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ORIGINAL ARTICLE
Year : 2022 | Volume
: 40
| Issue : 2 | Page : 108-113
Alcohol consumption, aldehyde dehydrogenase 2 gene rs671 polymorphism, and psoriasis in Taiwan
Ya-Ching Chang1, Lung-An Hsu2, Yu-Huei Huang1
1 Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
2 Division of Cardiovascular, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
Correspondence Address:
Dr. Ya-Ching Chang
Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ds.ds_21_22
Background: Although alcohol use has been determined as a predisposing factor for psoriasis, research findings have been inconsistent. Objectives: This study investigated whether alcohol intake is causally linked to psoriasis. Methods: The presence of rs671 polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene was investigated in 258 psoriasis patients and 605 healthy controls. The rs671 was employed as an instrumental variable for predicting alcohol use. Mendelian randomization (MR) was utilized to assess the causality between genetically determined alcohol consumption and psoriasis using the two-stage least-square (2SLS) approach. A replication study of MR analysis with inverse-variance weighting (IVW), MR-Egger regression, and weighted median methods was performed using openly accessible alcohol consumption and psoriasis summary statistics from the UK Biobank. Results: Between psoriasis and controls, there were no significant differences in genotype and allele frequencies for the ALDH2 rs671 polymorphism. The G allele of the rs671 was positively linked with alcohol intake. The ALDH2 rs671 genetically determined alcohol intake was not linked to the risk of psoriasis in the 2SLS analysis (β = −0.011, P = 0.960). The MR replication study also found no evidence of genetic propensity to greater alcohol consumption increasing the risk of psoriasis (β = −0.00065, P = 0.6002 in IVW; β = −0.00099, P = 0.6851 in MR-Egger; and β = −0.00181, P = 0.3558 in weighted median analysis). Conclusion: ALDH2 rs671 may not have a role in psoriasis susceptibility in Taiwanese. The MR analysis found no causality between alcohol consumption and psoriasis.
Keywords: Alcohol consumption, aldehyde dehydrogenase 2, Mendelian randomization, polymorphisms, psoriasis
Psoriasis is a chronic inflammatory illness that attacks skin, joints, or both. It is a genetic, immune-mediated disease.[1] Although the cause of psoriasis is unknown, interactions between genetic susceptibility variants, immune network, and environmental factors play a part in the progression of chronic inflammatory processes.[1] Many environmental factors have been proposed to cause psoriasis, including stress, skin damage, bacterial infection, some medicines, smoking, obesity, Western diet, and alcohol intake, but their involvement remains unclear.[2] Among these factors, alcohol use has been considered a predisposing factor for psoriasis, despite conflicting data on its impact on the disease's progression.[3] Alcohol use was linked to the risk of psoriasis in a meta-analysis, implying that alcohol intake had a negative impact on the occurrence of psoriasis.[4] Nonetheless, observational investigations are powerless against predisposition, including residual confounding and reverse causation, preventing an unmistakable comprehension of the effect of alcohol use on psoriasis.
Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme that converts acetaldehyde (a harmful transitional of ethanol digestion) to acetic acid in the mitochondria.[5] About 40% of East Asians have a dysfunctional variant known as the ALDH2 rs671 G > A (Glu487 Lys) polymorphism, which has been demonstrated to significantly impair ALDH2 enzyme activity.[5] The ALDH2 rs671 polymorphism has been linked to an elevated risk of upper aerodigestive tract malignancies in Asians who drink alcohol.[6] Previous investigations have also linked the ALDH2 rs671 polymorphism to cardiovascular diseases.[7],[8] Despite this, not much is understood about the role of rs671 in psoriasis susceptibility.
Mendelian randomization (MR) is an approach that uses genetic variation as an instrumental variable (IV) to determine if the observed association between exposures and outcomes is due to causality.[9] People with the A allele of rs671 suffer from acetaldehyde-induced facial flushing, nausea, and headache when they consume alcohol, preventing them from drinking heavily.[10] Hence, the ALDH2 rs671 has been considered a good IV for predicting alcohol consumption.[11] Until now, no previous investigations have utilized the MR method to address the causality between alcohol consumption and psoriasis hazard. Thus, the goal of this study was to see if the ALDH2 rs671 is linked to the risk of psoriasis in Taiwanese people and if alcohol consumption is causally connected with psoriasis utilizing the ALDH2 rs671 genetic instrument in MR analysis.
