECTIVE To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. DESIGN, SETTING, AND PARTICIPANTS Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. EXPOSURES Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). MAIN OUTCOMES AND MEASURES The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. RESULTS Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). CONCLUSIONS AND RELEVANCE The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
-
5.
[Functional implications of single nucleotide polymorphisms (SNPs) in protein-coding and non-coding RNA genes in multifactorial diseases].
Ramírez-Bello, J, Jiménez-Morales, M
Gaceta medica de Mexico. 2017;(2):238-250
Abstract
Single nucleotide polymorphisms (SNPs) represent the most common type of variation in the human genome. The SNPs located in protein-coding and non-coding RNA genes are classified as neutral and functional. The neutral have no effect, while the functional affect different biological processes and continually confer risk for multifactorial diseases. Functional SNPs found in the promoters of protein-coding and non-coding RNA genes (microRNAs: miRNAs) termed regulatory SNP (rSNPs) and miRNAs rSNPs (miR-rSNPs), respectively, affect the gene expression. Functional SNPs located on the structure of the precursor mRNAs (exons and introns), mature mRNA (5´ untranslated region [UTR], coding sequence, and 3´ UTR), and primary, precursor, and mature miRNAs are termed structural RNA SNPs (srSNPs) and miR-srSNPs, respectively. The srSNPs affect the splicing (and alternative splicing), srSNPs affect the splicing (and alternative splicing), the translation, stability, amino acid sequence, structure, and function of proteins and interaction between mRNA/miRNAs. Finally, the miR-srSNPs affect the structure, processing and interaction between miRNAs/mRNAs. Functional characterization of potentially harmful risk alleles of the SNPs located in protein-coding and non-coding RNA genes have contributed to an understanding of their functions in the complex diseases. The objective of this review is update the reader on the functional role of the SNPs located in protein-coding and non-coding RNA genes and their relationship with multifactorial diseases.
-
6.
Role of genetic polymorphism in nutritional supplementation therapy in personalized medicine.
Peneş, NO, Weber, B, Păun, SD
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2017;(1):53-58
Abstract
Genetic-guided nutritional supplementation therapy in personalized medicine is the type of treatment that prevents and acts against errors during the copying process of a cell's deoxyribonucleic acid (DNA), mistakes that lead to diversification in the DNA sequence at certain locations, called single nucleotide polymorphisms (SNPs). Positive results are quickly achieved using one of the four types of therapy. These types are: personalized, when individual human genetic variations drive individual treatment, preventive, with a tailored healthcare strategy and therapeutic preventive drugs and vaccines, participatory, when empowered patients make informed choices and take responsibility of their own health and predictive, using a proactive approach to health and medicine.
-
7.
PCSK1 Variants and Human Obesity.
Ramos-Molina, B, Martin, MG, Lindberg, I
Progress in molecular biology and translational science. 2016;:47-74
-
-
Free full text
-
Abstract
PCSK1, encoding prohormone convertase 1/3 (PC1/3), was one of the first genes linked to monogenic early-onset obesity. PC1/3 is a protease involved in the biosynthetic processing of a variety of neuropeptides and prohormones in endocrine tissues. PC1/3 activity is essential for the activating cleavage of many peptide hormone precursors implicated in the regulation of food ingestion, glucose homeostasis, and energy homeostasis, for example, proopiomelanocortin, proinsulin, proglucagon, and proghrelin. A large number of genome-wide association studies in a variety of different populations have now firmly established a link between three PCSK1 polymorphisms frequent in the population and increased risk of obesity. Human subjects with PC1/3 deficiency, a rare autosomal-recessive disorder caused by the presence of loss-of-function mutations in both alleles, are obese and display a complex set of endocrinopathies. Increasing numbers of genetic diagnoses of infants with persistent diarrhea has recently led to the finding of many novel PCSK1 mutations. PCSK1-deficient infants experience severe intestinal malabsorption during the first years of life, requiring controlled nutrition; these children then become hyperphagic, with associated obesity. The biochemical characterization of novel loss-of-function PCSK1 mutations has resulted in the discovery of new pathological mechanisms affecting the cell biology of the endocrine cell beyond simple loss of enzyme activity, for example, dominant-negative effects of certain mutants on wild-type PC1/3 protein, and activation of the cellular unfolded protein response by endoplasmic reticulum-retained mutants. A better understanding of these molecular and cellular pathologies may illuminate possible treatments for the complex endocrinopathy of PCSK1 deficiency, including obesity.
-
8.
Association between the ENPP1 K121Q polymorphism and risk of diabetic kidney disease: a systematic review and meta-analysis.
Sortica, DA, Buffon, MP, Souza, BM, Nicoletto, BB, Santer, A, Assmann, TS, Crispim, D, Canani, LH
PloS one. 2015;(3):e0118416
Abstract
The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.
-
9.
BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis.
Harrisberger, F, Smieskova, R, Schmidt, A, Lenz, C, Walter, A, Wittfeld, K, Grabe, HJ, Lang, UE, Fusar-Poli, P, Borgwardt, S
Neuroscience and biobehavioral reviews. 2015;:107-18
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and synaptic plasticity in the central nervous system, especially in the hippocampus, and has been implicated in the pathophysiology of several neuropsychiatric disorders. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a functionally relevant single nucleotide polymorphism affecting the secretion of BDNF and is implicated in differences in hippocampal volumes. METHODS This is a systematic meta-analytical review of findings from imaging genetic studies on the impact of the rs6265 SNP on hippocampal volumes in neuropsychiatric patients with major depressive disorder, anxiety, bipolar disorder or schizophrenia. RESULTS The overall sample size of 18 independent clinical cohorts comprised 1695 patients. Our results indicated no significant association of left (Hedge's g=0.08, p=0.12), right (g=0.07, p=0.22) or bilateral (g=0.07, p=0.16) hippocampal volumes with BDNF rs6265 in neuropsychiatric patients. There was no evidence for a publication bias or any demographic, clinical, or methodological moderating effects. Both Val/Val homozygotes (g=0.32, p=0.004) and Met-carriers (g=0.20, p=0.004) from the patient sample had significantly smaller hippocampal volumes than the healthy control sample with the same allele. The magnitude of these effects did not differ between the two genotypes. CONCLUSION This meta-analysis suggests that there is no association between this BDNF polymorphism and hippocampal volumes. For each BDNF genotype, the hippocampal volumes were significantly lower in neuropsychiatric patients than in healthy controls.
-
10.
Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.
, , Cornelis, MC, Byrne, EM, Esko, T, Nalls, MA, Ganna, A, Paynter, N, Monda, KL, Amin, N, Fischer, K, et al
Molecular psychiatry. 2015;(5):647-656
-
-
Free full text
-
Abstract
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.