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 (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(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

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

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

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

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

Abstract 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

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