MethodsStudy population
The study involved a total of 258 psoriasis patients and 605 control participants. Clinical and/or histological features were used to diagnose psoriasis. Controls were recruited during routine health checkups with no previous history or clinical evidence of psoriasis. Controls and patients were surveyed about age, alcohol consumption, smoking history, hypertension, and diabetes using questionnaires and medical chart records, respectively. Alcohol consumption was defined as those who consumed alcohol ≥2 days per week. Previous and infrequent alcohol consumers were incorporated as nondrinkers. Smoking was defined as those who regularly smoked cigarettes at the time of the survey. Hypertension was defined as a systolic blood pressure (BP) of ≥140 mmHg and/or a diastolic BP of ≥90 mmHg or a self-reported history of hypertension. Diabetes mellitus was defined as a fasting plasma glucose level ≥126 mg/dL, a glycohemoglobin value ≥6.5%, or a self-reported history of diabetes. The study was approved by the hospital ethics committee (Chang Gung Medical Foundation Institutional Review Board 104-3412C) and followed the principles of the Declaration of Helsinki. All subjects gave written informed consent.
Genotyping of aldehyde dehydrogenase 2 rs671 polymorphism
Genomic DNA was extracted from the peripheral blood leukocytes using QIAamp DNA Blood Mini Kits (Qiagen, Santa Clarita, CA, USA). The ALDH2 gene rs671 polymorphism genotyping was conducted using TaqMan SNP Genotyping Assays from Applied BioSystems (ABI, Foster City, CA, USA).
Statistical analyses
Clinical characteristics of continuous variables are presented as mean ± standard deviation and tested using two-sample t-test or one-way ANOVA. The Chi-square test was used to examine the differences in categorical variables and to compare the genotype and allelic frequencies. The independent association of studied genotypes on the risk of psoriasis was evaluated using binary logistic regression analysis, controlled for age, sex, smoking, alcohol intake, hypertension, diabetes, and body mass index (BMI).
Mendelian randomization approaches
We conducted an MR analysis by using two-stage least-square (2SLS) method to examine whether the rs671 variant was associated with psoriasis susceptibility through its association with alcohol consumption. In the first step, hereditarily anticipated alcohol consumption was determined for the ALDH2 rs671 genotypes. After controlling for age, gender, smoking, BMI, hypertension, and diabetes, the risk of psoriasis was predicted from genetically predicted alcohol use in the subsequent stage. The replication MR studies utilized the database and analytical platform MR-Base[9] (http://www.mrbase.org/; App version: 1.2.2 3a435d), which contained statistical summaries from numbers of genome-wide association studies (GWASs). When summary statistics on the exposure and outcome were acquired from independent GWASs, two-sample MR was used to search causal effects. Three different estimate methods were used: inverse-variance weighting (IVW), MR-Egger regression, and weighted median.[9] As the exposure, we used openly accessible summary statistics databanks from GWASs for alcohol intake frequency from the 336,965 people in the UK Biobank (UKB-a: 25).[12] The frequency of alcohol drinking was classified as “weekly consumption” or “nonfrequent or infrequent.”[12] Based on linkage disequilibrium, R2 of 0.001, clumping distance of 10,000 kb, and P value threshold of 5.00 × 10–8 (genome-wide significance), single nucleotide polymorphisms (SNPs) associated with exposure were selected as exposure instruments to improve inference. The outcome was a self-reported diagnosis of psoriasis. As the outcome, we used summary statistics from a psoriasis GWAS in the UK Biobank (UKB-b: 10537), which included 5314 psoriasis patients and 457,619 European descent controls.[13]
ResultsAldehyde dehydrogenase 2 rs671 and psoriasis
The study included 258 psoriasis patients and 605 controls. The characteristics of the cases and controls are listed in [Table 1]. Psoriasis patients had significantly greater rates of males, diabetes mellitus, and smoking than control subjects. Psoriasis patients' average BMI was likewise significantly greater than that of control persons. [Table 2] shows the genotype and allele frequencies of patients and control participants. In either the cases or the controls, there was no substantial divergence from Hardy–Weinberg equilibrium for the ALDH2 rs671 polymorphism. Between patients and controls, there were no significant differences in genotype or allele frequencies for the ALDH2 rs671 [Table 2]. In multivariate logistic regression analysis, neither the rs671 A allele carriers (odds ratio [OR] = 0.95, 95% confidence interval [CI] [0.65–1.41], P = 0.806) nor alcohol consumption (OR = 0.83, 95% CI [0.49–1.41], P = 0.493) was associated with the risk of psoriasis.
