PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 × 10⁻⁹), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10⁻⁵), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10⁻⁷), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.     

Genetic variation at the FADS1-FADS2 gene locus influences delta-5 desaturase activity and LC-PUFA proportions after fish oil supplement

Delta-5 and delta-6 desaturases (D5D and D6D) are key enzymes in endogenous synthesis of long-chain PUFAs. In this sample of healthy subjects (n = 310), genotypes of single nucleotide polymorphisms (SNPs) rs174537, rs174561, and rs3834458 in the FADS1-FADS2 gene cluster were strongly associated with proportions of LC-PUFAs and desaturase activities estimated in plasma and erythrocytes. Minor allele carriage associated with decreased activities of D5D (FADS1) (5.84 × 10⁻¹⁹ ≤ P ≤ 4.5 × 10⁻¹⁸) and D6D (FADS2) (6.05 × 10⁻⁸ ≤ P ≤ 4.20 × 10⁻⁷) was accompanied by increased substrate and decreased product proportions (0.05 ≤ P ≤ 2.49 × 10⁻¹⁶). The significance of haplotype association with D5D activity (P = 2.19 × 10⁻¹⁷) was comparable to that of single SNPs, but haplotype association with D6D activity (P = 3.39 × 10⁻²⁸) was much stronger. In a randomized controlled dietary intervention, increasing eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) intake significantly increased D5D (P = 4.0 × 10⁻⁹) and decreased D6D activity (P = 9.16 × 10⁻⁶) after doses of 0.45, 0.9, and 1.8 g/day for six months. Interaction of rs174537 genotype with treatment was a determinant of D5D activity estimated in plasma (P = 0.05). In conclusion, different sites at the FADS1-FADS2 locus appear to influence D5D and D6D activity, and rs174537 genotype interacts with dietary EPA+DHA to modulate D5D.     

Telomere Shortening Unrelated to Smoking,Body Weight,Physical Activity,and Alcohol Intake: 4,576 General Population Individuals with Repeat Measurements 10 Years Apart

Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3×10⁻⁷⁷), current smoking (P = 8×10⁻³), increased body mass index (P = 7×10⁻¹⁴), physical inactivity (P = 4×10⁻¹⁷), but not with increased alcohol intake (P = 0.10). At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1×10⁻³⁰⁰) and age at baseline (P = 1×10⁻²⁷), but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population.     

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

HDL-associated paraoxonase-1 (PON1) is an enzyme whose activity is associated with cerebrovascular disease. Common PON1 genetic variants have not been consistently associated with cerebrovascular disease. Rare coding variation that likely alters PON1 enzyme function may be more strongly associated with stroke. The National Heart, Lung, and Blood Institute Exome Sequencing Project sequenced the coding regions (exomes) of the genome for heart, lung, and blood-related phenotypes (including ischemic stroke). In this sample of 4,204 unrelated participants, 496 had verified, noncardioembolic ischemic stroke. After filtering, 28 nonsynonymous PON1 variants were identified. Analysis with the sequence kernel association test, adjusted for covariates, identified significant associations between PON1 variants and ischemic stroke (P = 3.01 × 10⁻³). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants (P = 5.03 × 10⁻³). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of PON1_Val109Ile (overall P = 7.88 × 10⁻³; AA P = 6.52 × 10⁻⁴), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identified in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted.     

Novel common and rare genetic determinants of paraoxonase activity: FTO,SERPINA12, and ITGAL

HDL-associated paraoxonase 1 (PON1) activity is associated with cardiovascular and other human diseases. As the role of genetic variants outside of the PON gene cluster on PON1 activity is unknown, we sought to identify common and rare variants in such loci. We typed 33,057 variants on the CVD chip in 1,362 subjects to test for their effects on adjusted-PON1 activity. Three novel genes (FTO, ITGAL, and SERPINA12) and the PON gene cluster had SNPs associated with PON1 arylesterase (AREase) activity. These loci were carried forward for rare-variant analysis using Exome chip genotypes in an overlapping subset of 1,051 subjects using sequence kernel association testing. PON1 (P = 2.24 × 10⁻⁴), PON3 (P = 0.022), FTO (P = 0.019), and SERPINA12 (P = 0.039) had both common and rare variants associated with PON1 AREase. ITGAL variants were associated with PON1 activity when using weighted sequence kernel association testing (SKAT) analysis (P = 2.63 × 10⁻³). When adjusting for the initial common variants, SERPINA12 became marginally significant (P = 0.09), whereas all other findings remained significant (P < 0.05), suggesting independent rare-variant effects. We present novel findings that common and rare variants in FTO, SERPINA12, and ITGAL predict PON1 activity. These results further link PON1 to diabetes and inflammation and may inform the role of HDL in human disease.     

