-
TGFB1 genetic polymorphisms and coronary heart disease risk: a meta-analysis
Background:
Genetic variations in TGFB1 gene have been studied in relation to coronary heart disease (CHD) risk, but the results were inconsistent.
Methods:
We performed a systematic review of published studies on the potential role of TGFB1 genetic variation in CHD risk. Articles that reported for the association of TGFB1 genetic variants with CHD as primary outcome were searched via Medline and HuGE Navigator through July 2011. The reference lists from included articles were also reviewed.
Results:
Data were available from 4 studies involving 1777 cases and 7172 controls for rs1800468, 7 studies involving 5935 cases and 10677 controls for rs1800469, 7 studies involving 6634 cases and 9620 controls for rs1982073, 5 studies involving 5452 cases and 9999 controls for rs1800471, and 4 studies involving 5143 cases and 4229 controls for rs1800472. The pooled odds ratios (ORs) for CHD among minor T allele carriers of rs1800469, minor C allele carriers of rs1982073, and minor C allele carriers of rs1800471 versus homozygous major allele carriers was 1.14 (95% confidence interval [CI]: 1.05-1.24), 1.18 (95% CI: 1.04-1.35), and 1.16 (95% CI: 1.02-1.32), respectively. No substantial heterogeneity for ORs was detected among the included Caucasian populations for all SNPs. However, for rs1800471, the statistical significance disappeared after adjusting for potential publication bias. No significant association was found between rs1800468 and rs1800472 variants and CHD risk.
Conclusion:
Two genetic variants (rs1800469 and rs1982073) in TGFbeta1 are associated with CHD risk, minor allele carriers having a 15% increased risk.
-
Circulating leukocyte telomere length is highly heritable among families of Arab descent
Background:
Telomere length, an indicator of ageing and longevity, has been correlated with several biomarkers of cardiometabolic disease in both Arab children and adults. It is not known,however, whether or not telomere length is a highly conserved inheritable trait in thishomogeneous cohort, where age-related diseases are highly prevalent. As such, the aim of this study was to address the inheritability of telomere length in Saudi families and the impactof cardiometabolic disease biomarkers on telomere length.
Methods:
A total of 119 randomly selected Saudi families (123 adults and 131 children) were included in this cross-sectional study. Anthropometrics were obtained and fasting blood samples weretaken for routine analyses of fasting glucose and lipid profile. Leukocyte telomere length was determined using quantitative real time PCR.
Results:
Telomere length was highly heritable as assessed by a parent-offspring regression [h2 = 0.64 (p = 0.0006)]. Telomere length was modestly associated with BMI (R2 0.07; p-value 0.0087),total cholesterol (R2 0.08; p-value 0.0033), and LDL-cholesterol (R2 0.15; p-value 3 x 10-5) after adjustments for gender, age and age within generation.
Conclusion:
The high heritability of telomere length in Arab families, and the associations of telomere length with various cardiometabolic parameters suggest heritable genetic fetal and/or epigenetic influences on the early predisposition of Arab children to age-related diseases and accelerated ageing.
-
Reliable and rapid characterization of functional
FCN2 gene variants reveals diverse geographical
patterns
Background:
Ficolin-2 coded by FCN2 gene is a soluble serum protein and an innate immune recognitionelement of the complement system. FCN2 gene polymorphisms reveal distinct geographicalpatterns and are documented to alter serum ficolin levels and modulate disease susceptibility.
Methods:
We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET)method to genotype four functional SNPs including -986 G > A (#rs3124952), -602 G > A(#rs3124953), -4A > G (#rs17514136) and +6424 G > T (#rs7851696) in the ficolin-2(FCN2) gene. We characterized the FCN2 variants in individuals representing Brazilian (n =176), Nigerian (n = 180), Vietnamese (n = 172) and European Caucasian ethnicity (n = 165).
Results:
We observed that the genotype distribution of three functional SNP variants (986 G > A, -602 G > A and -4A > G) differ significantly between the populations investigated (p <0.0001). The SNP variants were highly linked to each other and revealed significantpopulation patterns. Also the distribution of haplotypes revealed distinct geographicalpatterns (p < 0.0001).
Conclusions:
The observed distribution of the FCN2 functional SNP variants may likely contribute toaltered serum ficolin levels and this may depend on the different disease settings in worldpopulations. To conclude, the use of FRET based real-time PCR especially for FCN2 genewill benefit a larger scientific community who extensively depend on rapid, reliable methodfor FCN2 genotyping.
-
The MAP2K5-linked SNP rs2241423 is associated
with BMI and obesity in two cohorts of Swedish and
Greek children
Background:
Recent genome-wide association studies have identified a single nucleotide polymorphismwithin the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults.MAP2K5 is a component of the MAPK-family intracellular signaling pathways, respondingto extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nervegrowth factor (NGF). In this study, we examined the association of this variant in two cohortsof children from Sweden and Greece.
