Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of ischemic stroke in Han Chinese of eastern China

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke.This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China.A total of 690 ischemic stroke cases and 767 controls were recruited.The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.On the basis of that,two polymorphisms of the ALOX5AP gene (rs10507391 and rs12429692) were determined by TaqMan genotyping assay.In addition,plasma leukotriene B4 (LTB4) levels were analyzed in these subjects.There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes.Haplotype analysis and stratification analysis according to sex,age,body mass index,hypertension,and diabetes also showed negative association.Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls (70.06±14.75 ng/L vs 57.34±10.93 ng/L;P=0.000) and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels (P=0.000).The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China.     

Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians

Genetic factors contribute to the risk of ischemic stroke (IS). The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population. In an attempt to better define the contributory role of PDE4D and ALOX5AP genes to the risk of IS in humans, we carried out the present association study in a well-characterized, earlier published, genetically homogenous population from the island of Sardinia, Italy. In this cohort, including 294 cases and 235 controls, age, hypertension, hypercholesterolemia, and atrial fibrillation represent risk factors for IS. The PDE4D gene was evaluated by four single nucleotide polymorphisms (SNP32, SNP45, SNP83, SNP87) and by the microsatellite AC008818-1; the ALOX5AP gene was characterized by three SNPs (SG13S32, SG13S89, ALO2A). The results of our study provide no evidence of association between any single PDE4D and ALOX5AP gene variant with the risk of IS in the Sardinian cohort. Haplotype analysis, including that constructed with allele 0 of microsatellite AC008818-1 and SNP45 of the PDE4D gene, was also negative. In conclusion, we found no evidence of association between PDE4D and ALOX5AP genes and the risk of IS in a genetically homogenous population from Sardinia.     

The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility

Background: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl‐LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB₄ in airway disease. LTA₄ hydrolase and 5‐lipoxygenase activating protein have key roles in LTB₄ production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB₄ production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Methods: Three hundred and forty‐one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper‐responsiveness, FEV₁) were undertaken using the Family Based Association Test. Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042–0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41–3.32). Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB₄ in disease pathogenesis.     

Association of ALOX5AP gene single nucleotide polymorphisms and cerebral infarction in the Han population of northern China

ABSTRACT: BACKGROUND: To explore the association of ALOX5AP single nucleotide polymorphisms (SNPs) and haplotype with the occurrence of cerebral infarction in the Han population of northern China. METHODS: Blood samples were collected from 236 patients of Han ancestry with a history of cerebral infarction and 219 healthy subjects of Han ancestry with no history of cerebral infarction or cardiovascular disease. Applied Biosystems(R) TaqMan(R) SNP Genotyping Assays for SNP genotyping were used to determine the genotypes of 7 ALOX5AP SNP alleles (rs4073259, rs4769874, rs9315050, rs9551963, rs10507391, rs9579646, and rs4147064). RESULTS: One SNP allele (A) of rs4073259 was significantly associated with development of cerebral infarction (P = 0.049). In comparison to control groups, haplotype rs9315050&rs9551963 AAAC [OR (95 % CI) =1.53 (1.02-2.29)], and genotypes rs4147064 CT [OR (95 % CI) =1.872 (1.082-3.241)], and rs9551963 AC [OR (95 % CI) = 2.015 (1.165-3.484)] increased the risk of cerebral infarction in patients with hypertension. Genotype rs9579646 GG [OR (95 % CI) = 2.926 (1.18-7.251)] increased the risk of, while rs4073259 GG [OR (95 % CI) = 0.381 (0.157-0.922)] decreased the risk of cerebral infarction in patients with diabetes. CONCLUSION: These results suggest the ALOX5AP SNP A allele in rs4073259 and genotype rs9579646 GG, rs9551963 AC, and haplotype rs9315050 & rs9551963 AAAC were associated with an increased risk of ischemic stroke in the Han population, while rs4073259 GG was associated with a decreased risk.     

Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia

Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation‐associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti‐inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population‐based case‐control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20–0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ≤ 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia. © 2013 Wiley Periodicals, Inc.     

No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes

Background

While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD.

Methods

In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes.

Results

Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (p_nom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (p_threshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed.

Limitations

Low statistical power might increase our type II error rate.

Conclusions

The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development.     

