Common and ethnic-specific genetic determinants of hemoglobin concentration between Taiwanese Han Chinese and European Whites: findings from comparative two-stage genome-wide association studies.

Human iron nutrition is a result of interplays between genetic and environmental factors. However, there has been scarcity of data on the genetic variants associated with altered iron homeostasis and ethnic-specific associations are further lacking. In this study, we compared between the Taiwanese Han Chinese (HC) and European Whites the genetic determinants of hemoglobin (Hb) concentration, a biochemical parameter that in part reflects the amount of functional iron in the body. Through sex-specific two-stage genome-wide association studies (2S-GWAS), we observed the consistent Hb-association of SNPs in TMPRSS6 (chr 22), ABO (chr 9), and PRKCE (chr 2) across sexes in both ethnic groups. Specific to the Taiwanese HC, the Hb-association of AXIN1, together with other loci near the chr 16 alpha-globin gene cluster, was found novel. On the other hand, majority of the Hb-associated SNPs among Europeans were identified along the chr 6 major histocompatibility complex (MHC) region, which has established roles in immune system control. We report here strong Hb-associations of HFE and members of gene families (SLC17; H2A, H2B, H3, H4, H1; TRIM; ZSCAN, ZKSCAN, ZNF; HLA; BTN, OR), numerous SNPs in/nearby CARMIL1, PRRC2A, PSORS1C1, NOTCH4, TSBP1, C6orf15, and distinct associations with non-coding RNA genes. Our findings provide evidence for both common and ethnic-specific genetic determinants of Hb between East Asians and Caucasians. These will help to further our understanding of the iron and/or erythropoiesis physiology in humans and to identify high risk subgroups for iron imbalances - a primary requirement to meet the goal of precision nutrition for optimal health.

Pharmacometabolomic study of drug response to antihypertensive medications for hypertension marker identification in Han Chinese individuals in Taiwan.

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.

Positive or U-Shaped Association of Elevated Hemoglobin Concentration Levels with Metabolic Syndrome and Metabolic Components: Findings from Taiwan Biobank and UK Biobank.

Iron overnutrition has been implicated with a higher risk of developing metabolic and cardiovascular diseases, including metabolic syndrome (MetS), whereas iron deficiency anemia exacerbates many underlying chronic conditions. Hemoglobin (Hb) concentration in the blood, which reflects a major functional iron (i.e., heme iron) in the body, may serve as a surrogate of the nutritional status of iron. We conducted sex-specific observational association studies in which we carefully titrated the association between Hb deciles and MetS and its components among the Taiwanese Han Chinese (HC) from the Taiwan Biobank and Europeans of White ancestry from the UK Biobank, representing two large ethnicities. Our data show that at higher-than-normal levels of Hb, increasing deciles of Hb concentration were significantly associated with MetS across all sex subgroups in both ethnicities, with the highest deciles resulting in up to three times greater risk than the reference group [Taiwanese HC: OR = 3.17 (95% CI, 2.75-3.67) for Hb ≥ 16.5 g/dL in men, OR = 3.11 (2.78-3.47) for Hb ≥ 14.5 g/dL in women; European Whites: OR = 1.89 (1.80-1.98) for Hb ≥ 16.24 g/dL in men, OR = 2.35 (2.24-2.47) for Hb ≥ 14.68 g/dL in women]. The association between stronger risks and increasing Hb deciles was similarly observed with all metabolic components except diabetes. Here we found that both the highest Hb decile groups and contrarily the lowest ones, with respect to the reference, were associated with higher odds of diabetes in both ethnic groups [e.g., Taiwanese HC men: OR = 1.64 (1.33-2.02) for Hb ≥ 16.5 g/dL, OR = 1.71 (1.39-2.10) for Hb ≤ 13.5 g/dL; European Whites women: OR = 1.39 (1.26-1.45) for Hb ≥ 14.68 g/dL, OR = 1.81 (1.63-2.01) for Hb ≤ 12.39 g/dL]. These findings confirm that elevated Hb concentrations, a potential indicator of iron overnutrition, may play a role in the pathophysiology of MetS and metabolic components.

Particulate matters, aldehydes, and polycyclic aromatic hydrocarbons produced from deep-frying emissions: comparisons of three cooking oils with distinct fatty acid profiles.

