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PubMed1997

Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study.

A specific mutation termed FH-North Karelia [FH-NK] accounts for almost 90% of familial hypercholesterolemia [FH] cases in the Finnish North Karelia, with a population of about 180,000. Extensive search for its presence in the entire North Karelia province revealed 340 carriers of this mutation. Other mutations of the LDL receptor [LDLR] gene accounted for 67 cases of heterozygous FH. This gives a minimum FH prevalence of 1 in 441 inhabitants in North Karelia, with the highest density of patients in the Polvijärvi commune (1 in 143 inhabitants). Old parish records, confirmation records, and tax records were used to track a common ancestor for most of the present-day North Karelian FH-NK patients in the village of Puso, located within an area where the FH prevalence today is the highest. DNA analysis indicated that 2% of the subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol [LDL-C] determinations alone. Common genetic variations of apolipoprotein E [apoE], XbaI, polymorphism of apolipoprotein B [apoB], and PvuII polymorphism of the intact LDLR allele contributed little to serum lipid variation in established carriers of the FH-NK allele, although apoE2/4 genotype and the presence of the PvuII restriction site tended to be associated with relatively low LDL-C levels. Coronary heart disease (CHD) was present in 65 (30%) out of the 179 FH gene carriers aged > or = 25 years, and 19 individuals had a previous history of acute myocardial infarction (AMI). The average age (mean +/- SD) at onset of CHD was 42 +/- 7 years for males and 48 +/- 11 years for females (P < .05). In stepwise logistic regression analysis carried out in carriers of the FH-NK allele, age, gender, smoking, and apoE allele E2 all emerged as independent determinants of risk of CHD or AMI. It may be concluded that the relatively high prevalence of FH patients in North Karelia province provides a unique founder population in which genetic and nongenetic factors modifying the course of FH can be effectively investigated.

Adolescent↗
PubMed1998

A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels.

Microsomal triglyceride transfer protein (MTP) is required for the assembly and cellular secretion of apolipoprotein B (apoB) -containing lipoproteins from the liver and intestine. The secretion pattern of apoB-containing lipoproteins is likely to influence the VLDL and LDL levels in plasma. By initial opportunistic screening for polymorphic sites in the regulatory region of the MTP gene by gene sequencing in 20 healthy male subjects, a common functional G/T polymorphism was detected 493 bp upstream from the transcriptional start point. There was differential binding of unique nuclear proteins at this site, as shown by electrophoretic mobility shift assay. The G variant seemed to bind two or three nuclear proteins that do not bind to the T variant. Expression studies with minimal promoter constructs linked to the chloramphenicol acetyltransferase reporter and transfected into HepG2 cells revealed marked enhancement of transcriptional activity with the T variant. The prevalence of the MTP promoter genotypes was investigated in a group of 184 healthy, middle-aged white men; the frequency of homozygosity for the MTP -493 T variant was .06 and the allele frequency of MTP -493T was .25 in the population. These homozygous subjects had a 22% lower LDL cholesterol concentration than did heterozygotes or subjects homozygous for the MTP -493 G variant (2.9+/-0.6 versus 3.7+/-0.8 mmol/L, P<.05). Analysis of apoB and triglyceride contents in VLDL subfractions revealed a markedly changed balance within the VLDL population. Subjects homozygous for the MTP -493 T variant had fewer but more lipid-rich VLDL particles, thereby arguing for an effect of MTP expression on the hepatic secretion of triglyceride-rich, apoB-containing lipoproteins. This common genetic variation of the MTP promoter is likely to have important implications for cardiovascular disease.

Adult↗
PubMedDate not supplied

Apolipoprotein B allotypes MB19(1) and MB19(2) in subjects with coronary artery disease and hypercholesterolemia.