Impact of population admixture on the distribution of immune response co-stimulatory genes polymorphisms in a Brazilian population

Co-stimulatory molecules are essential in the orchestration of immune response and polymorphisms in their genes are associated with various diseases. However, in the case of variable allele frequencies among continental populations, this variation can lead to biases in genetic studies conducted in admixed populations such as those from Brazil. The aim of this study was to evaluate the influence of genomic ancestry on distributions of co-stimulatory genes polymorphisms in an admixed Brazilian population. A total of 273 individuals from the north of Brazil participated in this study. Nine single nucleotide polymorphisms in 7 genes (CD28, CTLA4, ICOS, CD86, CD40, CD40L and BLYS) were determined by polymerase chain reaction-restriction fragment length polymorphism. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. The analysis showed that the main contribution was European (43.9%) but also a significant contribution of African (31.6%) and Amerindian (24.5%) ancestry. ICOS, CD40L and CD86 polymorphisms were associated with genomic ancestry. However there were no significant differences in the proportions of ancestry for the other SNPs and haplotypes studied. Our findings reinforce the need to apply AIMs in genetic association studies involving these polymorphisms in the Brazilian population.     

Genetic variants in COL13A1, ADIPOQ and SAMM50, in addition to the PNPLA3 gene,confer susceptibility to elevated transaminase levels in an admixed Mexican population

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥ 40 IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9–12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1–4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis.     

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.     

Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study

Essential hypertension is a major cardiovascular risk factor and a large proportion of this risk is genetic. Identification of genomic regions consistently associated with hypertension has been difficult in association studies to date as this requires large sample sizes.We previously published a large genome-wide linkage scan in Americans of African (AA) and European (EA) descent in the GenNet Network of the Family Blood Pressure Program (FBPP). A highly significant linkage peak was identified on chr1q spanning a region of 100 cM. In this study, we genotyped 1569 SNPs under this linkage peak in 2379 individuals to identify whether common genetic variants were associated with blood pressure (BP) at this locus.Our analysis, using two different family-based association tests, provides suggestive evidence (P≤2 × 10⁻⁵) for a collection of single nucleotide polymorphisms (SNPs) associated with BP. In EAs, using diastolic BP as a quantitative phenotype, three variants located in or near the GPA33, CD247, and F5 genes, emerge as our top hits; for systolic BP, variants in GPA33, CD247, and REN are our best findings. No variant in AAs came close to suggestive evidence after multiple-test corrections (P≥8 × 10⁻⁵).In summary, we show that systematic follow-up of a linkage signal can help discover candidate variants for essential hypertension that require a follow-up in yet larger samples. The failure to identify common variants is either because of low statistical power or the existence of rare coding variants in specific families or both, which require additional studies to clarify.     

Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region

Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies reported ambiguous findings. We examined 932 ischaemic stroke patients from a Swedish population-based stroke register, and 396 control subjects. We assessed possible associations between ischaemic stroke and nine preselected SNPs in the chromosome regions of the PDE4D gene, including rs12188950 (SNP45) and rs3887175 (SNP39); the ALOX5AP gene, including rs17222814 (SG13S25) and the promoter region of the MHC class II transactivator, MHC2TA. The T allele of SNP45 showed negative association with ischaemic stroke (odds ratio, OR=0.72; 95% confidence interval (CI): 0.58-0.91; P=0.0055). Among hypertensive subjects, this influence of the T allele of SNP45, and the T allele of SNP39, were more pronounced (with OR=0.52; 95% CI: 0.37-0.73; P=0.0001 and OR=0.57; 95% CI: 0.41-0.79; P=0.0007, respectively). These SNPs also interacted with hypertension with a relative excess risk due to interaction of -1.66 (P=0.0002) for SNP45 and -1.65 (P=0.0005) for SNP39. The P-values remained significant after correction for multiple testing. Among nonhypertensives, the A allele of SG13S25 indicated increased stroke risk (OR=1.82; 95% CI: 1.21-2.74; P=0.0039; not significant after Bonferroni correction). SNP45 was associated with ischaemic stroke even when controlling for hypertension, diabetes, heart disease and smoking. Our meta-analysis of 13 studies (including ours) showed no overall influence of SNP45 on ischaemic stroke. However, the 13 studies may differ because of nonrandom causes, as suggested by the heterogeneity test (P=0.042). This might support previously undetected mechanisms causing fluctuating ischaemic stroke risk.European Journal of Human Genetics (2008) 16, 1117-1125; doi:10.1038/ejhg.2008.62; published online 9 April 2008.     

Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome

Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11 K single nucleotide polymorphisms (SNPs) following the manufacturer’s protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5′ UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.     

Dengue hemorrhagic fever is associated with polymorphisms in JAK1

To identify genes associated with the clinical presentation of dengue, 50 cases of probable or possible dengue hemorrhagic fever (DHF), 236 dengue fever (DF), and 236 asymptomatic infections were genotyped for 593 single-nucleotide polymorphisms (SNPs) in 56 genes across the type 1 interferon (IFN) response pathway as well as other important candidate genes. By single locus analysis comparing DHF with DF, 11 of the 51 markers with P<0.05 were in the JAK1 gene. Five markers were significantly associated by false discovery rate criteria (q<0.20 when P<6 × 10⁻⁴). The JAK1 SNPs showed differential distribution by ethnicity and ancestry consistent with epidemiologic observations in the Americas. The association remained significant after controlling for ancestry and income. No association was observed with markers in the gene encoding CD209 (DC-SIGN). An association between DHF and JAK1 polymorphisms is in agreement with expression profiles showing generalized decreased type 1 IFN-stimulated gene expression in these patients.     

The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos

Background Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of arachidonate 5‐lipoxygenase‐activating protein (ALOX5AP) and leukotriene A₄ hydrolase (LTA4H) in asthma have been inconclusive. Objective To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans. Methods The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single‐nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analysed for associations with asthma and asthma‐related phenotypes in 687 parent–child trios of Mexican and Puerto Rican origin. Results In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P=0.007 and 0.05, respectively). Among the Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (odds ratio=0.78, P=0.02) and baseline lung function (P=0.018) in Puerto Ricans. A gene–gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P=0.003, in the combined sample). Conclusion Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations. Cite this as: M. Via, A. De Giacomo, H. Corvol, C. Eng, M. A. Seibold, C. Gillett, J. Galanter, S. Sen, H. Tcheurekdjian, R. Chapela, J. R. Rodríguez‐Santana, W. Rodríguez‐Cintrón, S. Thyne, P. C. Avila, S. Choudhry and E. González Burchard on behalf of the Genetics of Asthma in Latino Americans (GALA) Study, Clinical & Experimental Allergy, 2010 (40) 582–589.     

Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis

A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI=1.08–1.54), rs11808092 (P=0.048, OR=1.19; 95% CI=1.03–1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI=1.07–1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r²=1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS.     

MYO9B polymorphisms in multiple sclerosis

Single-nucleotide polymorphisms (SNPs) in the 3′ region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.     

Sickle cell anemia: Intracranial stenosis and silent cerebral infarcts in children with low risk of stroke

Purpose:Children with sickle cell anemia (SCA), who have mean blood flow velocities <170 cm/s in the terminal internal carotid (tICA) or middle cerebral (MCA) arteries on transcranial Doppler ultrasonography (TCD), are considered to be at low risk of stroke. The prevalence of intracranial stenosis, which raises the risk of stroke, is not known in these children. Here, we estimated the prevalence of stenosis and explored its association with silent cerebral infarcts determined based on Magnetic Resonance (MR) scans.Patients/methodsWe studied prospectively a cohort of 67 children with SCA without prior clinically overt stroke or TIA (median age 8.8 years; range limits 2.3–13.1 years; 33 females) and with TCD mean velocity <170 cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries.ResultsIn 7 children (10.5%, 95% CI: 4.9–20.3%) we found 10 stenoses, including 4 with isolated left tICA stenosis and 3 with multiple stenoses. We found silent infarcts in 26 children (37.7%, 95% CI: 27.2–49.5%). The median number of infarcts in an affected child was 2 (range limits: 1–9), median volume of infarcts was 171 mm³ (range limits: 7–1060 mm³), and median infarct volume in relation to total brain volume was 0.020% (range limits: 0.001–0.101%). The number and volume of infarcts were significantly higher in children with arterial stenosis (both p = 0.023).ConclusionsThe prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170 cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts.     

Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

Background

Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.

Methods

Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).

Results

Associations at p < 10^-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10^-3; lowest p-value, rs6683968, p = 1 × 10^-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.

     

Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.