It is recognized that hazardous emissions produced from frying oils may be related to oil properties, particularly the fatty acid composition. However, investigations have been limited and partial. In this work, the emissions from deep-frying foods with three oils (palm, olive, and soybean oils) with distinct fatty acid profiles were comprehensively examined in a simulated kitchen, and the interrelationship among emitted substances, oil quality parameters, and fatty acids profiles was explored. Firstly, palm oil emitted the highest number concentration of total particle matters ((3895 ± 1796) × 103 #/cm3), mainly in the Aitken mode (20-100 nm). We observed a positive correlation between particle number concentration and levels of palmitic acid, a major saturated fatty acid (SAFA) (rs = 0.73, p < 0.05), and total polar compounds (TPC) (rs = 0.68, p < 0.05) in the fried oil, a degradation marker which was also positively correlated with that of black carbon (BC) (rs = 0.68, p < 0.05). Secondly, soybean oil emitted the highest level of gaseous aldehydes (3636 ± 607 µg/m3), including acrolein, propinoaldehyde, crotonaldehyde, hexanal, and trans-2-heptenal; the total aldehyde concentration were positively correlated with α-linolenic acid (ALA) percentage (rs = 0.78, p < 0.01), while hexanal and trans-2-heptenal were with linoleic acid (LA) (rs = 0.73 and 0.67, p < 0.05). LA and ALA were two major polyunsaturated fatty acids in non-tropical plant oils. Thirdly, palm oil emitted the most particle-bound polycyclic aromatic hydrocarbons (PAHs), and a positive association was discovered between two PAHs and SAFA percentage. Olive oil seems superior to soybean and palm oils with regards to toxic emissions during deep-frying.

Identification of Serum Oxylipins Associated with the Development of Coronary Artery Disease: A Nested Case-Control Study.

Coronary artery disease (CAD) is among the leading causes of death globally. The American Heart Association recommends that people should consume more PUFA-rich plant foods to replace SFA-rich ones to lower serum cholesterol and prevent CAD. However, PUFA may be susceptible to oxidation and generate oxidized products such as oxylipins. In this study, we investigated whether the blood oxylipin profile is associated with the risk of developing CAD and whether including identified oxylipins may improve the predictability of CAD risk. We designed a nested case-control study with 77 cases and 148 matched controls from a 10-year follow-up of the Nutrition and Health Survey in a Taiwanese cohort of 720 people aged 50 to 70. A panel of 46 oxylipins was measured for baseline serum samples. We discovered four oxylipins associated with CAD risk. 13-oxo-ODE, which has been previously found in formed plagues, was positively associated with CAD (OR = 5.02, 95%CI = 0.85 to 15.6). PGE2/PGD2, previously shown to increase cardiac output, was inversely associated (OR = 0.16, 95%CI = 0.06 to 0.42). 15-deoxy-PGJ2, with anti-inflammatory and anti-apoptosis effects on cardiomyocytes (OR = 0.26, 95%CI = 0.09 to 0.76), and 5-HETE, which was associated with inflammation (OR = 0.28, 95%CI = 0.10 to 0.78), were also negatively associated as protective factors. Adding these four oxylipins to the traditional risk prediction model significantly improved CAD prediction.

The causal role of elevated uric acid and waist circumference on the risk of metabolic syndrome components.

BACKGROUND/OBJECTIVES: Hyperuricemia has been found to cluster with multiple components of metabolic syndrome (MetS). It is unclear whether hyperuricemia is a downstream result of MetS or may play an upstream role in MetS development. Using the Mendelian randomization (MR) method, we examined the causal relationship between elevated uric acid and the various components of MetS with waist circumference as a positive control. SUBJECTS/METHODS: Data from 10k participants of Taiwan Biobank was used to carry out MR analysis with uric acid risk score (wGRS) and waist circumference wGRS as instrumental variables and components of MetS as the outcomes. RESULTS: We found that genetically increased serum uric acid corresponds to a significant increment of triglyceride (ß = 0.065, p < 0.0001), systolic blood pressure (ß = 1.047, p = 0.0005), diastolic blood pressure (ß = 0.857, p < 0.0001), and mean arterial pressure (ß = 0.920, p < 0.0001), but a significant reduction of high-density lipoprotein cholesterol (ß = -0.020, p = 0.0014). Uric acid wGRS was not associated with fasting serum glucose, HbA1C, waist circumference, or BMI. On the other hand, waist circumference was causally associated with all the components of MetS including uric acid. CONCLUSIONS: Our MR investigation shows that uric acid increment may augment the risk of MetS through increasing blood pressure and triglyceride levels and lowering HDL-C value but not through accumulating fat or hyperglycemia. High waist circumference may be a causal agent for all the components of MetS including hyperuricemia.

Genome-wide association study of morbid obesity in Han Chinese.