Common Variation in the β-Carotene 15,15′-Monooxygenase 1 Gene Affects Circulating Levels of Carotenoids: A Genome-wide Association Study

Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with α-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the α-Tocopherol, β-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the β-carotene 15,15′-monooxygenase 1 (BCMO1) gene, was associated with higher β-carotene (p = 1.6 × 10⁻²⁴) and α-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 × 10⁻⁵), and lutein (p = 7.3 × 10⁻¹⁵) levels, with effect sizes ranging from 0.10–0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with α-tocopherol (meta-analysis p = 7.8 × 10⁻¹⁰) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.     

A Genome-Wide Association Study of Total Serum and Mite-Specific IgEs in Asthma Patients

Immunoglobulin E (IgE) is one of the central players in asthma and allergic diseases. Although the serum IgE level, a useful endophenotype, is generally increased in patients with asthma, genetic factors influencing IgE regulation in asthma are still not fully understood. To identify the genetic variations associated with total serum and mite-specific IgEs in asthmatics, a genome-wide association study (GWAS) of 657,366 single nucleotide polymorphisms (SNPs) was performed in 877 Korean asthmatics. This study found that several new genes might be associated with total IgE in asthmatics, such as CRIM1 (rs848512, P = 1.18×10⁻⁶; rs711254, P = 6.73×10⁻⁶), ZNF71 (rs10404342, P = 7.60×10⁻⁶), TLN1 (rs4879926, P = 7.74×10⁻⁶), and SYNPO2 (rs1472066, P = 8.36×10⁻⁶; rs1038770, P = 8.66×10⁻⁶). Regarding the association of specific IgE to house dust mites, it was observed that intergenic SNPs nearby to OPRK1 and LOC730217 might be associated with Dermatophagoides pteronyssinus (D.p.) and Dermatophagoides farinae (D.f.) in asthmatics, respectively. In further pathway analysis, the phosphatidylinositol signaling system and adherens junction pathways were estimated to play a role in the regulation of total IgE levels in asthma. Although functional evaluations and replications of these results in other populations are needed, this GWAS of serum IgE in asthmatics could facilitate improved understanding of the role of the newly identified genetic variants in asthma and its related phenotypes.     

Maternal dietary intake of folate,vitamin B12 and MTHFR 677C>T genotype: their impact on newborn’s anthropometric parameters

In this study, we evaluated the effects of dietary intake of vitamin B₁₂ and folate during pregnancy and their interactions with maternal polymorphism of MTHFR (677C>T; 1298A>C) on intrauterine development. Anthropometric parameters were obtained from 231 newborns that belong to a prospective birth cohort in Morelos, Mexico. Maternal dietary intake of vitamin B₁₂ and folate was assessed using a semi-quantitative questionnaire administered during the first and third trimesters of the pregnancy. Maternal MTHFR 677C>T and 1298 A>C genotypes were determined by PCR–RFLP. The associations between deficient dietary intake of vitamin B₁₂ (<2.0 μg/d) and folate (<400 μg/d) in the first and third trimesters and maternal polymorphisms of MTHFR on anthropometric parameters at birth were estimated using a multivariate linear regression model. During pregnancy, the deficient dietary intake was roughly 60 % for folate and 19 % for vitamin B₁₂. Allelic frequencies of 677T and 1298C were 59 and 10 %, respectively. After adjusting for confounders, deficiency in maternal dietary intake of vitamin B₁₂ (<2.0 μg/d) was associated with a significant reduction in length (β ~ −2.4; 95 % CI −4.3; −0.6) and length-for-age at birth (β ~ −1.2; 95 % CI −2.3; −0.1) among infants whose mothers were carriers of the 677TT genotype (p for interaction = 0.02). In contrast, no association was observed between deficiency in maternal dietary intake of folate (<400 μg/d) and any anthropometric parameter of newborns. These results suggest that supplementation with vitamin B₁₂ during pregnancy could have a favorable impact on intrauterine fetal development mainly in populations that are genetically susceptible.     

A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS) of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2-RASGEF1A genomic region (_rawP = 5.69×10⁻¹⁹ before a Bonferroni correction; _corrP = 4.31×10⁻¹³ after a Bonferroni correction) and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (_adjP = 2.71×10⁻⁶), RORA (_adjP = 1.26×10⁻⁵), and ABCC9 (_adjP = 1.86×10⁻⁵) as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different significance levels among subgroups: short-segment (S-HSCR, _corrP = 1.71×10⁻⁵), long-segment (L-HSCR, _corrP = 6.66×10⁻⁴), and total colonic aganglionosis (TCA, _corrP>0.05). This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS) development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis.     

