Importance Of Genetic Factors Research Articles

Genetics of Size at Birth

Size at birth is strongly related to a number of maternal factors including parity, length of gestation, mother's adult size, and mother's own birth weight (1). The importance of genetic factors has come from studies of monozygous and dizygous twins, where estimates of heritability of birth weight range from 30 to 70% (2,3). Ounsted et al. (4), however, reported that there may be a stronger relationship between the birth weight of the mother and that of the offspring, particularly in infants born with a low birth weight, and that these relationships may vary with parity. These data suggest that not only fetal genes but also genes that regulate the maternal uterine environment could be important in determining size at birth. Size at birth is the strongest determinant of perinatal survival (5), yet in most populations, mean birth weight is slightly lower than optimal for offspring survival (6). Thus, it would appear that all fetal growth is subject to some degree of restraint by the maternal uterine environment (7), perhaps reflecting the importance to the mother of restricting the nutritional demands of the fetus if it would threaten her survival in times of poor nutrition. Although maternal undernutrition may (8) or may not (9) be a less common determinant of birth weight in contemporary populations, restraint of fetal growth is still evident, particularly in first pregnancies. First babies have a lower birth weight and tend to be thinner than subsequent babies, with a preserved head circumference and length, suggesting reduced adiposity. Postnatally, these babies demonstrate rapid catch-up growth (1). Such a growth pattern is evident in infants whose intrauterine environment has been affected by poor placental function, secondary to maternal hypertension and preeclampsia, but a similar pattern is also evident in uncomplicated pregnancies, where it is predicted by maternal …

Genetic background of the multifactorial liver and bile duct diseases

The majority of liver diseases, are complex. They are the results of interactions between several genes and environmental factors. Familial aggregation and higher concordance rate of monozygotic twins compared to those of dizygotic twins provide evidence for the importance of genetic factors in the pathogenesis. There are only limited data in connection with the genetic background of multifactorial liver diseases. In the future, the genetic background may permit prevention, early, accurate diagnosis, prediction of disease course, complications, prognosis, as well as treatment response.

177 Epidemiology of childhood OSAS

Pediatric obstructive sleep apnea syndrome (OSAS) is a disorder characterized by repetitive episodes of upper airway obstruction, intermittent hypoxemia and hypercapnia, and snoring. Increasing data indicate the disorder is common, particularly among vulnerable subgroups, and associated with a wide range of co-morbidities. Limited epidemiological data suggest that the disorder affects 1–4% of children. Childhood OSAS appears to vary among age, gender, and ethnic subgroups. Childhood OSASprevalence tends to peak at two ages. The first peak occurs in children 2–6 years of age and coincides with the peak age of lymphoid hypertrophy. A second peak occurs during adolescence and appears related to an increase in prevalence of overweight.Gender differences are less than what has been observed in adult populations, with approximately equal distributionofOSASamongpre-adolescent boys and girls. However, a greater prevalence of OSAS has been observed among adolescent boys compared to adolescent girls. Associations between overweight and childhood OSAS also seem stronger among adolescents than among younger children. Themost commonly recognized risk factor for childhood OSAS is adeno-tonsillar lymphoid hypertrophy. Several studies, however, suggest that OSASmay persist in 9–30% of children post-tonsillectomy/adenoidectomy. Paradoxically, a history of tonsillectomy is associated with a twoto threefold increased risk of snoring, suggesting that symptoms of OSAS may trigger surgery, but addressing lymphoid tissue may not always resolve intermittent upper airway obstruction. Susceptibility to childhood OSAS may also relate to other factors that influence airway patency, including genetic factors, craniofacial morphology, abnormalities in ventilatory control, as well as overweight, suggesting the complexity of the phenotype. The importance of genetic factors is suggested by ethnic differences in OSAS prevalence, which is twoto fourfold higher in Black children [1,2]; symptoms of OSAS also appear increased inHispanic children [3]. In addition, recent data suggest that OSAS is also more common in children from poor neighborhoods [4], suggesting that environmental influences associated with chronic irritant/allergen exposures or physical environment stresseswhich influence airway inflammation or breathing and sleep properties may be of importance. Influences of developmental factors on airway and/or respiratory function are also suggested by increased risk of childhood OSAS among former preterm children. The chronic co-morbidities associated with untreated pediatric OSAS include cognitive deficits, behavioral problems (inattention, hyperactivity, aggression, conduct problems, Attention-Deficit/Hyperactivity Disorder), mood impairments, excessive daytime sleepiness, impaired school performance, and poor quality of life [5–8]. Untreated pediatric OSAS also has been associated with adverse cardiovascular and metabolic outcomes. Children with OSAS have higher levels of blood pressure, C-reactive protein (an inflammatory risk factor associated with cardiovascular disease) and increased insulin resistance, as well as left ventricular hypertrophy [9–12] [13], suggesting that childhood OSAS also may increase the risk of developing severe chronic cardiovascular and metabolic conditions. Despite the frequency and severity of OSAS during childhood, there are large knowledge gaps, including scant data that address causal pathways and population vulnerability to the disorder, responses to therapy, and long term influences on health.