Methods:
We examine the association of rs2241423 to BMI in a cohort of 474 Swedish childrenadmitted for treatment of childhood obesity and 519 children matched for gender, ethnicityand socioeconomic background from the Stockholm area, as well as a cross-sectional cohortof 2308 Greek school children (Healthy Growth Study). Children were genotyped using apredesigned TaqMan polymorphism assay. Logistic regression was used to test for anassociation of rs2241423 to obesity in the cohort of Swedish children. Linear regression wasused to test for an association of rs2241423 to BMI z-score and phenotypic in the cohort ofGreek children. Models were adjusted for age and gender. In the cohort of Greek children themodel was also adjusted for stage of pubertal development.
Results:
The minor allele of rs2241423, allele A, was associated with a protective effect againstobesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), andwith a lower BMI z-score in the cohort of Greek children (p = 0.028, beta = 0.092). Noassociation to phenotypic measurements of body fat distribution could be observed in ourstudy.
Conclusions:
rs2241423 was associated with BMI and obesity in two independent European cohortssuggesting a role for MAP2K5 in early weight regulation.
-
Computational identification and experimental
validation of microRNAs binding to the Alzheimerrelated
gene ADAM10
Background:
MicroRNAs (miRNAs) are post-transcriptional regulators involved in numerous biologicalprocesses including the pathogenesis of Alzheimer's disease (AD). A key gene of AD,ADAM10, controls the proteolytic processing of APP and the formation of the amyloidplaques and is known to be regulated by miRNA in hepatic cancer cell lines. To predictmiRNAs regulating ADAM10 expression concerning AD, we developed a computationalapproach.
Methods:
MiRNA binding sites in the human ADAM10 3' untranslated region were predicted using theRNA22, RNAhybrid and miRanda programs and ranked by specific selection criteria withrespect to AD such as differential regulation in AD patients and tissue-specific expression.Furthermore, target genes of miR-103, miR-107 and miR-1306 were derived from six publiclyavailable miRNA target site prediction databases. Only target genes predicted in at least fourout of six databases in the case of miR-103 and miR-107 were compared to genes listed in theAlzGene database including genes possibly involved in AD. In addition, the target geneswere used for Gene Ontology analysis and literature mining. Finally, we used a luciferaseassay to verify the potential effect of these three miRNAs on ADAM10 3' UTR in SH-SY5Ycells.
Results:
Eleven miRNAs were selected, which have evolutionary conserved binding sites. Three ofthem (miR-103, miR-107, miR-1306) were further analysed as they are linked to AD and moststrictly conserved between different species. Predicted target genes of miR-103 (p-value =0.0065) and miR-107 (p-value = 0.0009) showed significant overlap with the AlzGenedatabase except for miR-1306. Interactions between miR-103 and miR-107 to genes wererevealed playing a role in processes leading to AD. ADAM10 expression in the reporter assaywas reduced by miR-1306 (28%), miR-103 (45%) and miR-107 (52%).
Conclusions:
Our approach shows the requirement of incorporating specific, disease-associated selectioncriteria into the prediction process to reduce the amount of false positive predictions. Insummary, our method identified three miRNAs strongly suggested to be involved in AD,which possibly regulate ADAM10 expression and hence offer possibilities for thedevelopment of therapeutic treatments of AD.
-
A novel multiplex PCR-RFLP method for
simultaneous detection of the MTHFR 677 C > T,
eNOS +894 G > T and - eNOS -786 T > C variants
among Malaysian Malays
Background:
Hyperhomocysteinemia as a consequence of the MTHFR 677 C > T variant is associated withcardiovascular disease and stroke. Another factor than can potentially contribute to thesedisorders is a depleted nitric oxide level, which can be due to the presence of eNOS +894 G > Tand eNOS 786 T > C variants that make an individual more susceptible to endothelialdysfunction. A number of genotyping methods have been developed to investigate these variants.However, simultaneous detection methods using polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) analysis are still lacking. In this study, a novel multiplexPCR-RFLP method for the simultaneous detection of MTHFR 677 C > T and eNOS +894 G > Tand eNOS 786 T > C variants was developed. A total of 114 healthy Malay subjects wererecruited. The MTHFR 677 C > T and eNOS +894 G > T and eNOS 786 T > C variants weregenotyped using the novel multiplex PCR-RFLP and confirmed by DNA sequencing as well assnpBLAST. Allele frequencies of MTHFR 677 C > T and eNOS +894 G > T and eNOS 786 T >C were calculated using the Hardy Weinberg equation.
Methods:
The 114 healthy volunteers were recruited for this study, and their DNA was extracted. Primerpair was designed using Primer 3 Software version 0.4.0 and validated against the BLASTdatabase. The primer specificity, functionality and annealing temperature were tested usinguniplex PCR methods that were later combined into a single multiplex PCR. RestrictionFragment Length Polymorphism (RFLP) was performed in three separate tubes followed byagarose gel electrophoresis. PCR product residual was purified and sent for DNA sequencing.
Results:
The allele frequencies for MTHFR 677 C > T were 0.89 (C allele) and 0.11 (T allele); for eNOS+894 G > T, the allele frequencies were 0.58 (G allele) and 0.43 (T allele); and for eNOS 786 T> C, the allele frequencies were 0.87 (T allele) and 0.13 (C allele).
