Functional validity, role, and implications of heavy alcohol consumption genetic loci

Thompson, Andrew; Cook, James P.; Choquet, Hélène; Jorgenson, Eric; Yin, Jie; Kinnunen, Tarja; Barclay, Jeff W.; Morris, Andrew P.; Pirmohamed, Munir

doi:10.1126/sciadv.aay5034

Cited by 56 publications

(66 citation statements)

References 78 publications

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“…Genome-wide association studies have identified FGF21 gene variants associated with higher carbohydrate and lower fat and protein consumption ( 19 – 21 ). Furthermore, several KLB gene variants (rs11940694, rs13130794, rs9991733) were associated with higher alcohol consumption ( 22 – 24 ). In mice, recombinant FGF21 analogs reduced sweetened food/water and alcohol consumption ( 22 , 25 , 26 ), and in monkeys, FGF21 altered sweet preference ( 25 ).…”

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confidence: 99%

Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Baruch¹,

Wong²,

Chinn³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

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confidence: 99%

Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Baruch¹,

Wong²,

Chinn³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…All participants of the original studies included in the GWASs had provided informed written consent. The data of tobacco and heavy alcohol use were extracted from a large-scale genome-wide association studies with smoking initiation, cigarettes per day, smoking cessation, age at initiation of regular smoking and heavy alcohol intake (Additional file 1 : Table 1) [ 15 , 16 ]. Genetic instrumental variables for the exposure were selected at the genome-wide significance level ( P < 5 × 10 −8 ).…”

Section: Methodsmentioning

confidence: 99%

Genetically determined tobacco and alcohol use and risk of atrial fibrillation

Guo

Lin

et al. 2021

BMC Med Genomics

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Background The causality between the use of alcohol and cigarettes and atrial fibrillation (AF) remains controversial. We conducted a Mendelian randomization (MR) study to evaluate the association of genetic variants related to tobacco and alcohol use with AF. Methods Single nucleotide polymorphisms (SNPs) related to smoking initiation (N = 374), age at initiation of regular smoking (N = 10), cigarettes per day (N = 55), and smoking cessation (N = 24) were derived from a genome-wide association studies (GWAS) of tobacco use (N = 1.2 million individuals). SNPs related to heavy alcohol use (N = 6) were derived from a GWAS of UK biobank (N = 125,249 individuals). The genetically matching instrumented variables were obtained from the GWAS of AF (N = 588,190 individuals). The estimates between tobacco and alcohol use and AF were combined by inverse-variance weighted (IVW), simple median, weighted median, MR-robust adjusted profile score method, MR-PRESSO, and multivariable MR. Results A total of 65,446 AF patients and 522,744 referents were included. In the IVW analysis, the odds ratio per one-unit increase of smoking initiation was 1.11 (95% CI, 1.06–1.16; P = 3.35 × 10−6) for AF. Genetically predicted age at initiation of regular smoking, cigarettes per day and smoking cessation were not associated with AF. The IVW estimate showed that heavy alcohol consumption increased AF risk (OR, 1.11; 95% CI, 1.04–1.18; P = 0.001). The results were consistent in complementary analyses and multivariable MR. Conclusion Our MR study indicated that regular smoking was associated with increased risk of AF, no matter the age at initiation of regular smoking, or the number of cigarettes smoked per day. Genetically predicted heavy alcohol consumption increased the risk of AF.

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“…Previous genome-wide association study (GWAS) of alcohol consumption in white British participants of UK Biobank identified 14 single nucleotide polymorphisms (SNPs) associated with alcohol consumption[24]. In addition, a study using data from UK Biobank and Genetic Epidemiology Research in Adult Health and Aging (GERA) datasets identified 6 SNPs (Alcohol Dehydrogenase 1B (ADH1B, rs1229984); Klotho Beta (KLB, rs13130794); Basic Transcription Factor 3 Pseudogene 13 (BTF3P13, rs144198753); Glucokinase Regulator (GCKR, rs1260326); Solute Carrier Family 39 Member 8 (SLC39A8, rs13107325); Dopamine Receptor D2 (DRD2, rs11214609)) significantly associated with alcohol consumption[25].…”

Section: Methodsmentioning

confidence: 99%

“…However, the use of this single SNP may not adequately explain genetic variance in alcohol consumption because of the low minor allele frequency (2.2%) of rs1229984 in the UK Biobank[26]. In order to overcome the potential for weak instrument bias, we generated an allele score utilizing three SNPs: rs1229984 (ADH1B), rs1260326 (GCKR), and rs13107325 (SLC39A8), based on the results of the previous GWAS[25]. These three SNPs were directly genotyped on both the UK BiLEVE and UKB Axiom Arrays and the missingness of these SNPs in participants selected in this study less than 1%.…”

Section: Methodsmentioning

confidence: 99%

“…These three SNPs were directly genotyped on both the UK BiLEVE and UKB Axiom Arrays and the missingness of these SNPs in participants selected in this study less than 1%. Three additional SNPs (rs13130794 (KLB), rs144198753 (BTF3P13), and rs11214609 (DRD2) were identified in a previous GWAS[25] and were excluded here because they were not directly genotyped (805,426 markers) on the UK Biobank arrays. Detailed information about the three selected SNPs included in this study is shown in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

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Alcohol Consumption is Associated with Poor Prognosis in Obese Patients with COVID-19: a Mendelian Randomization Study using UK Biobank

Fan

Liu

Poulsen

et al. 2020

Preprint

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BackgroundAcute and chronic alcohol abuse have adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19.MethodWe conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated weighted and unweighted allele scores using three genetic variants (rs1229984, rs1260326, and rs13107325) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participates with and without obesity.ResultsOf the 12,937 participants, 4,496 were never or infrequent drinkers and 8,441 were frequent drinkers. (including 1,156 light drinkers, 3,795 moderate drinkers, and 3,490 heavy drinkers). Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with (OR=0.963, 95%CI 0.800-1.159; q =1.000) or without obesity (OR=0.891, 95%CI 0.755-1.053; q =.319). However, frequent drinking (HR=1.565, 95%CI 1.012-2.419; q =.079), especially heavy drinking (HR=2.071, 95%CI 1.235-3.472; q =.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (HR=1.480, 95%CI 1.059-2.069; q =.099).ConclusionsOur findings suggested alcohol consumption may had adverse effects on the progression of COVID-19 in white participants with obesity, but was not associate with susceptibility to SARS-CoV-2 infection.

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Functional validity, role, and implications of heavy alcohol consumption genetic loci

Cited by 56 publications

References 78 publications

Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Genetically determined tobacco and alcohol use and risk of atrial fibrillation

Alcohol Consumption is Associated with Poor Prognosis in Obese Patients with COVID-19: a Mendelian Randomization Study using UK Biobank

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