Genome-wide association study identifies novel and confirms established loci associated with serum lipids levels in Brazilians.

> It is not in the stars to hold our destiny but in ourselves > > —William Shakespeare The widespread availability and lower costs of genotyping and sequencing have resulted in the performance of a large number of genotype–phenotype association studies in cardiovascular medicine. The stringent requirements for correction for multiple testing and replication have particularly favored genotype–phenotype studies examining the association between genetic variation and quantitative traits that allows for greater statistical power. Multiple genome-wide association studies and a subsequent meta-analysis have identified >180 common and rare genetic variants associated with lipid traits.1,2 However, the effect size of these individual genetic variants is small, explaining only a small fraction of phenotypic variation prompting investigators to use genetic risk scores (GRS) that represent an aggregate of genetic risk to demonstrate clinical utility. Single-nucleotide polymorphisms (SNPs) and GRS have been used to predict cardiovascular disease such as coronary artery disease (CAD) and hypertension, surrogate markers of disease such as coronary calcium, cardiovascular outcomes such as myocardial infarction, and intermediate traits such as blood pressure and lipids.3 Article, see p 495 The Global Lipids Genetics Consortium has performed the largest genetic association study of lipid levels in 188 577 individuals from a total of 60 studies.1,2 There were 157 genetic loci that were identified, 95 were described previously and 62 were novel. The lipid level variance explained by the novel loci in this study ranged from 1.6% for high-density lipoprotein cholesterol (HDL-C) levels to 2.6% for total cholesterol levels. The total lipid variance explained by the previously described loci was 10% to 12%. The population studied was predominantly of European ancestry, and subjects on lipid-lowering therapy were excluded. The association of these genetic loci with lipid levels and a change in lipid levels with intervention in a prediabetic population …

Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are modifiable risk factors for cardiovascular disease. Several genetic loci for predisposition to abnormal LDL-C, HDL-C and TG have been identified. However, it remains unclear whether these loci are consistently associated with serum lipid levels at each age or with unique developmental trajectories. Therefore, we assessed the association between genome wide association studies (GWAS) derived polygenic genetic risk scores and LDL-C, HDL-C, and triglyceride trajectories from childhood to adulthood using data available from the 27-year European ‘Cardiovascular Risk in Young Finns’ Study. For 2,442 participants, three weighted genetic risk scores (wGRSs) for HDL-C (38 SNPs), LDL-C (14 SNPs) and triglycerides (24 SNPs) were computed and tested for association with serum lipoprotein levels measured up to 8 times between 1980 and 2011. The categorical analyses revealed no clear divergence of blood lipid trajectories over time between wGRSs categories, with participants in the lower wGRS quartiles tending to have average lipoprotein concentrations 30 to 45% lower than those in the upper-quartile wGRS beginning at age 3 years and continuing through to age 49 years (where the upper-quartile wGRS have 4–7 more risk alleles than the lower wGRS group). Continuous analyses, however, revealed a significant but moderate time-dependent genetic interaction for HDL-C levels, with the association between HDL-C and the continuous HDL-C risk score weakening slightly with age. Conversely, in males, the association between the continuous TG genetic risk score and triglycerides levels tended to be lower in childhood and become more pronounced after the age of 25 years. Although the influence of genetic factors on age-specific lipoprotein values and developmental trajectories is complex, our data show that wGRSs are highly predictive of HDL-C, LDL-C, and triglyceride levels at all ages.

Background: Although plasma low density lipoprotein cholesterol (LDL-C) appears to be a causative factor in animal models of aortic valve (AV) disease, randomized trials with cholesterol lowering therapies in established disease have failed to reduce progression. We sought to evaluate whether life-long genetic elevations in LDL-C, high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) are associated with AV disease. Methods: Using 144 single nucleotide polymorphisms associated with LDL-C, HDL-C or TG in genomewide association studies (GWAS), we constructed three separate genetic risk scores (GRS). We estimated the association between each GRS and (1) the presence of AV calcium determined by computed tomography in 6942 participants of white European ancestry from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium using summary level GWAS data and; (2) incidence of aortic stenosis in 28,585 participants from the Malmo Diet and Cancer Study (MDCS) over a mean follow-up time of 15.8 years. Results: The LDL-C GRS, but not the HDL-C or the TG GRS, was associated with presence of AV calcium (OR per predicted mmol/L LDL-C, 1.38 95% CI 1.09-1.74; p=0.007). The LDL-C GRS was also associated with incident aortic stenosis (HR per mmol/L LDL-C, 3.04 (1.34-6.91, p=0.008). In sensitivity analyses excluding SNPs also associated with HDL-C or TG to reduce pleiotropy, the LDL-C GRS remained associated with AV calcium (OR per predicted mmol/L LDL-C 1.39 95% CI 1.04-1.90; p=0.03) and aortic stenosis (HR per mmol/L LDL-C 3.85, 95% CI 1.37-10.79, p=0.01). Further analyses to exclude residual pleiotropic effects of HDL-C and TG, did not materially change these findings. Conclusions: Genetic predisposition to increased LDL-C is associated with presence of AV calcium and incidence of aortic stenosis, providing novel supportive evidence that LDL-C is a causal factor for the development of AV disease. Earlier intervention to reduce LDL-C merits further investigation to prevent AV disease.