Table 2: Genotype and allele frequencies of the aldehyde dehydrogenase 2 rs671 in the study populationMendelian randomization study
[Table 3] shows the study population's baseline characteristics based on ALDH2 rs671 genotypes. In terms of gender, age, smoking, hypertension, diabetes, and BMI, there were no significant differences between the ALDH2 rs671 genotypes. Individuals with the ALDH2 rs671 A allele have significantly reduced alcohol consumption frequencies in a dose-dependent manner [Table 3], consistent with earlier results.[11] GG genotype had the highest frequencies of alcohol consumption [Table 2]. The F-statistic for rs671 associated with alcohol consumption was 23.6, showing that rs671 is a valid drinking instrument (≥10). The R2 for rs671 on alcohol consumption was 0.027. In the 2SLS IV analysis for the causality of the alcohol intake and psoriasis, no significant association was noted between the ALDH2 rs671 genetically predicted alcohol consumption and psoriasis [β = −0.011, standard error [SE] = 0.219, P = 0.960, [Table 4]]. Our results indicated no causal effect between alcohol use and psoriasis in the Taiwanese.
Table 3: Baseline characteristics of study population according aldehyde dehydrogenase 2 rs671 genotypes
Table 4: Instrumental aldehyde dehydrogenase 2 rs671 two-stage least square analysis with alcohol consumption and psoriasisReplication Mendelian randomization study
To verify our findings, we performed a replication MR study using MR-Base platform. From the GWASs on alcohol intake frequency, we selected 43 independent SNPs as IVs. They were all significantly linked to the frequency of alcohol consumption at the genome-wide level [Supplemental Table 1]. The genetic variants accounted for 0.78% of the variance (R2) in alcohol intake frequency. The two-sample MR analysis indicated no evidence of a genetic predilection for higher alcohol intake frequency increasing the susceptibility of psoriasis (β = −0.00065, SE = 0.001234, P = 0.6002 in IVW; β = −0.00099, SE = 0.002438, P = 0.6851 in MR-Egger; and β = −0.00181, SE = 0.001963, P = 0.3558 in weighted median analysis) [Table 5] and [Figure 1], [Figure 2]. No directional pleiotropic effects were identified according to the MR-Egger regression analysis (intercept = 1.28 × 10 − 5, P = 0.868). Cochran's Q-test did not reveal significant heterogeneity [Table 5]. Again, the replication MR analysis found no causality between alcohol consumption and psoriasis.
Table 5: Mendelian randomization estimates from each method to access the causal effect of alcohol intake frequency on psoriasis risk
Figure 1: Forest plot of causality of single nucleotide polymorphisms associated with frequency of alcohol intake on psoriasis.
Figure 2: Scatter plot of genetic associations with frequency of alcohol intake versus genetic associations with psoriasis. Each method's causal association is shown by the slopes of each line. The inverse-variance weighted estimate is shown in blue, the weighted median estimate is shown in green, and the Mendelian randomization-Egger estimate is shown in dark blue. SNP: Single nucleotide polymorphism, MR: Mendelian randomization. Discussion In this investigation, we found no evidence that the SNP rs671 in the ALDH2 gene is associated with the risk of psoriasis among Taiwanese people. Using the 2SLS method and the ALDH2 rs971 genetic instrument, an MR investigation indicated that genetically determined alcohol consumption was not linked with psoriasis. A two-sample MR analysis using publicly accessible summary statistics from GWASs of alcohol intake frequency and psoriasis confirms this finding.
