P. Bennett

The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report.

We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystemss Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS≥0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.

Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22

Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16–q21 (MLS=2.61) and 4q12–q21 (MLS=2.38). 6q16–q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male–male pairs. Our scan also provides support for linkage (MLS≥1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14–p12 and 18q22.

Ethnicity and peripheral artery disease

Peripheral arterial disease (PAD) is an important healthcare problem and is an indicator of widespread atherosclerosis in other vascular territories, such as the cerebral and coronary circulations. PAD is associated with considerable morbidity and mortality. Most population-based studies investigating PAD prevalence and risk factors for its development and progression have been based on predominantly White ethnic groups. Much less is known about the characteristics of this disease in other ethnic groups. Understanding the epidemiology of PAD amongst ethnic minority groups is relevant, given that the population of minority ethnic groups in countries such as the United Kingdom rose by 53% between 1991 and 2001 and is expected to rise further in the future. This article aims to provide an overview of possible pathophysiological differences between ethnic groups for PAD, focussing predominantly on South Asians (people originating from India, Bangladesh and Pakistan) and Blacks (people of Black Caribbean and Black African descent) as these groups comprise the majority of all ethnic minorities in the United Kingdom.

Peripheral arterial disease and Virchow’s triad

Peripheral arterial disease (PAD) is an important global healthcare problem associated with considerable morbidity and mortality. This disease is an important manifestation of atherosclerosis and the pathophysiological processes involved in its development, progression and complications are atherothrombosis and thromboembolism. Over 150 years ago, Virchow described a triad of abnormalities (abnormal blood flow, abnormal vessel wall and abnormal blood constituents) associated with thrombus formation (thrombogenesis). An improvement in biochemical techniques has allowed quantification of various components of Virchows triad, and as a consequence, there has been increasing interest in the measurement of such biomarkers in understanding the development and progression of PAD, as well as its symptomatic complications. This review discusses quantifiable components of Virchows triad that have been associated with PAD and their clinical utility as risk factors for PAD.

A direct correlation between nicotinamide N-methyltransferase activity and protein levels in human liver cytosol

Phenotypic differences in nicotinamide N-methyltransferase (NNMT, E. C. 2.1.1.1) activity may be due to a genetic polymorphism. We report the characterisation of the hepatic NNMT activity in cytosol from normal human livers, enzyme protein levels determined by Western blotting and ELISA and mRNA levels determined by SDS-PAGE/Northern blotting. Subjects with high NNMT activity had high levels of NNMT protein and NNMT mRNA levels in hepatic cytosol and the converse was true for individuals with low NNMT activity. No differences in sequences were seen when cDNAs of individuals with high and low NNMT activity were compared. Thus phenotypic differences in the general population are due to differences in steady-state mRNA levels and not because of a polymorphism in the coding region of the NNMT gene.

Ethnic differences in common carotid intima-media thickness, and the relationship to cardiovascular risk factors and peripheral arterial disease: the Ethnic-Echocardiographic Heart of England Screening Study.

OBJECTIVE To compare the mean and maximum common carotid intima-media thickness (CCIMT) in Blacks (Black Caribbean and Black African) and South Asians (People originating from India, Pakistan and Bangladesh) in a population survey and make associations with established cardiovascular risk factors and peripheral arterial disease (PAD). PATIENTS AND METHODS A subset of 492 (293 South Asians and 199 Blacks) out of 572 participants aged ≥ 45 years recruited in a sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) epidemiological study had mean and maximum CCIMT measured. A questionnaire, anthropometric measurements and Ankle Brachial Pressure Index (ABPI) and Intermittent Claudication assessments were made. RESULTS Black participants had greater mean but not maximum CCIMT when compared to South Asians overall (P = 0.022), in men (P = 0.04) and in women (P = 0.044). Black ethnicity was an independent predictor of CCIMT even after adjustment for traditional cardiovascular risk factors (P < 0.05). After adjustment for age, ethnicity and traditional cardiovascular risk factors, the presence of PAD remained independently predictive of mean (P = 0.019) and maximum (P = 0.012) CCIMT. CONCLUSION Black ethnicity is related to greater mean and maximum CCIMT when compared to South Asians, even after adjusting for traditional cardiovascular risk factors. The presence of PAD independently predicts mean and maximum CCIMT adjusting for ethnicity, age and cardiovascular risk factors.

The contribution of cardiovascular risk factors to peripheral arterial disease in South Asians and Blacks: a sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study

OBJECTIVE To determine whether differences exist in prevalence of peripheral arterial disease (PAD) between South Asians (people originating from India, Pakistan and Bangladesh) and Blacks (Black Caribbean and Black African), the two largest minority ethnic groups in the UK. To determine if associations with cardiovascular risk factors and this disease differ between these two ethnic groups. PATIENTS AND METHODS We recruited 572 patients (356 South Asian and 216 Blacks) > or = 45 years as a sub-study to a community screening project, the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study. All subjects completed an interviewer-led questionnaire, anthropometric measurements and blood sampling. Ankle brachial pressure index (ABPI) was calculated and intermittent claudication was assessed using the Edinburgh Claudication Questionnaire. The presence of PAD was defined as ABPI <0.9. RESULTS The mean age was 62 years overall with no difference between the two ethnic groups. The prevalence of PAD was 13.2% [95% confidence interval (CI) 9.7-16.7] in South Asians and 10.2% (95% CI 6.2-14.2) in Blacks with no significant difference between the two ethnic groups. The prevalence of PAD was higher in South Asian women than Black women (16.3 vs. 6.1%; P = 0.011). No difference in prevalence was found in men (11 vs. 14% P = 0.47, in South Asians and Blacks, respectively). The prevalence of intermittent claudication was 0.9% (95% CI 0.11-1.63). On multivariate logistic regression, mean systolic blood pressure, diabetes, smoking and male sex were independently associated with PAD in South Asians (P = 0.016, 0.022, 0.037 and 0.008, respectively). In Blacks, only age remained independently associated with PAD on multivariate logistic regression (P = 0.003). CONCLUSION The prevalence of PAD is similar in South Asians and Blacks, and similar to levels reported in pre-dominantly White populations. South Asian women had a higher prevalence of PAD than Black women, which is not explained by traditional cardiovascular risk factors.