We recently characterized a common form of genetic polymorphism in human apolipoprotein (apo) B, using the specific monoclonal antibody MB19 (Young SG, et al. Proc Natl Acad Sci USA 1986; 83:1101-1105). Antibody MB19 binds apo B with one of three distinct patterns of immunoreactivity (strong, intermediate, or weak). These three binding patterns are the result of the codominant inheritance of two common apo B alleles which encode for apo B allotypes MB19(1) and MB19(2), which have high and low affinity, respectively, for antibody MB19. Thus, subjects with strong or weak binding patterns are homozygous for MB19(1) or MB19(2), respectively, whereas those with an intermediate pattern are heterozygotes. To assess whether the MB19 polymorphism was related to hypercholesterolemia (HC) or to coronary artery disease (CAD), we determined the MB19 binding pattern and plasma lipoprotein concentrations in 129 normal subjects, 51 patients with HC, and 149 patients with CAD. The percentages of normal subjects having the strong, intermediate, and weak binding patterns were 11.6%, 41.9%, and 46.5%, respectively. The frequency of the three MB19 binding patterns was nearly the same in the groups with HC and CAD. Also, within each of the three groups of subjects, the MB19 binding pattern did not influence the plasma lipoprotein concentrations. We conclude that the genetic polymorphism in apo B defined by antibody MB19 is a common allelic variation in apo B, and that in the populations studied, it does not appear to be associated with the development of coronary artery disease or hypercholesterolemia.

Antibodies, Monoclonal↗
PubMed2004

Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects.

BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of ischemic heart disease (IHD), but data from published studies with individually low statistical power are conflicting. To evaluate the role of polymorphisms in the eNOS gene in IHD, we considered all available studies in a meta-analysis. METHODS AND RESULTS: Case-control studies evaluating the association between the Glu298Asp, -786T>C, and intron-4 polymorphisms and IHD were searched in MEDLINE and EMBASE up to January 2003. The principal prior hypothesis was that homozygosity for eNOS Asp298, the -786C allele in the promoter, or the intron-4 (a allele) would be associated with an increased risk of IHD. Data were available for 9867 cases and 13 161 controls from 26 studies. Homozygosity for the Asp298 was associated with an increased risk of IHD (OR, 1.31; 95% CI, 1.13 to 1.51). Although there was significant heterogeneity among studies of Asp298 (P(Het)=0.0002), which was largely accounted for by a single study, the increase in risk was still significant after exclusion of that study from analysis. Homozygosity for the intron-4a allele was also significantly associated with higher risk of IHD (OR, 1.34; 95% CI, 1.03 to 1.75). However, no significant association was found with the -786C allele (OR, 1.06; 95% CI, 0.89, 1.25). CONCLUSIONS: Individuals homozygous for the Asp298 and intron-4a alleles of eNOS are at moderately increased risk of IHD. These findings support the proposal that common genetic variations in the eNOS gene contribute to atherosclerosis susceptibility, presumably by effects on endothelial NO availability.

Adult↗
PubMed2005

MEF2A sequence variants and coronary artery disease: a change of heart?

Rare mutations in MEF2A have been proposed as a cause of coronary artery disease (CAD) and myocardial infarction (MI). In this issue of the JCI, Pennacchio and colleagues report sequencing MEF2A in 300 patients with premature CAD and in controls. Only 1 CAD patient was found to carry a missense mutation not found in controls. The specific 21-bp deletion in MEF2A previously proposed as causal for CAD and/or MI was observed in unaffected individuals and did not segregate with CAD in families. These results do not support the hypothesis that mutations in MEF2A are a cause of CAD and/or MI but do illustrate general principles regarding the difficulty of connecting genetic variation to common diseases.

Chromosomes, Human, Pair 15↗
PubMed2004

Anatomy and anaesthesia of the lumbar somatic plexus.

Cadaveric dissection demonstrated the lumbar plexus to lie within the substance of psoas major, with the major branches of the lumbar plexus emerging into the psoas compartment adjacent to the L5 vertebra. Within psoas major, the lateral femoral cutaneous and femoral nerves were separated from the obturator nerve by a muscular fold in 36 of 60 plexuses. Anatomical variations were common, with the accessory obturator nerve being identified in 12 per cent of plexuses. All previously described lumbar plexus block approaches positioned the needle within close proximity to the lumbar plexus. Modifications to these approaches may increase efficacy and reduce complication rates.

