Efficient identification of trait-associated loss-of-function variants in the UK Biobank cohort by exome-sequencing based genotype imputation.

The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r2 is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10-3 , 0.01), 0.805 at (1.0 × 10-4 , 1.0 × 10-3 ), 0.664 at (1.0 × 10-5 , 1.0 × 10-4 ) and 0.410 at (0, 1.0 × 10-5 ). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.

Association of three SNPs in adiponectin gene with lipid traits of Tianzhu Black Muscovy (Cairina moschata).

Adiponectin plays a critically biological role in atherosclerosis, glucose utilization, lipid and carbohydrate metabolism, and triglyceride synthesis in animals and humans. However, little is known about the effect of adiponectin on lipid metabolism of the avian species. The aim of the preset study was to investigate the potential associations between adiponectin gene single nucleotide polymorphisms (SNPs) and the lipid traits in 348 females of Tianzhu Black Muscovy. Three novel SNPs (167G>A, 290T>C and 711G>A) were detected in adiponectin gene. 167G>A and 290T>C has linked very closely, and then 711G>A with 167G>A and 290T>C has no strong linkage disequilibrium, respectively. The Chi square test showed that allelic frequency and genotype frequency of two SNPs (167G>A and 711G>A) didn't agree with the Hardy-Weinberg equilibrium (P>0.05). Four haplotypes and nine diplotypes were formed on the three SNPs of adiponectin gene. Association analysis indicated that the 167G>A genotypes were strongly associated with intramuscular fat (IMF) of chest muscle and serum total cholesterol (TC) (P < 0.01); the 290T>C genotypes were strongly associated with IMF, TC, and serum triglyceride (TG) (P < 0.01); furthermore, the 711G>A genotypes were significantly associated with TG and TC (P < 0.05); the diplotypes were strongly associated with IMF, TC, and TG (P < 0.01). Therefore, three SNPs in adiponectin were potential markers for improving IMF in Muscovy ducks.

Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.

Association of the HNF1A polymorphisms and serum lipid traits, the risk of coronary artery disease and ischemic stroke.

BACKGROUND: Hepatocyte nuclear factor-1α gene (HNF1A) single nucleotide polymorphisms (SNPs) have been associated with serum lipid traits in several previous genome-wide association studies. However, little is known about such associations in the Chinese populations. The present study aimed to determine the association of the HNF1A rs1169288, rs2259820, rs2464196 and rs2650000 SNPs and serum lipid traits, the risk of coronary artery disease (CAD) and ischemic stroke (IS). METHODS: The genotypes of the four SNPs in 562 CAD and 521 IS patients, as well as 594 healthy controls, were detected using the Snapshot technology. RESULTS: The genotype and allele distribution of the four SNPs was not different between controls and CAD or IS patients (p > 0.05 for all). rs1169288, rs2259820 and rs2464196 SNPs were significantly associated with serum lipid levels in both controls and CAD patients (p < 0.004-0.009). rs2259820 and rs2464196 SNPs were significantly associated with a lower risk of CAD [odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44-0.91, p = 0.015 and OR =0.62, 95% CI = 0.43-0.89, p = 0.010, respectively]. Significant linkage disequilibrium was noted among the four SNPs (r2  > 0.5, D' > 0.8). The haplotype of rs1169288A-rs2259820C-rs2464196G-rs2650000A was associated with an increased risk of CAD (OR =1.95, 95% CI: 1.13-3.37, p = 0.015). Interactions of SNP-SNP (rs1169288-rs2464196-rs2650000) and haplotype-environment on the risk of CAD (A-C-G-A-smoking) or IS (A-C-G-A-sex and A-T-A-C-alcohol consumption) were also observed among these SNPs. CONCLUSIONS: These findings suggest that the HNF1A polymorphisms may be the genetic risk factors for CAD and IS.

Quantitative trait loci at the 11q23.3 chromosomal region related to dyslipidemia in the population of Andhra Pradesh, India.