Ethnic/racial differences in circulating markers of angiogenesis and their association with cardiovascular risk factors and cardiovascular disease.

OBJECTIVE To determine (a) whether ethnic/racial differences exist in circulating markers of angiogenesis (Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), soluble Tie-2 receptor (sTie-2) and Angiogenin) between South Asian (SA; from India, Pakistan and Bangladesh); Black African-Caribbean and White (W) ethnic groups, and (b) associations between these markers in stable cardiovascular disease (CVD) and its risk factors. PATIENTS AND METHODS We recruited 243 subjects (82 SA, 84 Black and 77 W) with symptomatic and clinically confirmed CVD (n=108), risk factor controls (with ≥ 1 cardiovascular risk factor, e.g. smoking, diabetes mellitus, dyslipidaemia, hypertension) and with ankle brachial pressure index >1) (n=64) and healthy controls free of CVD and risk factors (n=56). Angiogenic markers were measured by enzyme linked immunoassay. RESULTS In healthy controls, angiogenin was higher in SA and Black subjects, compared to Whites (p<0.05). sTie-2 correlated inversely with angiogenin (p=0.001), was higher in women (p=0.029) and was lower in smokers (p=0.007). Overall, age (p=0.001) was the only independent factor associated with angiopoietin-1. Angiogenin (p=0.01) and SBP (p=0.014) were both independently higher in the Black group compared to the White group. CONCLUSIONS Ethnic, racial, and demographic differences are evident in certain circulating markers of angiogenesis. With the exception of an effect of smoking on sTie-2, these differences are not influenced by the presence of other risk factors, nor the presence of stable cardiovascular disease.

Vital exhaustion and cardiovascular disease: Are circulating fibrinogen and D-dimer levels a plausible link?

Vital exhaustion has been implicated in the development and progression of cardiovascular disease. In addition, elevated levels of fibrinogen and D-dimer have been associated with an increased risk of cardiovascular disease. Some studies have suggested that fibrinogen and D-dimer are associated with acute, chronic, and perceived stress. In this issue, Kudielka et al examine the relationship between circulating fibrinogen and D-dimer levels and vital exhaustion in a cross-sectional study of middle-aged teachers in Germany, to examine the plausible link between chronic stress and the development of cardiovascular disease. This commentary discusses the limited available evidence of the mechanisms responsible for the association between vital exhaustion and the development of cardiovascular disease and highlights the limitations of previous research and discusses future directions.

Validation of the Edinburgh Claudication Questionnaire in 1st generation Black African-Caribbean and South Asian UK migrants: A sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study

BackgroundWe determined the diagnostic accuracy of the Edinburgh Claudication Questionnaire (ECQ) in 1st generation Black African-Caribbean UK migrants as previous diagnostic questionnaires have been found to be less accurate in this population. We also determined the diagnostic accuracy of translated versions of the ECQ in 1st generation South Asian UK migrants, as this has not been investigated before.MethodsSubjects were recruited from the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study, a community based screening survey for heart failure in minority ethnic groups. Translated versions of the ECQ were prepared following a recognised protocol. All participants attending screening between October 2007 and February 2009 were asked to complete the ECQ in the language of their choice (English, Punjabi, Bengali, Urdu, Hindi or Gujarati). Subjects answering positively to experiencing leg pain or discomfort on walking were asked to return to have Ankle Brachial Pressure Index (ABPI) measured.Results154 out of 2831 subjects participating in E-ECHOES (5.4%) were eligible to participate in this sub-study, for which 74.3% returned for ABPI assessment. Non-responders were younger than participants (59[9] vs. 65[11] years; p = 0.015). Punjabi, English and Bengali questionnaires identified participants with Intermittent Claudication, so these questionnaires were assessed. The sensitivities (SN), specificities (SP), positive (PPV) and negative (NPV) predictive values were calculated. English: SN: 50%; SP: 68%; PPV: 43%; NPV: 74%. Punjabi: SN: 50%; SP: 87%; PPV: 43%; NPV: 90%. Bengali: SN: 33%; SP: 50%; PPV: 13%; NPV: 73%. There were significant differences in diagnostic accuracy between the 3 versions (Punjabi: 83.8%; Bengali: 45%; English: 62.2%; p < 0.0001). No significant differences were found in sensitivity and specificity between illiterate and literate participants in any of the questionnaires and there was no significant different difference between those under and over 60 years of age.ConclusionsOur findings suggest that the ECQ is not as sensitive or specific a diagnostic tool in 1st generation Black African-Caribbean and South Asian UK migrants than in the Edinburgh Artery Study, reflecting the findings of other diagnostic questionnaires in these minority ethnic groups. However this study is limited by sample size so conclusions should be interpreted with caution.