Aged↗
PubMed2003

Cardiovascular pharmacogenomics: current status, future prospects.

Pharmacogenomics is a field dedicated to exploring the contribution of genetics to interindividual variability in drug response. A goal of cardiovascular pharmacogenomics is to guide cardiovascular drug development and selection so as to optimize therapeutic benefit and minimize the potential for toxicity. Genetic-based differences in drug metabolism have long been recognized but just now are on the verge of wider clinical application. Differences in efficacy of cardiovascular drugs (independent of drug concentration) based on common genetic variations (polymorphisms) only recently have begun to be explored, but the potential for clinical application appears promising. Examples are presented of important pharmacodynamic effects of genetic variants on several drugs, including those in antiarrhythmic, reninangiotensin, beta-blocker, lipid-lowering, and antithrombotic classes. Principles of pharmacogenomics applied to drug metabolism are discussed that are relevant to drug development and clinical use, and examples are given for CYP450 phase I enzymes, phase II enzymes, and drug transporters. Challenges in establishing true pharmacogenetic associations are discussed, and current and future clinical potential is summarized. Rapid research progress and initial clinical applications with pharmacogenomics are foreseen in the near future.

Adrenergic beta-Antagonists↗
PubMed2006

Family identity: black-white interracial family health experience.

The purpose of this interpretive descriptive study was to describe how eight Black-White couples with school-aged children constructed their interracial family identity through developmental transitions and interpreted race to their children. Within and across-case data analytic strategies were used to identify commonalities and variations in how Black men and White women in couple relationships formed their family identities over time. Coming together was the core theme described by the Black-White couples as they negotiated the process of forming a family identity. Four major tasks in the construction of interracial family identity emerged: (a) understanding and resolving family of origin chaos and turmoil, (b) transcending Black-White racial history, (c) articulating the interracial family's racial standpoint, and (d) explaining race to biracial children across the developmental stages. The findings guide family nurses in promoting family identity formation as a component of family health within the nurse-family partnership with Black-White mixed-race families.

Adaptation, Psychological↗
PubMed2006

(A1) Identification of oral health care needs in children and adults, management of oral diseases.

The workshop considered five questions reviewing the identification of international oral health care needs of children and adults, and the management of oral diseases in resource-poor countries: (1) What is the role of the dental profession in the management of the HIV-infected individual? (2) Identifying health care needs-What are the epidemiology and disparities of HIV-associated oral lesions in children from different continents? (3) How effective is HIV treatment in controlling oral diseases? (4) Could we develop basic inexpensive oral and dental care protocols for economically deprived HIV-infected patients? and (5) What is the best method of arranging resources to meet the oral health care needs of people with HIV disease? The consensus of the workshop participants was that there is a need to re-target research efforts to non-established market economy countries and prioritize research in these regions to children with HIV disease. It will be important to assess commonalities and variations in oral health needs across geographical and cultural boundaries, and research efforts should be centralized in resource-poor countries to support multi-center longitudinal standardized studies. It is essential that oral health research be integrated into other health care research programs, to make these research priorities and public health initiatives feasible.

Adult↗
PubMed2006

Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph).

A role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.

Case-Control Studies↗
PubMed2006

Prion gene haplotypes of U.S. cattle.

BACKGROUND: Bovine spongiform encephalopathy (BSE) is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. Characterizing linkage disequilibrium (LD) and haplotype networks within the bovine prion gene (PRNP) is important for 1) testing rare or common PRNP variation for an association with BSE and 2) interpreting any association of PRNP alleles with BSE susceptibility. The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes. RESULTS: A 25.2-kb genomic region containing PRNP was sequenced from 192 diverse U.S. beef and dairy cattle. Sequence analyses identified 388 total polymorphisms, of which 287 have not previously been reported. The polymorphism alleles define PRNP by regions of high and low LD. High LD is present between alleles in the promoter region through exon 2 (6.7 kb). PRNP alleles within the majority of intron 2, the entire coding sequence and the untranslated region of exon 3 are in low LD (18.0 kb). Two haplotype networks, one representing the region of high LD and the other the region of low LD yielded nineteen different combinations that represent haplotypes spanning PRNP. The haplotype combinations are tagged by 19 polymorphisms (htSNPS) which characterize variation within and across PRNP. CONCLUSION: The number of polymorphisms in the prion gene region of U.S. cattle is nearly four times greater than previously described. These polymorphisms define PRNP haplotypes that may influence BSE susceptibility in cattle.

