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P M McKeigue

Publications and source records attributed to P M McKeigue.

At least 19 recordsLinked to original sources
PubMed2006

Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK.

AIMS/HYPOTHESIS: We examined prospectively whether measured risk factors can explain the higher CHD mortality in South Asians compared with Europeans. MATERIALS AND METHODS: Conventional CHD risk factors and those associated with insulin resistance were measured in 1,787 European and 1,420 South Asian men aged 40 to 69 years at baseline in the population-based Southall and Brent studies (London) between 1988 and 1990. Participants were followed up for mortality. RESULTS: By February 2006, there were 202 CHD deaths (108 Asian, 94 European). South Asian men had double the CHD mortality of European men in Cox regression analyses adjusted for age, smoking, and cholesterol (hazard ratio [HR] 2.14, 95% CI 1.56-2.94, p<0.001). Nearly half of all South Asian CHD deaths versus 13% of deaths among Europeans were among persons with diabetes. Asian men had greater CHD mortality than Europeans, both in the with- and the without-diabetes categories at baseline. CHD mortality remained significantly higher in South Asian men in multivariable models that adjusted for conventional risk factors and diabetes and/or impaired glucose regulation, features of insulin resistance, or the metabolic syndrome (HR 1.6-1.9). Accounting for co-morbidity and socio-economic status did not materially alter the findings. CONCLUSIONS/INTERPRETATION: These data confirm that South Asian men have significantly higher CHD mortality than their European counterparts, while indicating that neither conventional risk factors, nor insulin resistance parameters or metabolic syndrome criteria as currently defined can account for this excess risk. The contribution of unmeasured factors to the elevated vascular risk in South Asians should be addressed in future studies.

Asian People↗
PubMed2005

Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK population-based cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to study differences in the prevalence of the metabolic syndrome and its associations with prevalent CHD according to ethnicity and sex. METHODS: We performed a combined analysis of two population-based cross-sectional studies conducted between 1988 and 1991 that followed identical protocols. Participants (aged 40-69 years) comprised 2,346 Europeans (76% male), 1,711 South Asians (83% male) and 803 African-Caribbeans (57% male) resident in west London. Fasting blood, overnight urine collection, clinical and anthropometric measurements were performed. Clinical history or major ECG changes defined prevalent CHD. The metabolic syndrome was defined according to the criteria recommended by the World Health Organization (WHO) and the National Cholesterol Education Programme (NCEP). RESULTS: The prevalence of the metabolic syndrome was highest in South Asians (WHO, men 46%, women 31%; NCEP, men 29%, women 32%) and lowest in European women (WHO, 9%; NCEP, 14%). The prevalence of CHD was 10% in South Asian men, 9% in European men, 5-6% in African-Caribbeans and European women, and 2% in South Asian women. The metabolic syndrome was associated with prevalent CHD in European men [NCEP, odds ratio (OR)=1.6, 95% CI 1.2-2.4; WHO, OR=1.7, 95% CI 1.2-2.5] and South Asian men (NCEP, OR=2.1, 95% CI 1.5-3.1; WHO, OR=1.6, 95% CI 1.1-2.3). Associations with CHD were weaker in African-Caribbeans and were inconsistent among European women. CONCLUSIONS/INTERPRETATION: The current definitions of the metabolic syndrome give an inconsistent picture of cardiovascular disease risk when applied to different ethnic groups within the UK. Prospective studies are needed to validate workable ethnic-specific definitions.

Adult↗
PubMed2004

Design and analysis of admixture mapping studies.

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.

Black People↗
PubMed2004

Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping.

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado. We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

Adult↗
PubMed2003

Relation of risk of systemic lupus erythematosus to west African admixture in a Caribbean population.

Risk of systemic lupus erythematosus (SLE) is higher in people of west African descent than in Europeans. The objective of this study was to distinguish between genetic and environmental explanations for this ethnic difference by examining the relationship of disease risk to individual admixture (defined as the proportion of the genome that is of west African ancestry); 124 cases of SLE and 219 matched controls resident in Trinidad were studied. Analysis of admixture was restricted to 52 cases and 107 controls who reported no Indian or Chinese ancestry. These individuals were typed with a panel of 26 single-nucleotide polymorphisms and five insertion/deletion polymorphisms chosen to have large allele frequency differentials between west African, European and Native American populations. A Bayesian model for population admixture, individual admixture and locus ancestry was fitted by Markov chain simulation. Mean west African admixture (M) was 0.81 in cases and 0.74 in controls (P=0.01). The risk ratio for SLE associated with unit change in M was estimated as 32.5 with a 95% confidence interval (CI) of 2.0-518. Adjustment for measures of socioeconomic status (household amenities in childhood and years of education) altered this risk ratio only slightly (adjusted risk ratio: 28.4, 95% CI 1.7-485). These results support an additive genetic model for the ethnic difference in risk of SLE between west Africans and Europeans, rather than an environmental explanation or an "overdominant" model in which risk is higher in heterozygous than in homozygous individuals. This conclusion lays a basis for localizing the genes underlying this ethnic difference in risk of SLE by admixture mapping.