Longitudinal Genetic Analysis of Plasma Lipids

The consensus from published studies is that plasma lipids are each influenced by genetic factors, and that this contributes to genetic variation in risk of cardiovascular disease. Heritability estimates for lipids and lipoproteins are in the range .48 to .87, when measured once per study participant. However, this ignores the confounding effects of biological variation measurement error and ageing, and a truer assessment of genetic effects on cardiovascular risk may be obtained from analysis of longitudinal twin or family data. We have analyzed information on plasma high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides, from 415 adult twins who provided blood on two to five occasions over 10 to 17 years. Multivariate modeling of genetic and environmental contributions to variation within and across occasions was used to assess the extent to which genetic and environmental factors have long-term effects on plasma lipids. Results indicated that more than one genetic factor influenced HDL and LDL components of cholesterol, and triglycerides over time in all studies. Nonshared environmental factors did not have significant long-term effects except for HDL. We conclude that when heritability of lipid risk factors is estimated on only one occasion, the existence of biological variation and measurement errors leads to underestimation of the importance of genetic factors as a cause of variation in long-term risk within the population. In addition our data suggest that different genes may affect the risk profile at different ages.

Analysis of polygenic traits of Microcystis aeruginosa (Cyanobacteria) strains by Restricted Maximum Likelihood (REML) procedures: 1. Size and shape of colonies and cells

M. Rico, M. Altamirano, V. López-Rodas and E. Costas. 2006. Analysis of polygenic traits of Microcystis aeruginosa (Cyanobacteria) strains by Restricted Maximum Likelihood (REML) procedures: 1. Size and shape of colonies and cells. Phycologia 45: 237–242. DOI: 10.2216/03-44.1Traditionally, morphometrical traits are used to classify cyanobacteria. However, neither the importance of genetic factors in morphological variability nor genetic correlations between different morphometrical traits are known. Six morphometrical traits of individual cells and six morphometrical traits of colonies have been measured in 21 strains of Microcystis aeruginosa. A fixed model and a mixed model allowing genetic relationships between traits were both used to estimate genetic and residual correlations, and genetic variance/total phenotypic variance ratios were used to estimate the 12 morphometrical traits. Results showed that (1) colony size has a low genetic correlation with traits of individual cells; (2) traits measured on individual cells present a higher genetic variance/total phenotypic variance ratio than the corresponding trait in colonies; and (3) genetic correlations between directly measured traits (maximal diameter and axis, minimal diameter and axis, perimeter, and surface) are so high that they may be considered different expressions of the same underlying trait, namely size, so any one of them could be used without significant loss of information, instead of all of them. Fixed and mixed models showed the same conclusions, although mixed models preferably should be used because they take into account the common random genetic basis of traits. Maximal cell diameter was used as a discriminator trait for studying morphological differences between strains from different origins. Results suggest that environment may modulate strain mixtures in Microcystis populations.