BACKGROUND: Given the characteristic atherogenic dyslipidemia of south Indian population and crucial role of APOA1, APOC3, APOA4 and APOA5 genes clustered in 11q23.3 chromosomal region in regulating lipoprotein metabolism and cholesterol homeostasis, a large number of recently identified variants are to be explored for their role in regulating the serum lipid parameters among south Indians. METHODS: Using fluidigm SNP genotyping platform, a prioritized set of 96 SNPs of the 11q23.3 chromosomal region were genotyped on 516 individuals from Hyderabad, India, and its vicinity and aged >45 years. RESULTS: The linear regression analysis of the individual lipid traits viz., TC, LDLC, HDLC, VLDL and TG with each of the 78 SNPs that confirm to HWE and with minor allele frequency > 1%, suggests 23 of those to be significantly associated (p ≤ 0.05) with at least one of these quantitative traits. Most importantly, the variant rs632153 is involved in elevating TC, LDLC, TG and VLDLs and probably playing a crucial role in the manifestation of dyslipidemia. Additionally, another three SNPs rs633389, rs2187126 and rs1263163 are found risk conferring to dyslipidemia by elevating LDLC and TC levels in the present population. Further, the ROC (receiver operating curve) analysis for the risk scores and dyslipidemia status yielded a significant area under curve (AUC) = 0.675, suggesting high discriminative power of the risk variants towards the condition. The interaction analysis suggests rs10488699-rs2187126 pair of the BUD13 gene to confer significant risk (Interaction odds ratio = 14.38, P = 7.17 × 105) towards dyslipidemia by elevating the TC levels (ß = 37.13, p = 6.614 × 105). On the other hand, the interaction between variants of APOA1 gene and BUD13 and/or ZPR1 regulatory genes at this region are associated with elevated TG and VLDL. CONCLUSION: The variants at 11q23.3 chromosomal region seem to determine the quantitative lipid traits and in turn dyslipidemia in the population of Hyderabad. Particularly, the variants rs632153, rs633389, rs2187126 and rs1263163 might be risk conferring to dyslipidemia by elevating LDLC and TC levels, while the variants of APOC3 and APOA1 genes might be the genetic determinants of elevated triglycerides in the present population.

Functional and association studies of the cholesteryl ester transfer protein (CETP) gene in a Wannan Black pig model.

Some polymorphisms of the human CETP gene are causally and significantly associated with serum lipids levels; however, the information regarding this gene in pigs is sparse. To evaluate the effects of CETP on blood lipid traits and fat deposition in pig, porcine CETP tissue expression patterns were observed by quantitative real-time polymerase chain reaction (qPCR) first. High expression was detected in liver, spleen, gluteus medius (GM) muscle and backfat. A de novo polymorphism (AF333037:g.795C>T) in the intron 1 region of porcine CETP was identified. This polymorphism was further genotyped by direct sequencing of the PCR products of 390 Wannan Black pigs, a Chinese native breed population. Association analyses at 45 and 300 days of age revealed highly significant associations between CETP genotypes and serum lipid traits. Furthermore, this polymorphism was proved to be associated with differences in liver CETP mRNA levels: pigs at 300 days of age with the TT genotype had higher levels than did those with other genotypes (P = 0.021). Additionally, analysis at 300 days of age showed that GM CETP mRNA expression correlated positively with serum lipids levels as well as with carcass backfat thickness and intramuscular fat content in GM. These results indicate that CETP is involved in serum, adipose and muscle lipid metabolism in pigs. The mechanisms underlying such relationships and their functional implications are worthy of further research.

Genetic association with lipids in Filipinos: waist circumference modifies an APOA5 effect on triglyceride levels.

Blood levels of lipoprotein cholesterol and triglycerides (TGs) are highly heritable and are major risk factors for cardiovascular disease (CVD). Approximately 100 lipid-associated loci have been identified in populations of European ancestry. We performed a genome-wide association study of lipid traits in 1,782 Filipino women from the Cebu Longitudinal Health and Nutrition Survey, and tested for evidence of interactions with waist circumference. We conducted additional association and interaction analyses in 1,719 of their young adult offspring. Genome-wide significant associations (P < 5 × 10⁻8) were detected at APOE for low density lipoprotein cholesterol and total cholesterol, and at APOA5 for TGs. Suggestive associations (P < 10⁻6) were detected at GCKR for TGs, and at CETP and TOM1 for high density lipoprotein cholesterol. Our data also supported the existence of allelic heterogeneity at APOA5, CETP, LIPC, and APOE. The secondary signal (Gly185Cys) at APOA5 exhibited a single nucleotide polymorphism (SNP)-by-waist circumference interaction affecting TGs (Pinteraction = 1.6 × 10⁻4), manifested by stronger SNP effects as waist circumference increased. These findings provide the first evidence that central obesity may accentuate the effect of the TG-increasing allele of the APOA5 signal, emphasizing that CVD risk could be reduced by central obesity control.