Previous investigations have shown a predisposing effect of alcohol consumption on psoriasis. In one prospective cohort study, US women who drank five nonlight beers weekly had a 1.8 times higher incidence of psoriasis than women who did not consume alcohol.[14] In the same cohort, unrestricted alcohol consumption (>30 g/day) was linked to an elevated hazard of incident psoriatic arthritis (hazard ratio 4.45).[15] In addition, a meta-analysis of 15 case–control studies demonstrated a significant association between alcohol consumption and the susceptibility of psoriasis in participants who did and did not drink (OR 1.531, 95% CI 1.164–2.014).[4] Alcohol is thought to cause immunological malfunction, which leads to immunosuppression, making the body less capable of responding effectively to an attack by pathogens or other problems.[16] Moreover, drinkers have been found to be more susceptible to superficial infections such as those resulting from trauma and Streptococcus, which has been linked to the occurrence of psoriasis.[17] Furthermore, alcohol increases the synthesis of inflammatory cytokines and cell cycle activators, which may cause epidermal hyperproliferation.[18]
Previous GWAS research found that the genetic factors that influence alcohol consumption differ by race/ethnicity.[19] Alcohol dehydrogenase 1B (ADH1B) rs1229984 was the strongest association SNP in non-Hispanic white participants, while ALDH2 rs671 was the strongest association SNP in East Asians.[19] In a recent study, the prevalence of the ADH1B rs1229984 allele, which predisposes to alcohol use, was found to be higher in the Hungarian psoriasis population.[20] The limitation of their research is the lack of information on alcohol consumption and additional MR analysis. Therefore, it is difficult to determine whether the detected association is mainly due to influencing an individual's alcohol consumption or involving in the pathogenesis of psoriasis by the pleotropic effect of ADH1B rs1229984. Moreover, their findings were not replicated in Sweden[21] and UK cohorts [Supplemental Table 1]. In Asian population, ALDH2 rs671 has been documented as a good IV for alcohol consumption.[11] By contrast, the prevalence of the ALDH2 rs671 G allele, which predisposes to alcohol intake, was not shown to be higher in the Taiwanese psoriasis population. Since ALDH2 rs671 is rare or absent in other ethnicities,[19] we performed a replication study of MR analysis using openly accessible summary statistics from GWASs of the European population. In the replication study, the MR estimates using three different approaches were steady and found no causality between alcohol consumption and psoriasis susceptibility. Selected genetic variants were independently and strongly linked to alcohol intake at genome-wide significance. Cochran's Q-test found no substantial variability between IV estimations, implying that MR estimates are reliable. Similar to our findings, a nationwide population-based cohort study in Taiwan that investigated the impact of alcohol consumption on incident psoriasis revealed no significant link between alcohol use and the incidence of psoriasis.[22] Taken together, previously observed links between alcohol use and the development of psoriasis could be due to bias or confounding factors such as selection bias, the medicines used, few studies with tiny sample sizes, and reverse causation. For example, it is possible that patients increase alcohol ingestion to relieve skin itching or emotional distress.
The current study has a few limitations. First, because our Taiwanese population has a small sample size and we did not employ weighted multi-SNP genetic risk scores as IVs, we may have had low power to detect a connection. Because our patients are almost all plaque vulgaris and only about a third are female, extending our findings to other psoriasis subtypes and females should be done with caution. Second, alcohol consumption was only categorized based on the frequency of consumption (binary phenotype) rather than the average number of alcoholic drinks drank each week (quantitative phenotype). However, we further selected three independent SNPs from alcohol intake quantity GWAS in the UK Biobank as the IVs, and the results remained unchanged (data not shown). Third, genetic variants may just clarify a little extent of variance in alcohol consumption. Fourth, ascertainment and classification of psoriasis may have been coded incorrectly as the psoriasis cases were self-reported in the GWAS from UK Biobank. Finally, because the replication MR study relied on publicly accessible summary statistics, we were unable to adjust for additional confounders such as age, gender, or smoking, as well as relationships between the genetic instruments and phenotypes other than alcohol intake.
ConclusionsOur investigation suggests that the ALDH2 rs671 polymorphism may not have a role in psoriasis susceptibility in Taiwanese. Epidemiological observation for a direct association between alcohol consumption and a higher risk of psoriasis did not appear to be causal.
Acknowledgment
This investigation was funded by Chang Gung Memorial Hospital (CMRPG 1C0032 and 1F0063).
Financial support and sponsorship
This investigation was funded by Chang Gung Memorial Hospital (CMRPG 1C0032 and 1F0063).
Conflicts of interest
There are no conflicts of interest.
Supplementary Materials
References
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