Gene polymorphisms involved in the regulation of bone quality

Osteoporotic fractures in subjects at advanced age constitute a tremendous and growing problem. Established lifestyle risk factors can explain only a modest proportion of the liability to osteoporotic fractures. Bone mineral density (BMD) is considered the best established risk factor for osteoporotic fractures. The importance of genetic factors in the quality of bone is substantial, but no consensus exists yet on the genes that are involved. However, concomitant diseases, balance disorders and lifestyle habits are more important for fractures in elderly subjects. The abundance of common sequence variations, so-called polymorphisms, in the human genome and their high frequency in the population have made them targets to explain variation in the risk. Some genes have been identified that appear to be involved in the regulation of bone mass and in the pathogenesis of osteoporosis. Among these are those coding for the two estrogen receptors (ERα and ERβ), the androgen receptor (AR) and the vitamin D receptor (VDR). In addition, enzymes involved in the biogenesis of estrone and estradiol have attracted attention as well as polymorphisms in the regulatory region of the type I collagen gene, COLIA1, affecting the binding site for the transcription factor Specificity protein 1 (Sp1). Although evidence suggests that the quality of bone is determined to a large extent by genetic factors, research so far has not been able to unequivocally identify genes involved in this matter. Over the last years a large number of studies have pointed to the variability in many genes and their relation with BMD, bone-related symptoms or specific therapies. The findings emphasize the complexity of the genetics of bone mass and bone loss.

Familial Aggregation and Heterogeneity of Non-Hodgkin Lymphoma in Population-Based Samples

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.

Gene Expression Profiles of Mst1r-Deficient Mice during Nickel-Induced Acute Lung Injury

Previous studies have shown that mice deficient in the tyrosine kinase domain (TK-/-) of the receptor Mst1r have an increased susceptibility to nickel (Ni)-induced acute lung injury (ALI). Mst1r TK-/- mice have decreased survival times, alterations in cytokine and nitric oxide regulation, and an earlier onset of pulmonary pathology compared with control mice, suggesting that Mst1r signaling, in part, may regulate the response to ALI. To examine the role of Mst1r in ALI in more detail, we compared the gene expression profiles of murine lung mRNA from control and Mst1r TK-/- mice at baseline and after 24 h of particulate Ni sulfate exposure. Microarray analyses showed a total of 343 transcripts that were significantly changed, either by Ni treatment, or between genotypes. Genes responsible for inflammation, edema, and lymphocyte function were altered in the Mst1r TK-/- mice. Interestingly, the genes for several granzymes were increased in Mst1r TK-/- mice before Ni exposure, compared with controls. In addition, the Mst1r TK-/- lungs showed clusters of cells near the vascular endothelium and airways. Immunohistochemistry indicates these clusters are composed of macrophages, T cells, and neutrophils, and that the clusters display granzyme protein production. These results suggest that Mst1r signaling may be involved in the regulation of macrophage and T-lymphocyte activation in vivo during injury. This assessment of gene expression indicates the importance of genetic factors in contributing to lung injury, and points to strategies for intervention in the progression of inflammatory diseases.