Causal relationship between circulating lipid traits and periodontitis: univariable and multivariable Mendelian randomization.

Introduction: The correlation between dyslipidemia and periodontitis is revealed through epidemiological studies. However, the results are affected by several confounding factors. This study aims to elucidate the genetic causal association between circulating lipid traits and periodontitis by two-sample Mendelian randomization (MR) analysis. Methods: After the different screening processes, two cohorts of circulating lipid traits from the UK Biobank were used as exposure data, including five circulating lipid traits. The Periodontitis cohort was selected from the GeneLifestyle Interactions in Dental Endpoints (GLIDE) consortium as outcome data. In univariable MR, the inverse variance weighted (IVW) was used in conjunction with six additional analytical methods to assess causality. The Cochran Q test, IGX 2 statistic, MR-PRESSO, and MR-Egger intercept were used to quantify heterogeneity and pleiotropy. The multivariable MR-IVW (MVMR-IVW) and MVMR-robust were mainly used as analytical methods in the multiple MR analyses. Results: The IVW estimates showed that genetically predicted Apolipoprotein A1 (apo A1) [odds ratio (OR)=1.158, 95% confidence interval (CI)=1.007-1.331, P-value=0.040] was potentially associated with the risk of periodontitis, but the statistical power of the results was low. Multivariable MR analysis did not reveal any significant causal relationship between apo A1 and periodontitis (OR=0.72, 95% CI=0.36-1.41, P-value=0.34). In the validation cohort, there was also no significant causal relationship between apo A1 and periodontitis (OR=1.079, 95% CI=0.903-1.290, P-value=0.401). Meanwhile, genetically predicted Apolipoprotein B (apo B), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) (all P-values>0.05) were not significantly associated with the risk of periodontitis causal inference. Conclusion: This MR analysis was unable to provide genetic evidence for the influence of these five circulating lipid traits on periodontitis. However, a more extensive study with a more comprehensive circulating lipid profile and periodontitis data is needed due to study limitations.

Associations of genetically determined lipid traits and lipid-modifying agents with the risk of diabetic retinopathy: A Mendelian randomization study.

BACKGROUND AND AIMS: The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis. METHODS: Genetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments. RESULTS: Genetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52-0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83-0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR. CONCLUSIONS: This MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future.

Causal Effects of Blood Lipid Traits on Inflammatory Bowel Diseases: A Mendelian Randomization Study.

Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), have become a global health problem with a rapid growth of incidence in newly industrialized countries. Observational studies have recognized associations between blood lipid traits and IBDs, but the causality still remains unclear. To determine the causal effects of blood lipid traits, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) on IBDs, two-sample Mendelian randomization (MR) analyses were conducted using the summary-level genome-wide association study (GWAS) statistics of blood lipid traits and IBDs. Our univariable MR using multiplicative random-effect inverse-variance weight (IVW) method identified TC (OR: 0.674; 95% CI: 0.554, 0.820; p < 0.00625) and LDL-C (OR: 0.685; 95% CI: 0.546, 0.858; p < 0.00625) as protective factors of UC. The result of our multivariable MR analysis further provided suggestive evidence of the protective effect of TC on UC risk (OR: 0.147; 95% CI: 0.025, 0.883; p < 0.05). Finally, our MR-BMA analysis prioritized TG (MIP: 0.336; θ^MACE: -0.025; PP: 0.31; θ^λ: -0.072) and HDL-C (MIP: 0.254; θ^MACE: -0.011; PP: 0.232; θ^λ: -0.04) for CD and TC (MIP: 0.721; θ^MACE: -0.257; PP: 0.648; θ^λ: -0.356) and LDL-C (MIP: 0.31; θ^MACE: -0.095; PP: 0.256; θ^λ: -0.344) for UC as the top-ranked protective factors. In conclusion, the causal effect of TC for UC prevention was robust across all of our MR approaches, which provide the first evidence that genetically determined TC is causally associated with reduced risk of UC. The finding of this study provides important insights into the metabolic regulation of IBDs and potential metabolites targeting strategies for IBDs intervention.

Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.