Genetic Variants Associated with Lipid Profiles in Chinese Patients with Type 2 Diabetes

Dyslipidemia is a strong risk factor for cardiovascular disease among patients with type 2 diabetes (T2D). The aim of this study was to identify lipid-related genetic variants in T2D patients of Han Chinese ancestry. Among 4,908 Chinese T2D patients who were not taking lipid-lowering medications, single nucleotide polymorphisms (SNPs) in seven genes previously found to be associated with lipid traits in genome-wide association studies conducted in populations of European ancestry (ABCA1, GCKR, BAZ1B, TOMM40, DOCK7, HNF1A, and HNF4A) were genotyped. After adjusting for multiple covariates, SNPs in ABCA1, GCKR, BAZ1B, TOMM40, and HNF1A were identified as significantly associated with triglyceride levels in T2D patients (P < 0.05). The associations between the SNPs in ABCA1 (rs3890182), GCKR (rs780094), and BAZ1B (rs2240466) remained significant even after correction for multiple testing (P = 8.85×10⁻³, 7.88×10⁻⁷, and 2.03×10⁻⁶, respectively). BAZ1B (rs2240466) also was associated with the total cholesterol level (P = 4.75×10⁻²). In addition, SNP rs157580 in TOMM40 was associated with the low-density lipoprotein cholesterol level (P = 6.94×10⁻³). Our findings confirm that lipid-related genetic loci are associated with lipid profiles in Chinese patients with type 2 diabetes.     

Formation of carbon monoxide and bile pigment in red and blue-green algae

Chromium was not required for normal growth of romaine lettuce (Lactuca sativa L. subsp. longifolia), tomato (Lycopersicon esculentum Mill.), wheat (Triticum aestivum L.), or bean (Phaseolus vulgaris L.) in solution culture containing 3.8 × 10⁻⁴ μM Cr. Plants grown on this purified nutrient solution contained an average of 22 ng Cr/g dry weight. Duckweed (Lemna sp.) grew and reproduced normally on a dilute nutrient solution containing 3.8 × 10⁻⁵ μM Cr.     

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(−/−)] mice, which have a secondary defect in cholesterol esterification. Scarab(−/−)×LCAT-null [Lcat(−/−)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(−/−)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(−/−)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(−/−)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(−/−) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles.     

Fetal lung and placental methylation is associated with in utero nicotine exposure

In utero smoke exposure has been shown to have detrimental effects on lung function and to be associated with persistent wheezing and asthma in children. One potential mechanism of IUS effects could be alterations in DNA methylation, which may have life-long implications. The goal of this study was to examine the association between DNA methylation and nicotine exposure in fetal lung and placental tissue in early development; nicotine exposure in this analysis represents a likely surrogate for in-utero smoke. We performed an epigenome-wide analysis of DNA methylation in fetal lung tissue (n = 85, 41 smoke exposed (48%), 44 controls) and the corresponding placental tissue samples (n = 80, 39 smoke exposed (49%), 41 controls) using the Illumina HumanMethylation450 BeadChip array. Differential methylation analyses were conducted to evaluate the variation associated with nicotine exposure. The most significant CpG sites in the fetal lung analysis mapped to the PKP3 (P = 2.94 × 10⁻⁰³), ANKRD33B (P = 3.12 × 10⁻⁰³), CNTD2 (P = 4.9 × 10⁻⁰³) and DPP10 (P = 5.43 × 10⁻⁰³) genes. In the placental methylome, the most significant CpG sites mapped to the GTF2H2C and GTF2H2D genes (P = 2.87 × 10⁻⁰⁶ − 3.48 × 10⁻⁰⁵). One hundred and one unique CpG sites with P-values < 0.05 were concordant between lung and placental tissue analyses. Gene Set Enrichment Analysis demonstrated enrichment of specific disorders, such as asthma and immune disorders. Our findings demonstrate an association between in utero nicotine exposure and variable DNA methylation in fetal lung and placental tissues, suggesting a role for DNA methylation variation in the fetal origins of chronic diseases.     

Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻¹¹ for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10⁻⁵ for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻⁵), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10⁻⁴) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10⁻⁸), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.     

A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C

Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β = −0.08 mmol/l, P_overall = 1.2 × 10⁻⁷) and LDL-C (β = 0.13 mmol/l, P_overall = 1.5 × 10⁻⁴). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (P_overall = 1.7 × 10⁻⁵). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.     