Exploring Avenues for Raising HDL Cholesterol

Bai Ku Yao is an isolated subgroup of the Yao minority in China. Little is known about dyslipidemia in this population. The aim of this study was to compare the effects of demography, diet, and lifestyle on serum lipid levels between the Bai Ku Yao and Han populations. A total of 1,170 subjects of Bai Ku Yao and 1,173 subjects of Han Chinese aged 15-89 years were surveyed by a stratified randomized cluster sampling. The levels of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A-I (apoA-I), and apoB were significantly lower in Bai Ku Yao than in Han. Physical activity level and total dietary fiber intake were higher, whereas body mass index (BMI), waist circumference, total energy intake, and total fat intake were lower in Bai Ku Yao than in Han. Hyperlipidemia was positively correlated with BMI, waist circumference, and total energy and total fat intakes and negatively associated with physical activity level and total dietary fiber intake in both populations, but it was positively associated with age and alcohol consumption only in Han. The differences in the lipid profiles between the two ethnic groups were associated with different dietary habits, lifestyle choices, and levels of physical activities.

Multiple single-nucleotide polymorphisms have been associated with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels. In this paper, we evaluate a weighted and an unweighted approach for estimating the combined effect of multiple markers (using genotypes and haplotypes) on lipid levels for a given individual. Using data from the Framingham Heart Study SHARe genome-wide association study, we tested genome-wide genotypes and haplotypes for association with lipid levels and constructed genetic risk scores (GRS) based on multiple markers that were weighted according to their estimated effects on LDL-C, HDL-C, and TG. These scores (GRS-LDL, GRS-HDL, and GRS-TG) were then evaluated for associations with LDL-C, HDL-C, and TG, and compared with results of an unweighted method based on risk-allele counts. For comparability of metrics, GRS variables were divided into quartiles. GRS-LDL quartiles were associated with LDL-C levels (p = 2.1 x 10-24), GRS-HDL quartiles with HDL-C (p = 5.9 x 10-22), and GRS-TG quartiles with TG (p = 5.4 x 10-25). In comparison, these p-values were considerably lower than those for the associations of the unweighted GRS quartiles for LDL-C (p = 3.6 x 10-7), HDL-C (p = 6.4 x 10-16), and TG (p = 4.1 x 10-10). GRS variables were highly predictive of LDL-C, HDL-C, and TG measurements, especially when weighted based on each marker's individual association with those intermediate risk phenotypes. The allele-count GRS approach that does not weight the GRS by individual marker associations was considerably less predictive of lipid and lipoprotein measures when the same genetic markers were utilized, suggesting that substantially more risk-associated genetic marker information is encapsulated by the weighted GRS variables.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

Polygenic risk score for atopic dermatitis in the Canadian population

Introduction: Variability in lipid levels is decreased in childhood compared to adulthood. However, few studies have assessed whether genetic information may help to predict hyperlipidemia beyond measured lipid values at this critical developmental stage. Hypothesis: We hypothesized that a low-density lipoprotein cholesterol (LDL-C) genetic risk score (GRS) would predict hyperlipidemia and LDL-C over the life course, even after adjustment for childhood measures. Methods: The analysis included 651 Bogalusa Heart Study participants (63% women, 31% African American, baseline age=9.8 + 3.1 years, median follow-up=40 years) with genome-wide association study (GWAS) data and at least one childhood and one adulthood measure of LDL-C. A weighted LDL-C GRS was constructed using loci from previous GWAS meta-analyses. Hyperlipidemia was defined as an LDL-C > 130 mg/dL or statin use. Cox proportional hazards regression models examined the associations between GRS and hyperlipidemia. Linear and mixed linear regression models were employed to examine the associations of GRS with adulthood LDL-C and life-course LDL-C trajectory, respectively. All models adjusted for age, sex, and childhood LDL-C. Results: Among participants of European ancestry, increasing GRS tertile conferred strong, dose-response increases in the hazards of hyperlipidemia ( Figure ). Similarly, the highest GRS tertile was associated with a 20 mg/dl increased LDL-C level in middle-aged adults compared to the lowest tertile (P<0.0001). Each tertile increase in GRS was also associated with 5.5 mg/dL larger 10-year increase in LDL-C (interaction-P=0.04). No associations were observed among participants of African ancestry. Conclusions: A LDL-C GRS was associated with adulthood LDL-C phenotypes independently of childhood LDL-C values in participants of European but not African ancestry. These findings highlight a need for increased genomics research in diverse populations and suggest a predictive utility of genetic information in childhood.

