ABSTRACT
BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.
Subject(s)
Alcohol Drinking , East Asian People , Flushing , Humans , Male , Alcohol Dehydrogenase/genetics , Alcohol Drinking/genetics , Aldehyde Dehydrogenase, Mitochondrial/genetics , East Asian People/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Flushing/chemically inducedABSTRACT
BACKGROUND AND OBJECTIVES: Epidemiological studies have inconsistently shown an association between dioxin and risk of type 2 diabetes mellitus (T2DM) and cancer. This study aims to examine the effects of blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) on T2DM and thyroid cancer. METHODS: We conducted a nested case-control study within the Korean cancer prevention study-II (KCPS-II) consisting of 15 thyroid cancer cases, 30 T2DM cases, and 55 controls. A total of 500 samples were used in 100 pooling samples. An average value of a pooled sample was calculated weighted by the blood volume of each sample. RESULTS: The study population included 100 participants from the KCPS-II (median (IQR) baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05-1.43; thyroid cancer ORs = 1.34; 95% CI = 1.12-1.61). CONCLUSION: In this study, both T2DM and thyroid cancer were associated with the blood concentrations of PCDD/DFs. The association between PCDD/DFs and T2D was found among women but not among men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the association between dioxins concentrations and diseases.
Subject(s)
Benzofurans , Diabetes Mellitus, Type 2 , Dioxins , Polychlorinated Biphenyls , Polychlorinated Dibenzodioxins , Thyroid Neoplasms , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Male , Middle Aged , Polychlorinated Biphenyls/analysis , Thyroid Neoplasms/epidemiologyABSTRACT
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
