Family History of MI, Smoking, and Risk of Periodontal Disease.

Periodontal disease (PD) shares common risk factors with cardiovascular disease. Our hypothesis was that having a family history of myocardial infarction (FamHxMI) may be a novel risk factor for PD. Risk assessment based on FamHxMI, conditional on smoking status, was examined given the strong influence of smoking on PD.

Interleukin-1 genotypes modulate the long-term effect of lipoprotein(a) on cardiovascular events: The Ioannina Study.

Background: Lipoprotein(a) [Lp(a)] is a genetic risk factor for cardiovascular disease (CVD), and proinflammatory interleukin-1 (IL-1) genotypes may influence Lp(a)-mediated CVD events. The genotype IL-1(+) is associated with higher rates of inflammation than IL-1(-) genotype. Targeting IL-1β was recently shown to decrease CVD events independent of low-density lipoprotein-cholesterol levels.

Influence of Obesity on Periodontitis Progression Is Conditional on Interleukin-1 Inflammatory Genetic Variation.

Background: This study evaluates whether specific patterns of interleukin (IL)-1 gene variants, known to affect periodontitis severity, influence the previously reported association between obesity and subsequent periodontitis progression in a longitudinal database. The study population included 292 men (aged 29 to 64 years at entry) from the Veterans Affairs Dental Longitudinal Study from whom DNA and dental and anthropometric endpoints were collected during multiple examinations (approximately every 3 years for up to 27 years).

Methods: Key variables assessed included: 1) periodontitis; 2) body mass index; 3) waist circumference to height (WHTR) ratio for central adiposity; 4) age; 5) smoking; 6) glucose tolerance; and 7) two previously reported versions of IL-1 genetic patterns associated with periodontitis severity and progression.

Implementation of routine foot check in patients with diabetes on hemodialysis: associations with outcomes.

Objective: Patients with diabetes are at increased risk of foot ulcers, which may result in limb amputations. While regular foot care prevents ulcerations and amputation in those patients with diabetes not on dialysis, evidence is limited in diabetic hemodialysis patients. We investigated the association between the implementation of a routine foot check program in diabetic incident hemodialysis patients, and major lower limb amputations.

Association of interleukin-1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities.

Background And Objective: Genetic markers associated with disease are often non-functional and generally tag one or more functional "causative" variants in linkage disequilibrium. Markers may not show tight linkage to the causative variants across multiple ethnicities due to evolutionary divergence, and therefore may not be informative across different population groups. Validated markers of disease suggest causative variants exist in the gene and, if the causative variants can be identified, it is reasonable to hypothesize that such variants will be informative across diverse populations.

Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a).

Objectives: The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a).

Background: OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators.

Blood pressure stability in hemodialysis patients confers a survival advantage: results from a large retrospective cohort study.

The association between changes in systolic and diastolic blood pressure, and the use of cardioprotective drugs on survival of incident hemodialysis patients, was examined in this retrospective cohort study. Pre-hemodialysis systolic and diastolic blood pressures were averaged over the first month of hemodialysis. Slopes, reflecting temporal changes, were computed by linear regression of systolic blood pressures and Cox regression was used for survival analyses.

Differentiating population stratification from genotyping error using family data.

Identifying population stratification and genotyping error are important for candidate gene association studies using the Transmission Disequilibrium Test (TDT). Although the TDT retains the prespecified Type I error in the presence of population stratification, the test may have decreased power in the presence of population stratification. Genotyping error can also cause the TDT to have an elevated Type I error.

Testing for non-random mating: evidence for ancestry-related assortative mating in the Framingham heart study.

Population stratification leads to a predictable phenomenon-a reduction in the number of heterozygotes compared to that calculated assuming Hardy-Weinberg Equilibrium (HWE). We show that population stratification results in another phenomenon-an excess in the proportion of spouse-pairs with the same genotypes at all ancestrally informative markers, resulting in ancestrally related positive assortative mating. We use principal components analysis to show that there is evidence of population stratification within the Framingham Heart Study, and show that the first principal component correlates with a North-South European cline.

The power of the Transmission Disequilibrium Test in the presence of population stratification.

The Transmission Disequilibrium Test (TDT) is a family-based test for association based on the rate of transmission of alleles from heterozygous parents to affected offspring, and has gained popularity as this test preserves the Type I error rate. Population stratification results in a decreased number of heterozygous parents compared to that expected assuming Hardy-Weinberg Equilibrium (Wahlund Effect). We show that population stratification changes the relative proportion of the informative mating types.