Genetic Liability to Fractures in the Elderly

The genetic impact on the causation of osteoporotic fractures is unclear. A large twin study is ideally suited to determine the genetic liability to categories of fracture at various ages. A cohort of all 33 432 Swedish twins born from 1896 to 1944 was used to evaluate the genetic liability to fracture occurrence in the elderly. The Swedish Inpatient Registry and computer-assisted telephone interviews enabled us to identify 6021 twins with any fracture, 3599 with an osteoporotic fracture, and 1055 with a hip fracture after the age of 50 years. Genetic variation in liability to fracture differed considerably by type of fracture and age. Less than 20% of the overall age-adjusted fracture variance was explained by genetic variation. The age-adjusted heritability of any osteoporotic fracture was slightly greater (0.27; 95% confidence interval [CI], 0.09-0.28), and for hip fracture alone, it was 0.48 (95% CI, 0.28-0.57). Heritability was not attenuated after further adjustment for several known osteoporotic covariates but was considerably greater for first hip fractures before the age of 69 years (0.68; 95% CI, 0.41-0.78) and between 69 and 79 years (0.47; 95% CI, 0.04-0.62) than for hip fractures after 79 years of age (0.03; 95% CI, 0.00-0.26). The importance of genetic factors in propensity to fractures depends on fracture site and age. The search for susceptibility genes and environmental factors that may modulate expression of these genes in younger elderly patients with hip fracture, the most devastating osteoporotic fracture, should be encouraged. Prevention of fractures in the oldest elderly should focus on lifestyle interventions.

Genetic Factors in Seizures: A Population-Based Study of 47,626 US, Norwegian and Danish Twin Pairs

The purpose of the study was to describe a large sample of twins reporting a history of seizures, to characterize seizures in the three subpopulations, and to estimate the relative importance of genetic and environmental factors in seizure occurrence. Seizure history was determined by questionnaires completed by twins in population-based twin registries in the United States, Norway and Denmark. Concordance rates were calculated for all seizure categories within and across twin populations. Of 47,626 twin pairs evaluated, 6234 reported a history of seizures in one or both twins. Concordance rates were significantly higher for monozygotic (MZ) versus dizygotic (DZ)pairs for all seizure categories within and across populations. The results of this study involving the largest unselected, population-based sample of twins with seizures assembled to date confirm the importance of genetic factors in determining risk for epilepsy, febrile seizures, other seizures and staring spells. This sample is likely to provide an important resource for studying the genetics of epilepsy subtypes and febrile seizures.

Ceruloplasmin, Superoxide Dismutase and Copper in Autistic Patients

Autism is a neurodevelopmental disorder, involving a wide variety of sociobehavioural, linguistic and perceptuomotor abnormalities. The prevalence in the general population is at least 5 in 10,000, with a reported male/female ratio of 3– 4/1 (Lamb et al. 2000). Strong evidence from twin and family studies indicate the importance of genetic factors in the development of idiopathic autism (Lamb et al. 2000). In a study of population-based Danish registers, Lauritsen et al. (2002) noted a highly significant increased frequency of congenital malformations associated whith autism which is furthermore indicative of abnormal embryogenesis. In this context it should also be noted that the age-related changes seen in some neurones in autistic brains appear to be a prolonged process that extends from neural hyperthrophy in childhood to atrophy and cell loss in later adult life and are without concomitant gliosis or other outright signs of degeneration (Kemper & Bauman 1998). Ceruloplasmin is a copper-containing enzyme with a powerful redox activity in serum. Superoxide dismutase is another copper enzyme found in cytosol of most cells that dismutases superoxide anion radicals (iO2) to H2O2 and O2. In our previous studies we have measured the activity of the two enzymes, ceruloplasmin in serum and superoxide dismutase in erythrocytes and copper in plasma in some neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, amyothropic lateral sclerosis and also in Down’s syndrome, as Down’s syndrome is characterized by the development of dementia when the patients exceed 40–50 years of age. The results showed that copper dyshomeostasis prevailed in these diseases as the activity of both enzymes was either decreased or deranged although the levels of copper were the same (Snaedal et al. 1998; Torsdottir et al. 1999, 2000 & 2001).

Familial recurrence rates and genetic models of multiple sclerosis

Susceptibility to multiple sclerosis (MS) is determined by both inherited and non-inherited factors. The importance of genetic factors is demonstrated by the increased risk of disease in relatives of MS patients. Our objective was to determine the implications of the observed familial recurrence risks for the genetic basis of MS. We developed a computer program which calculates recurrence risks for monozygotic (MZ) twins, siblings, and second degree relatives, and used it to calculate recurrence risks for a wide variety of genetic models. We investigated models with different numbers of genes, different patterns of interaction between the genes, and dominant or recessive inheritance. The models that best reproduced the observed values had multiple loci with strongly synergistic interaction and autosomal dominant (AD) inheritance. At least six loci were required, and we found no upper limit on the number of loci. Models with genetic heterogeneity, where only a fraction of the risk loci are required for disease, are possible. In models with large numbers of loci the "abnormal" alleles conferring risk of disease are the most common allele. We conclude that a variety of genetic models with multiple genes, dominant inheritance, and synergistic interaction between risk genes are consistent with the observed familial recurrence rates in MS.

Designing mouse behavioral tasks relevant to autistic‐like behaviors

The importance of genetic factors in autism has prompted the development of mutant mouse models to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (1) face validity, i.e., resemblance to the human symptoms; (2) construct validity, i.e., similarity to the underlying causes of the disease; and (3) predictive validity, i.e., expected responses to treatments that are effective in the human disease. There is a growing need for mouse behavioral tasks with all three types of validity for modeling the symptoms of autism. We are in the process of designing a set of tasks with face validity for the defining features of autism: deficits in appropriate reciprocal social interactions, deficits in verbal social communication, and high levels of ritualistic repetitive behaviors. Social approach is tested in an automated three-chambered apparatus that offers the subject a choice between a familiar environment, a novel environment, and a novel environment containing a stranger mouse. Preference for social novelty is tested in the same apparatus, with a choice between the start chamber, the chamber containing a familiar mouse, and the chamber containing a stranger mouse. Social communication is evaluated by measuring the ultrasonic distress vocalizations emitted by infant mouse pups and the parental response of retrieving the pup to the nest. Resistance to change in ritualistic repetitive behaviors is modeled by forcing a change in habit, including reversal of the spatial location of a reinforcer in a T-maze task and in the Morris water maze. Mouse behavioral tasks that may model additional features of autism are discussed, including tasks relevant to anxiety, seizures, sleep disturbances, and sensory hypersensitivity. Applications of these tests include (1) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism, (2) characterization of mutant mice derived from random chemical mutagenesis, (3) DNA microarray analyses of genes in inbred strains of mice that differ in social interaction, social communication and resistance to change in habit, and (4) evaluation of proposed therapeutics for the treatment of autism.

Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database

AbstractThe importance of genetic factors in etiology of chronic lymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum of malignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk are unknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336 first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancer risks in relatives of cases were compared with those in relatives of controls using marginal survival models. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95% confidence interval [CI], 3.63-15.56), for non-Hodgkin lymphoma (RR = 1.45; 95% CI, 0.98-2.16), and for Hodgkin lymphoma (RR = 2.35; 95% CI, 1.08-5.08). CLL risks were similar in parents, siblings, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. We conclude that the familial component of CLL is shared with other lymphoproliferative malignances, suggesting common genetic pathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.

Genetic and environmental influences on symptomatic gallstone disease: a Swedish twin study of 43141 twin pairs

Aims: Human gallstone disease is a complex trait, but the overall importance of genetic factors has yet to be defined. Twin studies are a valuable source of information about the genetic basis of complex genetic traits. Our aim was to calculate the relative importance of genetic and environmental factors for susceptibility to symptomatic gallstone disease by analyzing a large twin population.

Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Epileptic seizures and syndromes in twins: the importance of genetic factors

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.

No Evidence for an Association between the T102C and 1438 G/A Polymorphisms of the Serotonin 2A Receptor Gene in Attention Deficit/Hyperactivity Disorder in a Turkish Population

Disturbances in the serotonergic neurotransmission system have been implicated in the etiology of attenion deficit/hyperactivity disorder (ADHD). As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We previously demonstrated that the polymorphisms of the serotonin transporter gene promoter and regions of variable number of tandem repeats were involved in the pathogenesis of ADHD. The purpose of this study was to examine the relationship between ADHD and two polymorphisms (T102C and 1438 G/A) in the 5-HT2A gene in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 70 patients with ADHD and in 100 healthy controls. There was no significant difference between the frequencies of the T, C, G and A alleles of both groups. No association was found between the studied polymorphisms of the 5-HT2A gene and ADHD in this sample consisting of Turkish children. Overall, our results suggest that the investigated 5-HT2A polymorphisms are not major susceptibility factors in the etiology of ADHD.

What can experimental research offer to rheumatology today--the viewpoint of molecular biology? Contribution of molecular biology to pathogenesis research in rheumatology using the example of rheumatoid arthritis

Molecular biology plays an increasing role for the development of innovative approaches to analyze the pathogenesis of rheumatic diseases and to improve diagnosis and therapy of these disorders. Some of these approaches/techniques have recently yielded important results, e.g. the analysis of 1) chromosomal aberrations (numerical and, in part, structural aberrations in synovial fibroblasts/macrophages from chronic joint inflammation); 2) cell clonality (oligoclonal expansion of synovial T-cells, B-cells, but also fibroblasts); 3) the importance of genetic factors (genome-wide screening for arthritis susceptibility genes); 4) mutations in key genes of cell cycle and/or function (mutations in p53 and proto-oncogenes in the inflamed synovial membrane); and 5) gene expression patterns (e.g. by high-density microarrays, custom arrays, in situ hybridization, and real-time PCR). It can be expected that these analyses will result in central new findings concerning the understanding of the pathogenetic basis of chronic inflammatory rheumatic diseases, with the potential to develop differential diagnostic criteria for these hitherto extremely heterogeneous diseases, and to create the basis for individual-oriented therapy.

Altered Na+/H+ exchanger isoform 1 activity in immortalized lymphoblasts from women with pre-eclampsia: evidence for an intermediate phenotype.

Previous studies have demonstrated a raised Na(+) content in leucocytes isolated from women with pre-eclampsia. Increased Na(+)/H(+) exchanger activity is one membrane transport abnormality that may contribute to this phenomenon and may be implicated in the abnormal volume homoeostasis and hypertension associated with the disease. Increased Na(+)/H(+) exchanger activity has been documented in nucleated white blood cells from both pre-eclamptic and post-partum pre-eclamptic women, and may suggest the importance of genetic influences on exchanger activity. In the present study, we used lymphoblasts from women with pre-eclampsia and from age- and gestation-matched normotensive pregnant controls to determine Na(+)/H(+) exchanger activity and intracellular resting pH using fluorimetry and the pH-sensitive dye BCECF-AM [bis(carboxyethyl)carboxyfluorescein acetoxymethyl ester]. Determination of Na(+)/H(+) exchanger protein abundance was performed by Western blotting. Intracellular pH was not significantly different in cells from pre-eclamptic women compared with those from normotensive controls. Na(+)/H(+) exchanger activity was measured when the intracellular pH was clamped at 6.0, and was found to be significantly higher in cells from pre-eclamptic women (20.77+/-0.92 mmol x min(-1) x l(-1)) compared with those from normotensive controls (15.22+/-0.92 mmol x min(-1) x l(-1); P =0.001). Na(+)/H(+) exchanger protein abundance was established to be similar in the two subject groups, suggesting that the turnover number for the Na(+)/H(+) exchanger is increased in the women with pre-eclampsia. These changes in Na(+)/H(+) exchanger activity indicate the importance of genetic factors in determining this particular phenotype, since in this cell culture model of pre-eclampsia it is likely that environmental or hormonal influences present in vivo would have declined. Overactivity of the Na(+)/H(+) exchanger may contribute to the raised intracellular Na(+) concentration reported previously in white blood cells from women with pre-eclampsia.