3' Untranslated Regions↗
PubMed2004

Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?

BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.

Journal Article↗
PubMed2006

The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.

BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.

Adult↗
PubMed2006

Genetic association studies in cancer: good, bad or no longer ugly?

For some time, investigators have appreciated that genetic association studies in cancer are complex because of the multi-stage process of cancer and the daunting challenge of analysing genetic variants in population and family studies. Because of recent technological advances and annotation of common genetic variation in the human genome, it is now possible for investigators to study genetic variation and cancer risk in many different settings. While these studies hold great promise for unravelling multiple genetic risk factors that contribute to the set of complex diseases called cancer, it is also imperative that study design and methods of interpretation be carefully considered. Replication of results in sufficiently large, well-powered studies is critical if genetic variation is to realise the promise of personalised medicine--namely, using genetic data to individualise medical decisions. In this regard, the plausibility of validated genetic variants can only be realised by the study of gene-gene and gene-environment interactions. The genetic association study in cancer has come a long way from the days of restriction fragment length polymorphisms, and now promises to scan an entire genome 'agnostically' in search of genetic markers for a disease or outcome. Moreover, the application and interpretation of these studies should be conducted cautiously.

Genetic Predisposition to Disease↗
PubMed2006

Single nucleotide polymorphisms and breast cancer: not yet a success story.

Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance. The failure to identify meaningful common genetic variation in relation to breast cancer should give us pause for thought and make us reconsider our current research strategies. The most recent directions of pooling samples to increase statistical power and pursuing whole genome screens may overcome some obstacles while also creating new challenges. Future studies should perhaps also consider alternative designs such as using surrogate (preferably continuous) markers of breast cancer, focusing on high-risk populations, and defining pathologically distinct outcomes.

Breast Neoplasms↗
PubMed2004

Single nucleotide polymorphism-based validation of exonic splicing enhancers.

Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant elimination reinforces functionality), which can be used to assess the extent of natural selection acting on an oligonucleotide motif or set of motifs predicted to have biological activity. As an application of this approach, we analyzed a set of 238 hexanucleotides previously predicted to have exonic splicing enhancer (ESE) activity in human exons using the relative enhancer and silencer classification by unanimous enrichment (RESCUE)-ESE method. Aligning the single nucleotide polymorphisms (SNPs) from the public human SNP database to the chimpanzee genome allowed inference of the direction of the mutations that created present-day SNPs. Analyzing the set of SNPs that overlap RESCUE-ESE hexamers, we conclude that nearly one-fifth of the mutations that disrupt predicted ESEs have been eliminated by natural selection (odds ratio = 0.82 +/- 0.05). This selection is strongest for the predicted ESEs that are located near splice sites. Our results demonstrate a novel approach for quantifying the extent of natural selection acting on candidate functional motifs and also suggest certain features of mutations/SNPs, such as proximity to the splice site and disruption or alteration of predicted ESEs, that should be useful in identifying variants that might cause a biological phenotype.

Alleles↗
PubMed2006

Application of genome-wide single nucleotide polymorphism typing: simple association and beyond.

The International HapMap Project and the arrival of technologies that type more than 100,000 SNPs in a single experiment have made genome-wide single nucleotide polymorphism (GW-SNP) assay a realistic endeavor. This has sparked considerable debate regarding the promise of GW-SNP typing to identify genetic association in disease. As has already been shown, this approach has the potential to localize common genetic variation underlying disease risk. The data provided from this technology also lends itself to several other lines of investigation; autozygosity mapping in consanguineous families and outbred populations, direct detection of structural variation, admixture analysis, and other population genetic approaches. In this review we will discuss the potential uses and practical application of GW-SNP typing including those above and beyond simple association testing.

Chromosomes, Human↗