BACKGROUND: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. METHODS: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random-effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. FINDINGS: Increased genetically proxied low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL-C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL-C) was associated with reduced T2DM liability (OR per SD increase in HDL-C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase in genetically proxied triglyceride (TG) levels was 0.884 [0.773 to 1.011, P = 0.072] . With respect to lipid-lowering drug targets, we found that genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with increased T2DM liability (OR per SD decrease in genetically proxied LDL-C = 1.68 [1.03-2.72, P = 0.04]) but we did not find evidence of a relationship between genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and T2DM liability. INTERPRETATION: Consistent with MR findings in Europeans, HDL-C exerts a protective effect on T2DM liability and HMGCR inhibition increases T2DM liability in African ancestry individuals. However, in contrast to European ancestry individuals, LDL-C may increase T2DM liability in African ancestry individuals. This raises the possibility of ethnic differences in the metabolic effects of dyslipidaemia in T2DM. FUNDING: See the Acknowledgements section for more information.

The role of lipid traits in mediating the effect of body mass index on serum urate.

Objective: To explore whether total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride (TG) are mediators in the pathway of body mass index (BMI) on serum urate and determine the proportion of the mediation effect. Methods: This study used observational and two-sample Mendelian randomization (MR) analyses to explore the mediation effects of TC, HDL, LDL, and TG in the pathway of BMI on serum urate. We determined the size and the extent to which these lipids mediate any effect of BMI on serum urate. Results: Observational analysis results showed that HDL and TG can partially explain the association of BMI on serum urate, and the proportion of mediation effect was 10.2% and 8.9%, respectively. MR results demonstrated that TG has a causal effect on serum urate (ß = 0.22, 95% CI: 0.15, 0.29; p = 2.28×10-10.) and its proportion of mediation effect was 14.1%. TC, HDL, and LDL are not the mediators in the pathway of BMI on serum urate in MR estimates. Conclusion: To a certain extent, TG mediates the effect of BMI on serum urate, and the risk of gout may be reduced by controlling both BMI and TG.

Association between Lipid Levels and Risk for Different Types of Aneurysms: A Mendelian Randomization Study.

BACKGROUND: Although the associations between serum lipid levels and aneurysms have been investigated in epidemiological studies, causality remains unknown. Thus, this study aimed to investigate the causal relationships of serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels on five types of aneurysms, using genetic variants associated with four lipid traits as instrumental variables in a Mendelian randomization (MR) analysis. METHODS: We performed two-sample Mendelian randomization (MR) analyses to evaluate the associations of HDL-C, LDL-C, TC, and TG levels with risks for five types of aneurysms and those of LDL-C- (HMGCR, NPC1L1, PCSK9, CETP, and LDLR) and TG-lowering targets (ANGPTL3 and LPL) with aneurysms. RESULTS: The sample sizes of the included studies ranged from nearly 80,000 to 410,000. We found inverse associations between genetically predicted HDL-C levels and aortic (OR = 0.74, 95% CI = 0.65-0.85) and abdominal aortic aneurysms (0.58, 0.45-0.75). A 1-SD increase in LDL-C and TC levels was associated with increased risks for aortic (1.41, 1.26-1.58 and 1.36, 1.18-1.56, respectively) and abdominal aortic aneurysms (1.82, 1.48-2.22 and 1.55, 1.25-1.93, respectively). TG levels were significantly associated with aortic (1.36, 1.18-1.56) and lower extremity artery aneurysms (2.76, 1.48-5.14), but limited to cerebral aneurysm (1.23, 1.06-1.42). Secondary analyses revealed a relationship between genetically proxied LDL-C-lowering targets and all types of aneurysms; however, the drug targets remained heterogeneous. We found a weak association between TG-lowering therapies and aortic (ANGPTL3, 0.51, 0.29-0.89) and abdominal aortic aneurysms (LPL, 0.64, 0.44-0.94). CONCLUSION: According to genetic evidence, lipid dysfunction is a causal risk factor for aneurysms. Lipid-lowering drugs may be a potential effective strategy in preventing and managing aneurysms.

Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians.

