Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study

<p>Abstract</p> <p>Background</p> <p>Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co-activator genes-<it>Cited2</it>, <it>p300</it>, <it>Cbp</it>, <it>Tfap2α</it>, <it>Carm1 </it>and <it>Cart1 </it>result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans.</p> <p>Methods</p> <p>Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case-control study conducted in California. 37 SNPs within <it>CITED2</it>, <it>EP300</it>, <it>CREBBP</it>, <it>TFAP2A</it>, <it>CARM1 </it>and <it>ALX1 </it>were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida.</p> <p>Results</p> <p>Several SNPs showed increased or decreased risk, including <it>CITED2 </it>rs1131431 (OR = 5.32, 1.04~27.30), <it>EP300 </it>rs4820428 (OR = 1.30, 1.01~1.67), <it>EP300 </it>rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), <it>EP300 </it>rs17002284 (OR = 0.43, 0.22~0.84), <it>TFAP2A </it>rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), <it>CREBBP </it>rs129986 (OR = 0.27, 0.11~0.69), <it>CARM1 </it>rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in <it>EP300 </it>and one in <it>TFAP2A </it>appeared to be associated with increased risk.</p> <p>Conclusions</p> <p>Modest associations were observed in <it>CITED2</it>, <it>EP300</it>, <it>CREBBP</it>, <it>TFAP2A </it>and <it>CARM1 </it>but not <it>ALX1</it>. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes.</p

Genetic Polymorphisms of the TYMS Gene Are Not Associated with Congenital Cardiac Septal Defects in a Han Chinese Population

Background: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Method: Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. Result: We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Conclusion: Our results show no association between common genetic polymorphisms of the regulatory region of th

Apolipoprotein E Genotype and Cardiovascular Diseases in the Elderly

The apolipoprotein E (APOE) genotype is a genetic risk factor for dementia, Alzheimer’s disease, and cardiovascular disease (CVD). It includes three alleles (e2, e3, e4) that are located on chromosome 19q3.2. The e3 allele is the most common and is more common in people of Northern European ancestry and less common in those of Asian ancestry. Those with at least one e4 allele are at increased risk for CVD outcomes. It is well established that the presence of an e4 allele is linked to higher low-density lipoprotein cholesterol levels, even at young ages. Even though most CVD occurs in older people, there are few studies of the effects of APOE on CVD in older people. This review addresses recent research on the links between APOE, CVD, and vascular mechanisms by which APOE may affect CVD in the elderly

118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

<p>Abstract</p> <p>Background</p> <p>Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.</p> <p>Methods</p> <p>Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983–86 or 1994–95. It also included 214 infants with conotruncal heart defects born during 1983–86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.</p> <p>Results</p> <p>Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: <it>BHMT </it>(rs3733890) OR = 1.8 (1.1–3.1), <it>CBS </it>(rs2851391) OR = 2.0 (1.2–3.1); <it>CBS </it>(rs234713) OR = 2.9 (1.3–6.7); <it>MTHFD1 </it>(rs2236224) OR = 1.7 (1.1–2.7); <it>MTHFD1 </it>(hcv11462908) OR = 0.2 (0–0.9); <it>MTHFD2 </it>(rs702465) OR = 0.6 (0.4–0.9); <it>MTHFD2 </it>(rs7571842) OR = 0.6 (0.4–0.9); <it>MTHFR </it>(rs1801133) OR = 2.0 (1.2–3.1); <it>MTRR </it>(rs162036) OR = 3.0 (1.5–5.9); <it>MTRR </it>(rs10380) OR = 3.4 (1.6–7.1); <it>MTRR </it>(rs1801394) OR = 0.7 (0.5–0.9); <it>MTRR </it>(rs9332) OR = 2.7 (1.3–5.3); <it>TYMS </it>(rs2847149) OR = 2.2 (1.4–3.5); <it>TYMS </it>(rs1001761) OR = 2.4 (1.5–3.8); and <it>TYMS </it>(rs502396) OR = 2.1 (1.3–3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with <it>TYMS</it>, <it>MTHFR</it>, <it>BHMT </it>and <it>MTR </it>for spina bifida.</p> <p>Conclusion</p> <p>Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.</p

Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels

Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5-1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05-0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between -1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The -1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the -1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05-0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05-0.01).The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption

Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report

Premature atherosclerosis in patients with xanthelasma.

BACKGROUND: Only about half the patients with xanthelasma are hyperlipidemic. The clinical significance of xanthelasma as a marker of cardiovascular disease is not yet well defined. OBJECTIVE: To determine the risk of cardiovascular disease in patients with normolipidemic and hyperlipidemic xanthelasma. METHODS: Carotid ultrasonography (7 MHz using B-mode images, Advanced Technology Laboratories) was used to detect carotid plaques and measure the intima-media thickness (IMT) of the common carotid arteries. Seventeen patients with normolipidemic and hyperlipidemic xanthelasma were examined and compared with 21 age-matched normal subjects. RESULTS: The risk of cardiovascular disease was significantly increased in patients with xanthelasma. Carotid plaques were more frequent in patients with xanthelasma than in controls (64.7% and 23.8%, respectively; P = 0.020), and IMT was significantly higher (mean +/- SD: 1.1 +/- 0.1 and 0.6 +/- 0.2 mm, respectively; P &lt; 0.001). The difference of carotid IMT between normolipidemic xanthelasma and hyperlipidemic xanthelasma was not statistically different (mean +/- SD: 1.1 +/- 0.1 and 1.1 +/- 0.2 mm, respectively; P = 0.577). CONCLUSION: Premature carotid atherosclerosis is observed in patients with normolipidemic and hyperlipidemic xanthelasma. Patients with xanthelasma should be considered to have an increased risk of cardiovascular disease independently to the level of plasma lipids. A larger number of patients is, however, needed to confirm this preliminary study