BACKGROUND: As obesity is becoming pandemic, morbid obesity (MO), an extreme type of obesity, is an emerging issue worldwide. It is imperative to understand the factors responsible for huge weight gain in certain populations in the modern society. Very few genome-wide association studies (GWAS) have been conducted on MO patients. This study is the first MO-GWAS study in the Han-Chinese population in Asia. METHODS: We conducted a two-stage GWAS with 1110 MO bariatric patients (body mass index [BMI] ≥ 35 kg/m2) from Min-Sheng General Hospital, Taiwan. The first stage involved 575 patients, and 1729 sex- and age-matched controls from the Taiwan Han Chinese Cell and Genome Bank. In the second stage, another 535 patients from the same hospital were genotyped for 52 single nucleotide polymorphisms (SNPs) discovered in the first stage, and 9145 matched controls from Taiwan Biobank were matched for confirmation analysis. RESULTS: The results of the joint analysis for the second stage revealed six top ranking SNPs, including rs8050136 (p-value = 7.80 × 10- 10), rs9939609 (p-value = 1.32 × 10- 9), rs1421085 (p-value = 1.54 × 10- 8), rs9941349 (p-value = 9.05 × 10- 8), rs1121980 (p-value = 7.27 × 10- 7), and rs9937354 (p-value = 6.65 × 10- 7), which were all located in FTO gene. Significant associations were also observed between MO and RBFOX1, RP11-638 L3.1, TMTC1, CBLN4, CSMD3, and ERBB4, respectively, using the Bonferroni correction criteria for 52 SNPs (p < 9.6 × 10- 4). CONCLUSION: The most significantly associated locus of MO in the Han-Chinese population was the well-known FTO gene. These SNPs located in intron 1, may include the leptin receptor modulator. Other significant loci, showing weak associations with MO, also suggested the potential mechanism underlying the disorders with eating behaviors or brain/neural development.

Is Hyperuricemia, an Early-Onset Metabolic Disorder, Causally Associated with Cardiovascular Disease Events in Han Chinese?

BACKGROUND: Serum uric acid (SUA) has gradually been recognized as a potential risk factor for cardiovascular disease (CVD). However, whether the relationship is causal remains controversial. METHODS: We employed two methods to demonstrate the importance of SUA in CVD development. First, we examined the onset sequence of hyperuricemia in relation to five cardiometabolic (CM) diseases. Second, we conducted a Mendelian randomization (MR) study to causally infer the relationship between SUA and CVD. The information collected from the Cardiovascular Disease Risk Factors Two-Township Study (CVDFACTS) and Taiwan Biobank was used, respectively. RESULTS: The onset sequence study showed that hyperuricemia and hypo-alpha-lipoproteinemia (low HDL-C) have earlier ages of onset than other CM diseases. For the MR analysis, the high weighted genetic risk score (WGRS) group had a significantly increased cumulative lifetime risk of CVD compared with the low WGRS group (OR = 1.62, (1.17-2.23), P = 0.003). Sensitivity analysis using the WGRS derived from other populations' SUA-influential SNPs revealed similar results. CONCLUSIONS: We showed that hyperuricemia is an earlier-onset metabolic disorder than hypertension, hypertriglyceridemia, and diabetes mellitus, indicating that high SUA plays an upstream role in CM development. Moreover, our MR study results support the idea that hyperuricemia may play a causal role in CVD development. Further validation studies in more populations are needed.

A Two-Stage Whole-Genome Gene Expression Association Study of Young-Onset Hypertension in Han Chinese Population of Taiwan.

Hypertension is an important public health problem in the world. Since the intermediate position of the gene expression between genotype and phenotype makes it suitable to link genotype to phenotype, we carried out a two-stage whole-genome gene expression association study to find differentially expressed genes and pathways for hypertension. In the first stage, 126 cases and 149 controls were used to find out the differentially expressed genes. In the second stage, an independent set of samples (127 cases and 150 controls) was used to validate the results. Additionally, we conducted a gene set enrichment analysis (GSEA) to search for differentially affected pathways. A total of nine genes were implicated in the first stage (Bonferroni-corrected p-value < 0.05). Among these genes, ZRANB1, FAM110A, PREP, ANKRD9 and LAMB2 were also differentially expressed in an existing database of hypertensive mouse model (GSE19817). A total of 16 pathways were identified by the GSEA. ZRANB1 and six pathways identified are related to TNF-α. Three pathways are related to interleukin, one to metabolic syndrome, and one to Hedgehog signaling. Identification of these genes and pathways suggest the importance of 1. inflammation, 2. visceral fat metabolism, and 3. adipocytes and osteocytes homeostasis in hypertension mechanisms and complications.

Association of circadian genes with diurnal blood pressure changes and non-dipper essential hypertension: a genetic association with young-onset hypertension.