BACKGROUND: The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. METHODS: We used data from Biobank Japan (n = 70,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. RESULTS: Our PRSs aggregating 84-549 genetic variants (0.251 < correlation coefficients (r) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 < r < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10- 103 < P < 1.3 × 10- 75) and 3-year lipid changes (1.4 × 10- 6 < P < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (ß ± SE = 0.052 ± 0.002), 11.7% in TG (ß ± SE = 0.111 ± 0.006), 5.8% in HDL-C (ß ± SE = 0.057 ± 0.003), and 8.4% in LDL-C (ß ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 < r < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5 × 10- 3 < P < 0.0400) and 0.029-0.069 in T2D patients (2.1 × 10- 10 < P < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (ß ± SE = 0.011 ± 0.005, Ptrend = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03-1.11)], TG [OR (95% CI) = 1.05 (1.01-1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10- 4 < P < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. CONCLUSIONS: The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.

Associations of a mixture of urinary phthalate metabolites with blood lipid traits: A repeated-measures pilot study.

Evidence is available about the associations of phthalates or their metabolites with blood lipids, however, the mixture effects of multiple phthalate metabolites on blood lipid traits remain largely unknown. In this pilot study, 106 individuals at three age groups of <18, 18- and ≥60 years were recruited from the residents (n = 1240) who were randomly selected from two communities in Wuhan city, China. The participants completed the questionnaire survey and physical examination as well as provided urine samples in the winter of 2014 and the summer of 2015. We measured urinary levels of nine phthalate metabolites using a high-performance liquid chromatography-tandem mass spectrometry. We estimated the associations of individual phthalate metabolite with blood lipid traits by linear mixed effect (LME) models, and assessed the overall association of the mixture of nine phthalate metabolites with blood lipid traits using Bayesian kernel machine regression (BKMR) models. LME models revealed the negative association of urinary mono-2-ethylhexyl phthalate (MEHP) with total cholesterol (TC) as well as of urinary mono-benzyl phthalate or urinary MEHP with low density lipoprotein cholesterol (LDL-C). BKMR models revealed the negative overall association of the mixture of nine phthalate metabolites with TC or LDL-C, and DEHP metabolites (especially MEHP) had a greater contribution to TC or LDL-C levels than non-DEHP metabolites. The findings indicated the negative overall association of the mixture of nine phthalate metabolites with TC or LDL-C. Among nine phthalate metabolites, MEHP was the most important component for the changes of TC or LDL-C levels, implying that phthalates exposure may disrupt lipid metabolism in the body.

Race-ethnic differences in the associations of maternal lipid trait genetic risk scores with longitudinal fetal growth.

BACKGROUND: Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors. OBJECTIVE: We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial-ethnic populations (Whites, Blacks, Hispanics, and Asians). METHODS: We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRSTChol), low-density lipoprotein cholesterol (GRSLDLc), and triglycerides (GRSTG) and lower high-density lipoprotein cholesterol (GRSHDLc). RESULTS: At 40 weeks' gestation, a unit increase in GRSTG was associated with 11.4 g higher fetal weight (95% confidence interval [CI] 2.8-20.0 g) among normal-weight Whites, 26.3 g (95% CI 6.0-46.6 g) among obese Blacks, and 30.8 g (95% CI 6.3-55.3 g) among obese Hispanics. Higher GRSHDLc was associated with increased fetal weight across 36 to 40 weeks among normal-weight Whites and across 13 to 20 weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40 weeks among normal-weight Hispanics. Higher GRSTChol was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids. CONCLUSION: Associations between fetal weight and maternal lipid GRS appear to vary by maternal race-ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth.

Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke.

Recent genome-wide association studies (GWAS) have identified genetic variants associated with coronary artery disease (CAD), ischemic stroke (IS) and serum lipid traits in different ethnic groups. Some loci were found to affect the risk of CAD and IS. However, there were no data in the southern Chinese populations. Our study was to assess the association of CELSR2-PSRC1-SORT1 rs599839, rs464218 and rs6698443 SNPs and serum lipid levels and the risk of CAD and IS. The genotypes of 3 SNPs were detected in 561 CAD and 527 IS patients, and in 590 healthy controls. The genotypic and allelic frequencies of the rs599839 SNP were different between the controls and IS patients (P < 0.05). The minor G alleles of rs599839 and rs464218 SNPs were associated with higher high-density lipoprotein cholesterol concentrations in CAD and IS patients (P < 0.05); respectively. No association was found between the SNPs of rs599839, rs464218 and rs6698843 at the CELSR2-PSRC1-SORT1 and the risk of CAD or IS. These results will be replicated in the other Chinese populations.