Dyslipidemia is an important risk factor for chronic cardiometabolic diseases. Lipid traits are highly heritable and there are currently >185 established loci influencing lipid levels in adults. Recent studies have confirmed that variants associated with lipids influence lipid levels across the lifecourse, and in ancestrally diverse populations. Given that Hispanic/Latinos (HL) shoulder much of the cardiometabolic burden in the United States, it is important to identify genetic variants that contribute the greatest risk for elevated lipid levels across life stages. Thus, our primary aim is to examine the association of known lipid variants with lipid traits identified in large study of adult participants from a Chilean infancy cohort of primarily European-descent. The sample assessed from 2008 to 2013 (n=546) had genotyping and well-measured lipid phenotypes (median age: 16.8 years, interquartile range: 16.6, 16.9). We assessed single variant associations using linear regression for high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), assuming an additive genetic model, adjusted for sex. Additionally, we regressed phenotypes onto weighted trait-specific polygenic risk scores (PRS). Only six variants from the Chilean sample met the a priori threshold of power > 0.8. We found statistically significant effect sizes (mmol/l (se)) for four of the six variants: rs3764261 (0.16 (0.04)) and rs1532085 (0.05 (0.04)) for HDL and rs1260326 (0.34 (0.15)) and rs964184 (0.33 (0.15)) for TG. For each significant variant, direction of effect matched the multiethnic adult GWAS from which SNPs were selected. We compared our findings to a previous study in Finnish children at age 18 years (n=1,216) and found an opposite direction of effect for our significant HDL variants. Likewise, when comparing coefficients for the PRS between the Chilean and Finnish youth sample we found the association to be stronger in the Chilean sample for every trait and gender group with the exception of LDL for males. The lipid loci explained the least amount of total variance for LDL (males=4% and females=5%) and the most amount of variance for HDL (males=20% and females=14%). In conclusion, there is evidence that lipid loci from a HL sample of adolescents contain similar associations as those from European children and adults. Despite the small sample size and possibility for bias with different ancestral groups we found meaningful and statistically significant associations relating lipid loci in a HL cohort of Chilean adolescents with those found in European ancestral groups. These associations emphasize the importance of adolescence as a time for disease prevention given studies demonstrating both the persistence of associations between PRS and lipids over the life course and the increasing role PRS plays in predicting disease.

Comparison of lipid profiles in normal and hypertensive pregnant women

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52×10-16, 1.38×10-6 and 5.59×10-9, respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population.

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

BackgroundCardiovascular diseases (CVDs) comprise major causes of death worldwide, leading to extensive burden on populations and societies. Alterations in normal lipid profiles, i.e., dyslipidemia, comprise important risk factors for CVDs. However, there is lack of comprehensive evidence on the genetic contribution to dyslipidemia in highly admixed populations. The identification of single nucleotide polymorphisms (SNPs) linked to blood lipid traits in the Brazilian population was based on genome-wide associations using data from the São Paulo Health Survey with Focus on Nutrition (ISA-Nutrition).MethodsA total of 667 unrelated individuals had genetic information on 330,656 SNPs available, and were genotyped with Axiom™ 2.0 Precision Medicine Research Array. Genetic associations were tested at the 10− 5 significance level for the following phenotypes: low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), high-density lipoprotein cholesterol (HDL-c), HDL-c/LDL-c ratio, triglycerides (TGL), total cholesterol, and non-HDL-c.ResultsThere were 19 significantly different SNPs associated with lipid traits, the majority of which corresponding to intron variants, especially in the genes FAM81A, ZFHX3, PTPRD, and POMC. Three variants (rs1562012, rs16972039, and rs73401081) and two variants (rs8025871 and rs2161683) were associated with two and three phenotypes, respectively. Among the subtypes, non-HDL-c had the highest proportion of associated variants.ConclusionsThe results of the present genome-wide association study offer new insights into the genetic structure underlying lipid traits in underrepresented populations with high ancestry admixture. The associations were robust across multiple lipid phenotypes, and some of the phenotypes were associated with two or three variants. In addition, some variants were present in genes that encode ncRNAs, raising important questions regarding their role in lipid metabolism.