Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5x10 -8 ), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Multidrug resistance-associated protein 3 (MRP3, ABCC3) plays an important role in protecting hepatocytes and other tissues by excreting an array of toxic organic anion conjugates, including bile salts. MRP3/ABCC3 expression is increased in the liver of some cholestatic patients, but the molecular mechanism of this up-regulation remains elusive. In this report, we assessed liver MRP3/ABCC3 expression in patients (n=22) with obstructive cholestasis due to gallstones blockage of bile ducts and non-cholestatic patient controls (n=22). MRP3/ABCC3 mRNA and protein expression were significantly increased 3.4- and 4.6- fold, respectively in these cholestatic patients where elevated plasma TNFα (4.7-fold, P<0.01) and hepatic SP1 and LRH-1 expression (3.1- and 2.1-fold at mRNA level, 3.5- and 2.5-fold at protein level, respectively) were also observed. The induction of hepatic MRP3/ABCC3 mRNA expression is significantly positively correlated with the level of plasma TNFα in these patients. In HepG2 cells, TNFα treatment induced SP1 and MRP3/ABCC3 expression in a dose- and time-dependent manner, where increased phosphorylation of JNK/SAPK was also detected. These inductions were significantly reduced in the presence of the JNK inhibitor SP600125. TNFα treatment enhanced HepG2 cell nuclear extract binding activity to the MRP3/ABCC3 promoter, but was abolished by SP600125 as demonstrated by EMSA. An increase in nuclear protein binding activity to the MRP3/ABCC3 promoter consisting primarily of SP1 was also seen in liver samples from cholestatic patients as assessed by supershift EMSA assays. Conclusions Our findings indicate that up-regulation of hepatic MRP3/ABCC3 expression in human obstructive cholestasis is likely triggered by TNFα, mediated by activations of JNK/SAPK and SP1.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10 −6 ) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10 −8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. alcohol consumption; cholesterol; gene-environment interactions; gene-lifestyle interactions; genome-wide association studies; lipids; triglycerides Abbreviations: A1CF, APOBEC1 complementation factor gene; APOBEC1, apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1; APOBEC1, apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 gene; CHARGE, Cohorts for Heart and Aging Research in Genomic Epidemiology; DEPICT, Data-driven Expression Prioritized Integration for Complex Traits; df, degrees of freedom; FDR, false discovery rate; GWAS, genome-wide association study(ies); HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCSK5, proprotein convertase subtilisin/kexin type 5; PCSK5, proprotein convertase subtilisin/kexin type 5 gene; PCSK9, proprotein convertase subtilisin/kexin type 9 gene; TG, triglycerides; VEGF-B, vascular endothelial growth factor B; VEGFB, vascular endothelial growth factor B gene.

We found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte‐derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti‐fibrotic therapies (eg macrophage subset‐targeted treatments) to combat liver fibrosis in the future.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.