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 × 10⁻⁷ – 1.7 × 10⁻⁸) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the ω-6 series (P = 2.11 × 10⁻¹³ – 1.8 × 10⁻²⁰). The minor allele across all SNPs was consistently associated with decreased ω-6 PUFAs, with the exception of dihomo-γ-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Δ-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA.     

Systematic Evaluation of Genetic Variants for Polycystic Ovary Syndrome in a Chinese Population

To date, eleven genome-wide significant (GWS) loci (P < 5×10⁻⁸) for polycystic ovary syndrome (PCOS) have been identified through genome-wide association studies (GWAS). Some of the risk loci have been selected for replications and validated in multiple ethnicities, however, few previous studies investigated all loci. Scanning all the GWAS variants would demonstrate a more informative profile of variance they explained. Thus, we analyzed all the 17 single nucleotide polymorphisms (SNPs) mapping to the 11 GWAS loci in an independent sample set of 800 Chinese subjects with PCOS and 1110 healthy controls systematically. Variants of rs3802457 in C9orf3 locus (P = 5.99×10⁻⁴) and rs13405728 in LHCGR locus (P = 3.73×10⁻⁴) were significantly associated with PCOS after the strict Bonferroni correction in our data set. The further haplotype analysis indicated that in the block of C9orf3 gene (rs4385527 and rs3802457), GA haplotype played a protective role in PCOS (8.7 vs 5.0, P = 9.85×10⁻⁶, OR = 0.548, 95%CI = 0.418–0.717), while GG haplotype was found suffering from an extraordinarily increased risk of PCOS (73.6% vs79.2%, P = 3.41×10⁻⁵, OR = 1.394, 95%CI = 1.191–1.632). Moreover, the directions of effects for all SNPs were consistent with previous GWAS reports (P = 1.53×10⁻⁵). Polygenic score analysis demonstrated that these 17 SNPs have a significant capacity on predicting case-control status in our samples (P = 7.17×10⁻⁹), meanwhile all these gathered 17 SNPs explained about 2.40% of variance. Our findings supported that C9orf3 and LHCGR loci variants were vital susceptibility of PCOS.     

Maize Yield Response to Water Supply and Fertilizer Input in a Semi-Arid Environment of Northeast China

Maize grain yield varies highly with water availability as well as with fertilization and relevant agricultural management practices. With a 311-A optimized saturation design, field experiments were conducted between 2006 and 2009 to examine the yield response of spring maize (Zhengdan 958, Zea mays L) to irrigation (I), nitrogen fertilization (total nitrogen, urea-46% nitrogen,) and phosphorus fertilization (P₂O₅, calcium superphosphate-13% P₂O₅) in a semi-arid area environment of Northeast China. According to our estimated yield function, the results showed that N is the dominant factor in determining maize grain yield followed by I, while P plays a relatively minor role. The strength of interaction effects among I, N and P on maize grain yield follows the sequence N+I >P+I>N+P. Individually, the interaction effects of N+I and N+P on maize grain yield are positive, whereas that of P+I is negative. To achieve maximum grain yield (10506.0 kg·ha⁻¹) for spring maize in the study area, the optimum application rates of I, N and P are 930.4 m³·ha⁻¹, 304.9 kg·ha⁻¹ and 133.2 kg·ha⁻¹ respectively that leads to a possible economic profit (EP) of 10548.4 CNY·ha⁻¹ (CNY, Chinese Yuan). Alternately, to obtain the best EP (10827.3 CNY·ha⁻¹), the optimum application rates of I, N and P are 682.4 m³·ha⁻¹, 241.0 kg·ha⁻¹ and 111.7 kg·ha⁻¹ respectively that produces a potential grain yield of 10289.5 kg·ha⁻¹.     

Association of Genetic Variants Influencing Lipid Levels with Coronary Artery Disease in Japanese Individuals

Background/Objective

In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD).

Methods

We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1×10⁻³⁰ in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls.

Principal Findings

Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci–APOB, APOE-C1, CETP, and APOA5–and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3×10⁻⁴¹), CETP rs3764261 for HDL-C (p = 5.2×10⁻²⁴), and APOA5 rs662799 for triglycerides (p = 5.8×10⁻⁵⁴). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7×10⁻⁸), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1×10⁻⁷), and APOE rs7412 (p = 6.1×10⁻¹³).

Conclusions

Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.     

A novel approach to oral apoA-I mimetic therapy

Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR^−/−) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy.