Robin J. Olds

Association of a duplicated repeat polymorphism in the 5′‐untranslated region of the DRD4 gene with novelty seeking

Novelty Seeking (NS) is a human personality trait in which impulsive, exploratory, and thrill‐seeking behaviors are displayed. Dopaminergic genes have been prime candidates in the search for the genetic factors underlying NS because of the central role that dopamine plays in the brains reward system. We have investigated whether there is an association between a polymorphic 120 base pairs (bp) repeat that is located in the 5′‐untranslated region of the dopamine D4 receptor gene (DRD4) and NS. We genotyped four separate groups from psychiatric clinical studies for the repeat polymorphism. There were significant associations with NS in the groups of bipolar (P = 0.01) and alcoholic (P = 0.006) families containing 267 and 172 subjects, respectively. Subjects who were homozygous for the single‐copy allele (SS genotype) had higher mean NS scores. This trend was also observed in the two other studies that contained unrelated subjects diagnosed with depression (N = 143 and N = 148) but the associations between DRD4 duplication genotype and NS were not significant in these groups. In the data combined from all four clinical groups those genotyped as SS had higher mean scores for all four NS subscales with significant associations for impulsivity (P = 0.0006), extravagance (P = 0.04), disorderliness (P = 0.02), and total NS (P = 0.0003). However, given the low frequency of the single‐copy allele, this polymorphism would account for only a small proportion of the variance of NS in the population.

Molecular genetics of antithrombin deficiency

Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism. Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence. The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identifed that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or ‘pleiotropic effects’ (Type II deficiency, altering both functional domains and the level of protein).

Evidence of associations between bipolar disorder and the brain‐derived neurotrophic factor (BDNF) gene

Sears C, Markie D, Olds R, Fitches A. Evidence of associations between bipolar disorder and the brain‐derived neurotropic factor (BDNF) gene. Bipolar Disord 2011: 13: 630–637.

Familial Bipolar Disorder: Preliminary Results from the Otago Familial Bipolar Genetic Study

Objective: This paper outlines the methodologies used, and preliminary descriptive data collected, on a cohort of familial bipolar disorder (BPD) probands and first-degree relatives taking part in a descriptive and genetic study into familial BPD in New Zealand. Method: Fifity-five bipolar probands and 67 first-degree relatives were interviewed using the modified Diagnostic Interview for Genetic Studies (DIGS) and Family Interview for Genetic Studies (FIGS). Data was also collated from other sources. Blood samples were taken for DNA genomic analysis. Results: New Zealand families in which BPD segregates proved willing participants in this familial based genetic research. The methodologies used were acceptable. High rates of comorbidity were found in probands (27.3% met DSM-IV criteria for panic disorder/sub-threshold panic disorder; 12.7% for phobic disorder; 1.8% for obsessive-compulsive disorder; 9.1% for alcohol-related disorders and 7.3% for an eating disorder) and relatives (major depression 34.3%; panic disorder/sub-threshold panic disorder 12.0%; phobias 11.9% and alcohol-related disorders 11.9%). The polarity of index BPD illness was related to age of onset and frequency of comorbidity. Suicidal behaviour was common. Conclusions: Psychiatric genetic research in New Zealand families is highly feasible. Emerging trends in the familial transmission of BPD include high rates of comorbidity, illness patterns based on polarity of index episode and frequent suicidal behaviour. Such trends will be delineated further as numbers accrue, perhaps enabling identification of more homogenous phenotypic subgroups than currently produced by diagnostic schemes.

The inherited basis of venous thrombosis

Summary Venous thrombosis represents a manifestation of disordered hemostatic balance. The classical presentation is of pain and swelling of the lower limb, although clinical history and examination are notoriously misleading in reaching a diagnosis. A number of acquired predispositions have been associated with a tendency to thrombosis, such as immobilisation, surgery, malignancy and certain types of oral contraception, but in at least half of the instances no predisposition can be identified. A variety of genetic risk factors have also been identified. Mutations within the genes for antithrombin, protein C and protein S are associated with a venous thromboembolic phenotype. The commonest thrombophilic predisposition however is a variant of coagulation factor V, factor V Leiden, which results from a single amino acid substitution rendering the factor V molecule resistant to activated protein C. Factor V Leiden is present in approximately 5% of individuals of European origin, and is found in up to 40% of those with confirmed venous thrombosis. Increasingly it is recognised that venous thrombosis should be considered a polygenic disorder, with interactions between the various single gene defects which predispose to thrombosis, as well as normal genetic variation between individuals in the levels of both procoagulant and anticoagulant proteins, all determining which individuals will express the phenotype of venous thrombosis.Abbreviations: APC, activated protein C.