Conclusions:
Our PCR-RFLP method is a simple, cost-effective and time-saving method. It can be used tosuccessfully genotype subjects for the MTHFR 677 C > T and eNOS +894 G > T and eNOS786 T > C variants simultaneously with 100 % concordance from DNA sequencing data. Thismethod can be routinely used for rapid investigation of the MTHFR 677 C > T and eNOS +894G > T and eNOS 786 T > C variants.
-
The genetic variants at the HLA-DRB1 gene are
associated with primary IgA nephropathy in Han
Chinese
Background:
Immunoglobulin A nephropathy (IgAN), an immune-complex-mediated glomerulonephritisdefined immunohistologically by the presence of glomerular IgA deposits, is the mostcommon primary glomerular disease worldwide and a significant cause of end-stage renaldisease. Familial clustering of patients with IgAN suggests a genetic predisposition.
Methods:
In this study, 192 patients with IgAN and 192 normal controls in the Sichuan cohort and 935patients with IgAN and 2,103 normal controls in the Beijing cohort were investigated. HLADRB1*01-DRB1*10 specificities were genotyped by the PCR-SSP technique in bothcohorts. Based on the HLA-DRB1*04-positive results, the subtypes of HLA-DRB1*04 wereanalyzed using sequencing-based typing (SBT) in 291 IgAN cases and 420 matched controls.
Results:
The frequency of HLA-DRB1*04 in the IgAN group was significantly higher than that in thecontrol group (0.129 vs. 0.092, P = 8.29 x 10-5, odds ratio (OR) =1.381, 95% confidenceinterval (CI) 1.178-1.619). Other alleles at the HLA-DRB1 locus were observed with nosignificant differences between the case and control groups. The dominant alleles of theHLA-DRB1*04 subtypes were DRB1*0405 in both cohorts. The frequencies of HLADRB1*0405 and 0403 were significantly increased in the patients compared to healthysubjects.
Conclusion:
HLA-DRB1*04 was significantly associated with primary IgAN in Chinese population. Thisresult implies that HLA-DRB1 gene plays a major role in primary IgAN.
-
No Association of nineteen COX-2 gene variants to
preclinical markers of atherosclerosis The
Cardiovascular Risk in Young Finns Study
BackgroudThe role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly beenstudied in relation to advanced atherosclerosis, but little is known how they contribute topreclinical disease. In the present study we analyzed whether COX-2 gene variants associateindependently with the early subclinical markers of atherosclerosis, carotid intima-mediathickness and carotid artery distensibility in a population of young healthy Caucasian adults.
Methods:
SNPs for association analysis were collected from the COX-2 gene and 5 kb up- anddownstream of it. There were 19 SNPs available for analysis, four genotyped and fifteenimputed. Genotype data was available for 2442 individuals participating in theCardiovascular Risk in Young Finns Study. Genotype imputation was performed usingMACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis wasperformed using linear regression with an additive model. PLINK was used for truegenotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate wasused to take into account multiple testing bias.
Results:
Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005)under the linear regression additive model. After adjustment with gender, age, body massindex and smoking status, association between these SNPs and distensibility remainedsignificant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid arterydistensibility compared to the major allele homozygotes. However, after correcting p-valuesfor multiple testing bias using false discovery rate, association was lost. Another COX-2variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) andmaximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjectscarrying the minor allele of rs4648261 had lower values of mean and maximal carotid intimamediathickness compared to subjects homozygote for major allele. After adjustments theassociations were lost with both mean and maximal carotid intima-media thickness. Thus, nostatistically significant associations of the studied COX-2 variants with carotid arterydistensibility or carotid intima-media thickness were found.
Conclusions:
Our results suggest that in a Finnish population, there are no significant associations betweenCOX-2 variants and early atherosclerotic changes in young adulthood.
-
Polymorphisms in the mitochondrial oxidative
phosphorylation chain genes as prognostic markers
for colorectal cancer
Background:
Currently, the TNM classification of malignant tumours based on clinicopathological stagingremains the standard for colorectal cancer (CRC) prognostication. Recently, we identified themitochondrial oxidative phosphorylation chain as a consistently overrepresented category inthe published gene expression profiling (GEP) studies on CRC prognosis.
Methods:
We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) ingenes from the oxidative phosphorylation chain with survival and disease prognosis in 613CRC patients from Northern Germany (PopGen cohort).
Results:
Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 andrs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR =0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group ofpatients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95%CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independentprognostic markers. Additionally, the TT carriers were ~2 times more likely to developtumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) wereassociated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also withdistant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model).
Conclusions:
This is the first report suggesting that markers in genes from the mitochondrial oxidativechain might be prognostic factors for CRC. Additional studies replicating the presentedfindings are needed.
-
Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III)
Background:
Hemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality.
Methods:
We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05.
Results:
RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (beta = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (beta = 0.021, p = 0.005) but not NHB (beta = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71).
Conclusion:
At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.
|