Interleukin 1 gene cluster, myocardial infarction at young age and inflammatory response of human mononuclear cells.

The objective was to investigate whether genotypes, haplotypes and haplotype-pairs of interleukin (IL) gene cluster are associated with risk of Myocardial Infarction (MI) at young age and with the release of IL-1B and expression of tissue factor pro-coagulant activity (TFPCA), after stimulation in vitro with lipopolysaccharide (LPS) of human peripheral blood mononuclear cells (PBMCs). Patients with MI at young age, frequency-matched for age, sex and recruitment centre, with healthy population-based controls and PBMCs from healthy volunteers were studied. Five single nucleotide polymorphisms (SNPs), identifying two haplotype-blocks, in IL-1B gene and one SNP in IL-1A and IL-RA genes were genotyped.

Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

Objective: Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection.

Research Design And Methods: We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes.

The association of race with erythropoietin dose in patients on long-term hemodialysis.

Background: Medicare data indicate that black hemodialysis patients receive greater doses of erythropoietin (EPO) than white patients when achieving similar hemoglobin levels. We confirmed and evaluated this observed association between race and EPO dose.

Study Design: Cross-sectional cohort study.

High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.

Objective: Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes.

Research Design And Methods: To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis.

IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1beta and C-reactive protein.

Interleukin-1beta (IL-1beta) activates inflammatory mediator cascades and has been implicated in the pathogenesis of several diseases. Single nucleotide polymorphisms (SNPs) of the IL1B promoter have been associated with various inflammatory diseases. We recently reported that IL1B gene transcription was influenced by four promoter SNPs, and that individual SNP function in vitro was governed by haplotype context.

Interleukin-1 genotype-selective inhibition of inflammatory mediators by a botanical: a nutrigenetics proof of concept.

Objective: Although observational studies have shown that genotype may influence nutritional effects on target outcomes, there are few reported studies that stratified subjects by genotype before a nutritional intervention. This proof-of-concept trial determined whether specifically formulated botanical mixtures reduced inflammation in individuals with genetic variations that predispose to overexpression of interleukin-1beta (IL-1beta) and early heart disease.

Methods: Healthy adults with elevated C-reactive protein (CRP) were stratified into genetic groups based on being positive (IL1(Pos)) or negative (IL1(Neg)) for the at-risk IL-1 gene variations.

Analysis of TBX1 variation in patients with psychotic and affective disorders.

A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders, including schizophrenia and other psychotic and affective symptoms, and the responsible gene/s are assumed to also play a significant role in the etiology of nonsyndromic psychiatric disease. The most common psychiatric diagnosis among patients with 22q11DS is schizophrenia, thought to result from neurotransmitter imbalances and also from disturbed brain development. Several genes in the 22q11 region with known or suspected roles in neurotransmitter metabolism have been analyzed in patients with isolated schizophrenia; however, their contribution to the disease remains controversial.

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes.

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results.

Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes.

The Genetics of Kidneys in Diabetes (GoKinD) study is an initiative that aims to identify genes that are involved in diabetic nephropathy. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled.

Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context.

We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays.

A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes.

The main hallmark of diabetic nephropathy is elevation in urinary albumin excretion. We performed a genome-wide linkage scan in 63 extended families with multiple members with type II diabetes. Urinary albumin excretion, measured as the albumin-to-creatinine ratio (ACR), was determined in 426 diabetic and 431 nondiabetic relatives who were genotyped for 383 markers.

A novel framework for sib pair linkage analysis.

Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs.

Novel pheochromocytoma susceptibility loci identified by integrative genomics.

Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies.

Variation in IL-1beta gene expression is a major determinant of genetic differences in arthritis aggressivity in mice.

In humans and in animal models, susceptibility to arthritis is under complex genetic control, reflecting influences on the immunological processes that initiate autoimmunity and on subsequent inflammatory mechanisms in the joints. The effector phases are conveniently modeled by the K/BxN serum transfer system, a robust model well suited for genetic analysis where arthritis is initiated by pathogenic Ig. Here, we mapped the genetic loci distinguishing the high-responder BALB/c vs.

Epidemic of end-stage renal disease in people with diabetes in the United States population: do we know the cause?

Background: The number of individuals initiating renal replacement therapy in the United States population grew exponentially over the past two decades. Cases of end-stage renal diseae (ESRD) attributed to diabetes accounted for most of this increase. In this report we examined factors that may account for the increase to determine whether it truly represents an epidemic of ESRD due to diabetes.