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SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention - the TULIP Study
Background:
Sirtuin1 (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes.
Methods:
A total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF) were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773) for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP). Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques) after the 9-month follow-up test in the TULIP study.
Results:
Minor allele (X/A) carriers of rs12413112 (G/A) had a significantly lower basal energy expenditure (p=0.04) and an increased respiratory quotient (p=0.02). This group (rs12413112: X/A) was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p=0.04), had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p=0.05) and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p=0.01).
Conclusions:
SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic variants may, therefore, represent a relevant determinant for the response rate of individuals undergoing caloric restriction and increased physical activity.
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A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan
Background:
Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667). Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene.
Methods:
A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4) were sequenced. A mutation-specific restriction enzyme digest (HphI) was performed for all family members and unrelated controls.
Results:
The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at theta = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C>T in this family predicting an arginine to stop codon exchange (p.R405X).
Conclusion:
We identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.
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Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPAR-gamma-2 gene polymorphisms. The AVENA Study
Background:
There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-gamma-2 (PPAR-gamma-2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13-18.5 years.
Methods:
A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated.
Results:
Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE epsilon3epsilon4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPAR-gamma-2 genotypes.
Conclusions:
The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE E3/E4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life.
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A new 500kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis
Background:
Hereditary Hemochromatosis(HH) is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables.
Methods:
Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers). An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters.
Results:
A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T) was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G) was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese patients were also observed in the geographically different population of Canadian patients, also predicting CD8+ T-lymphocyte numbers and the severity of disease.
Conclusions:
These results may have important implications not only for approaching the question of the penetrance of the hemochromatosis gene in different world populations but also to further narrow the region of interest to find a candidate gene involved in the setting of CD8+ T-lymphocyte numbers in humans.
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Non-synonymous sequence variants within the oxygen-dependent degradation domain of the HIF1A gene are not associated with pre-eclampsia in the Finnish population
Background:
Reduced placental perfusion predisposes to the maternal syndrome pre-eclampsia characterized by systemically reduced perfusion. Considerable data support the role of angiogenic factors in the development of the maternal syndrome. Hypoxia-inducible factor (HIF-1) mediates the cellular responses to hypoxia e.g. by promoting angiogenesis.
Methods:
Here we studied whether two single nucleotide sequence variants, c.1744 C>T that changes residue 582 of HIF-1alpha from proline to serine (P582S) and c.1762 G>A that changes residue 588 of HIF-1alpha from alanine to threonine in the exon 12 of the HIF1A gene, are associated with pre-eclampsia. We studied 108 women with pre-eclampsia in their first pregnancy, and 101 controls with normotensive pregnancies. Pre-eclampsia was defined as a blood pressure level of at least 140/90 mmHg in a woman who was normotensive before 20 weeks of gestation, and proteinuria at least of 0.3 g per 24-hour urine collection. The patients and controls were genotyped for variations in the exon 12 of HIF1A gene by sequencing
Results:
The frequencies of the c.1744 C>T and c.1762G>A sequence variants were not significantly different between women with pre-eclamptic first pregnancies and women with normotensive pregnancies. In addition, two synonymous variants (c.1740G>A and c.1800A>T) were detected at comparable levels in the two groups. All variants were identified in the heterozygous form.
Conclusions:
The sequence variants in the exon 12 of the HIF1A gene were not associated with pre-eclampsia in the Finnish population.
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Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene
Background:
Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations.
Methods:
87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.
Results:
In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.
Conclusion:
MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.
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Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population
Background:
It is known that steroid usage and alcohol abuse are major etiological factors in the development of avascular necrosis (AVN), a bone disease that produces osteonecrosis of the femoral head. The facilitation of fat biosynthesis by steroids and alcohol disrupts the blood supply into the femoral head. SREBP-2 plays a central role in the maintenance of lipid homeostasis through stimulating expression of genes associated with cholesterol biosynthetic pathways. The aim of this study was to examine the association between the polymorphisms of the SREBP-2 gene and AVN susceptibility in the Korean population.
Methods:
Four single nucleotide polymorphisms (SNP) in the SREBP-2 gene, IVS1+8408 T>C (rs2267439), IVS3-342 G>T (rs2269657), IVS11+414 G>A (rs1052717) and IVS12-1667 G>A (rs2267443), were selected from public databases and genotyped in 443 AVN patients and 273 control subjects by using single-based extension (SBE) genotyping.
Results:
The minor allele (C) frequency of rs2267439 showed a significant protective effect on AVN (P = 0.01, OR; 0.75, 95% CI; 0.604-0.935), and the genotype frequencies of this polymorphism were also different from the controls in all alternative analysis models (P range, 0.009 - 0.03, OR; 0.647-0.744). In contrast, rs1052717 and rs2267443 polymorphisms were significantly associated with AVN risk. Further analysis based on pathological etiology showed that the genotypes of rs2267439, rs1052717 and rs2267443 were also significantly associated with AVN susceptibility in each subgroup.
Conclusion:
This study is the first report to evaluate the association between SREBP-2 gene polymorphisms and the susceptibility of AVN in the Korean population.
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Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival
Background:
Persistent stimulation of cardiac beta1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the alpha2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients.
Methods:
Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation.
Results:
Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes.
Conclusions:
Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.
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Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene
Background:
Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.
Methods:
Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.
Results:
We identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.
Conclusion:
We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.
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Lack of association between the CALM1 core promoter polymorphism (-16C/T) and susceptibility to knee osteoarthritis in a Chinese Han population
Background:
CALM1 gene encodes calmodulin (CaM), an important and ubiquitous eukaryotic Ca2+-binding protein. Several studies have indicated that a deficient CaM function is likely to be involved in the pathogenesis of osteoarthritis (OA). Using a convincing genome-wide association study, a Japanese group has recently demonstrated a genetic association between the CALM1 core promoter polymorphism (-16C/T transition SNP, rs12885713) and OA susceptibility. However, the subsequent association studies failed to provide consistent results in OA patients of differently selected populations. The present study is to evaluate the association of the -16C/T polymorphism with knee OA in a Chinese Han population.
Methods:
A case-control association study was conducted. The polymorphism was genotyped in 183 patients who had primary symptomatic knee OA with radiographic confirmation and in 210 matched controls. Allelic and genotypic frequencies were compared between patients and control subjects.
Results:
No significant difference was detected in genotype or allele distribution between knee OA and control groups (all P > 0.05). The association was also negative even after stratification by sex. Furthermore, no association between the -16C/T SNP genotype and the clinical variables age, sex, BMI (body mass index) and K/L (Kellgren/Lawrence) score was observed in OA patients.
Conclusion:
The present study suggests that the CALM1 core promoter polymorphism -16C/T is not a risk factor for knee OA susceptibility in the Chinese Han population. Further studies are needed to give a global view of this polymorphism in pathogenesis of OA.
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