Red cell and hemorheological changes in multiple sclerosis

&NA; Blood rheology in multiple sclerosis (MS) was investigated in 15 subjects with varying degrees of locomotor difficulties who were members of the local MS Society. Control data were obtained from blood samples from 25 male and 25 female normal blood donors. Whole blood viscosity was measured and blood filterability was assessed. Six MS females provided blood samples for scanning electron microscopy. Erythrocyte membrane fatty acids and phospholipids were assayed. Whole blood viscosity in MS females was higher than controls at 3 of 4 shear rates (p < 0.001) but in MS males blood viscosity was higher only at shear rate of 1.0 s−1 (p<0.05). MS erythrocyte filtration rates were significantly lower than controls (p<0.001). Leucocyte counts in MS were greater than controls both in males (p <0.01) and females (p < 0.001). MS erythrocyte morphology was greatly different from controls (p<0.0001) and erythrocyte membranes contained less sphingomyelin than controls (p<0.01) but more phosphatidylinositol plus phosphatidylserine (p<0.02). We conclude that, because our findings indicate an identifiable and potentially correctable abnormality, it is possible to envisage an inhibition of the progressive nature of MS, with the hope of a better prognosis for patients.

The multigenic basis for venous thrombosis

The phenotype Venous thrombosis manifests principally as occlusion of deep veins of the leg, with other sites rarely affected. Clinical diagnosis is problematic and requires a high index of suspicion, although the use of specific criteria improves diagnostic accuracy (Wells et al, 1997). Complications of deep vein thrombosis include the post-thrombotic syndrome, which affects up to 30% of patients (Piovella & Barone, 1999), and pulmonary embolism, with the latter having a fatality rate of up to 2% (Anderson et al, 1991).

A reappraisal of the influence of blood rheology on glomerular filtration and its role in the pathogenesis of diabetic nephropathy

The basic assumptions concerning the mechanisms of normal glomerular filtration are discussed. Attention is drawn to blood rheologic changes that follow glomerular filtration and influence postglomerular blood flow adversely. It is proposed that the blood rheologic changes will increase the resistance to flow in the peritubular plexus commensurate with the dimensions of the capillaries and blood viscosity in accordance with the general principles of the Poiseuille formula, even though blood is a non-Newtonian fluid. For this reason, the conditions of flow in the plexus must be a determinant of intraglomerular capillary pressure. When blood rheology is abnormal, as in insulin-dependent diabetic patients, the abnormality will be amplified by glomerular filtration and it is suggested that the consequences will be manifest as problems of blood flow in the peritubular plexus. As the increase in postglomerular intravascular pressure needed to restore the rate of blood flow to normal necessitates dilation of the afferent arteriole and possibly more proximal vessels, such changes will result in an increase in intraglomerular pressure. The increase in pressure that increases filtration is therefore a direct consequence of abnormal blood rheology. This concept provides a basis for understanding the mechanism of diabetic proteinuria and for other proteinurias associated with abnormal blood rheology. A possible role for altered blood rheology in the pathogenesis of both focal and total glomerulosclerosis is discussed, and the potential benefits of agents that improve blood rheology are outlined.

Blood Rheology and Myalgic Encephalomyelitis: A Pilot Study

&NA; The blood rheology of EDTA‐anticoagulated blood samples from blood donors and subjects considered to have myalgic encephalomyelitis was assessed by multiple shear rate viscometry and by multiple‐pressure filterability. Although average viscosities of the two groups were different, the differences did not reach statistical significance. In contrast, the data from multiple‐pressure filtration of whole blood showed significant differences between females at the lowest (2.5 cm of water) filtration pressure. It appears that the acute phase of the disorder is associated with changes in blood rheology which could impair microcirculatory blood flow. In contrast, the chronic state does not appear to be associated with rheological abnormalities.

A novel antithrombin gene mutation: slippage and mispairing as a mechanism of genetic disease

&NA; There is a high degree of genetic heterogeneity underlying antithrombin deficiency indicating that a number of genetic mechanisms are responsible for the disorder. We report the identification of a five nucleotide (CAGAA) deletion in exon 2 of the antithrombin gene that results in a shift in the frame of translation of the mRNA and introduces a premature STOP signal in codon 70. The deleted nucleotides represent one repeat of a duplicated sequence within codons 36–39. The deletion may have arisen by slippage and mispairing of the repeated sequences at the replication fork during DNA synthesis.