Recent studies have suggested that circadian genes have important roles in maintaining the circadian rhythm of the cardiovascular system. However, the associations between diurnal BP changes and circadian genes remain undetermined. We conducted a genetic association study of young-onset hypertension, in which 24-h ambulatory blood pressure (BP) monitoring was performed. A total of 23 tag single-nucleotide polymorphisms (SNPs) on 11 genes involved in circadian rhythms were genotyped for correlations with diurnal BP variation phenotypes. A permutation test was used to correct for multiple testing. Five tag SNPs within five loci, including rs3888170 in NPAS2, rs6431590 in PER2, rs1410225 in RORßß, rs3816358 in BMAL1 and rs10519096 in RORα, were significantly associated with the non-dipper phenotype in 372 young hypertensive patients. A genetic risk score was generated by counting the risk alleles and effects for each individual. Genotyping was performed in an additional independent set of 619 young-onset hypertensive subjects. Altogether, non-dippers had a higher weighted genetic risk score than dippers (1.67±0.56 vs. 1.54±0.55, P<0.001), and the additive genetic risk score also indicated a graded association with decreased diurnal BP changes (P=0.006), as well as a non-dipper phenotype (P=0.031). After multivariable logistic analysis, only the circadian genetic risk score (odds ratio (OR), 1550; 95% confidence interval (CI), 1.225-1.961, P<0.001) and the use of ß-blockers (OR, 1.519; 95% CI, 1.164-1.982, P=0.003) were independently associated with the presence of non-dippers among subjects with young-onset hypertension. Genetic variants in circadian genes were associated with the diurnal phenotype of hypertension, suggesting a genetic association with diurnal BP changes in essential hypertension.

A three-stage genome-wide association study combining multilocus test and gene expression analysis for young-onset hypertension in Taiwan Han Chinese.

BACKGROUND: Although many large-scale genome-wide association studies (GWASs) have been performed, only a few studies have successfully identified replicable, large-impact hypertension loci; even fewer studies have been done on Chinese subjects. Young-onset hypertension (YOH) is considered to be a more promising target disorder to investigate than late-onset hypertension because of its stronger genetic component. METHODS: To map YOH genetic variants, we performed a 3-stage study combining 1st-stage multilocus GWASs, 2nd-stage gene expression analysis, and 3rd-stage multilocus confirmatory study. RESULTS: In the 1st stage, Illumina550K data from 400 case-control pairs were used, and 22 genes flanked by 14 single nucleotide polymorphism (SNP) septets (P values adjusted for false discovery rate (pFDR) < 3.16×10(-7)) were identified. In the 2nd stage, differential gene expression analysis was carried out for these genes, and 5 genes were selected (pFDR < 0.05). In the 3rd stage, we re-examined the finding with an independent set of 592 case-control pairs and with the joint samples (n = 992 case-control pairs). A total of 6 SNP septets flanking C1orf135, GSN, LARS, and ACTN4 remained significant in all 3 stages. Among them, the same septet flanking ACTN4 was also associated with blood pressure traits in the Hong Kong Hypertension Study (HKHS) and in the Wellcome Trust Case-Control Consortium Hypertension Study (WTCCCHS). LARS was detected in the HKHS, but not in the WTCCCHS. GSN may be specific to Taiwanese individuals because it was not found by either the HKHS or the WTCCCHS. CONCLUSIONS: Our study identified 4 previously unknown YOH loci in Han Chinese. Identification of these genes enriches the hypertension susceptibility gene list, thereby shedding light on the etiology of hypertension in Han Chinese.

Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study.

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.

Genome-wide association study of young-onset hypertension in the Han Chinese population of Taiwan.

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (-log(10)(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (-log(10)(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population.

Fluoride concentrations in three types of commercially packed tea drinks in Taiwan.

Tea is a popular drink around the world. It is also one of the major sources of fluoride intake. The objectives of this study were to assess fluoride concentrations in popular non-, semi-, and full-fermented tea drinks sold on the Taiwan market. Concentration differences among three types of commercially available tea drinks (tea leaf, tea bag, and packaged tea beverage) were explored. Several influential factors in intake concentrations were evaluated. The acute threshold intake (ATI) and allowable daily intake (ADI) of those tea drinks were also estimated. For each commercial type, samples from the most popular tea in one particular fermentation degree (non, semi, and full) were randomly purchased and analyzed for fluoride concentrations. Fluoride levels in different rounds of tea, in different containers, and with different ratios of water and tea leaf were also assessed. In total, 132 tea samples were analyzed. The mean fluoride concentrations in leaf tea without the first round, leaf tea with the first round, bagged tea, and packaged tea were 7.04, 7.79, 5.37, and 25.7 mg/l, respectively. Most of the intake concentrations in those samples exceeded 4 mg/l F, the lower bound of fluoride levels reported in the literatures to be associated with a lower IQ in children and a higher risk of bone fracture. Fluoride concentrations in packaged tea were the highest among the three types of commercially available tea. For studied leaf and bagged tea, almost a constant amount of fluoride was infused from the same amount of tea leaf regardless of the water volume. Besides this, making tea with glass or pottery tea makers would not affect fluoride intake concentrations. Acute intoxication is unlikely to occur. However, tea lovers in high fluoride content areas shall consider limit their consumption of tea drinks to avoid potential chronic effects.