Adult↗
PubMed2001

Epidemiological methods for studying genes and environmental factors in complex diseases.

Exploration of the human genome presents new challenges and opportunities for epidemiological research. Although the case-control design is quicker and cheaper for study of associations between genotype and risk of disease than the cohort design, cohort studies have been recommended because they can be used to study gene-environment interactions. Although the scientific relevance of statistical interaction is pertinent, the main disadvantage of the case-control design-susceptibility to bias when estimating effects of exposures that are measured retrospectively-does not necessarily apply when studying statistical interaction between genotype and environmental exposure. Because correctly designed genetic association studies are equivalent to randomised comparisons between genotypes, conclusions about cause can be drawn from genetic associations even when the risk ratio is modest. For adequate statistical power to detect such modest risk ratios, the case-control design is more feasible than the cohort design.

Case-Control Studies↗
PubMed2001

Birth outcome in relation to licorice consumption during pregnancy.

A role for glucocorticoids is suspected in the etiology of low birth weight. The authors tested whether maternal consumption of glycyrrhizin (an inhibitor of cortisol metabolism) in licorice affects birth weight in humans. A sample of 1,049 Finnish women and their healthy singleton infants was studied in 1998. Glycyrrhizin intake was calculated from detailed questionnaires on licorice consumption. Glycyrrhizin exposure was grouped into three levels: low (<250 mg/week; n = 751), moderate (250-499 mg/week; n = 145), and heavy (> or =500 mg/week; n = 110). Birth weight and gestational age (from ultrasound measurements) were obtained from hospital records. Babies with heavy exposure to glycyrrhizin were not significantly lighter at birth, but they were significantly more likely to be born earlier: The odds ratio for being born before 38 weeks' gestation was 2.5 (95% confidence interval: 1.1, 5.5; p = 0.03). Although the effect of heavy glycyrrhizin intake on mean duration of gestation was small (2.52 days) when expressed as an effect on the mean, this shift to the left of the distribution of duration of gestation was sufficient to double the risk of being born before 38 weeks. The association remained in multivariate analyses. In conclusion, heavy glycyrrhizin exposure during pregnancy did not significantly affect birth weight or maternal blood pressure, but it was significantly associated with lower gestational age.

Adult↗
PubMed2001

Systemic lupus erythematosus in migrants from west Africa compared with Afro-Caribbean people in the UK.

SLE has a high prevalence in Afro-Caribbean populations but has been reported to be rare in west Africa. We assessed prevalence (per 100000) of SLE in women in an area of south London and estimated it to be 177 (95% CI 135-220) in Afro-Caribbeans, 110 (58-163) in west Africans, and 35 (26-43) in Europeans. The high prevalence of SLE in recent migrants from west Africa suggests that the disease is not rare in west Africa, and that there is a genetic basis for the high risk of SLE in people of west African descent compared with other groups.

Adolescent↗
PubMed2001

Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina.

We analyzed admixture in samples of six different African-American populations from South Carolina: Gullah-speaking Sea Islanders in coastal South Carolina, residents of four counties in the "Low Country" (Berkeley, Charleston, Colleton, and Dorchester), and persons living in the city of Columbia, located in central South Carolina. We used a battery of highly informative autosomal, mtDNA, and Y-chromosome markers. Two of the autosomal markers (FY and AT3) are linked and lie 22 cM apart on chromosome 1. The results of this study indicate, in accordance with previous historical, cultural, and anthropological evidence, a very low level of European admixture in the Gullah Sea Islanders (m = 3.5 +/- 0.9%). The proportion of European admixture is higher in the Low Country (m ranging between 9. 9 +/- 1.8% and 14.0 +/- 1.9%), and is highest in Columbia (m = 17.7 +/- 3.1%). A sex-biased European gene flow and a small Native American contribution to the African-American gene pool are also evident in these data. We studied the pattern of pairwise allelic associations between the FY locus and the nine other autosomal markers in our samples. In the combined sample from the Low Country (N = 548), a high level of linkage disequilibrium was observed between the linked markers, FY and AT3. Additionally, significant associations were also detected between FY and 4 of the 8 unlinked markers, suggesting the existence of significant genetic structure in this population. A continuous gene flow model of admixture could explain the observed pattern of genetic structure. A test conditioning on the overall admixture of each individual showed association of ancestry between the two linked markers (FY and AT3), but not between any of the unlinked markers, as theory predicts. Thus, even in the presence of genetic structure due to continuous gene flow or some other factor, it is possible to differentiate associations due to linkage from spurious associations due to genetic structure.

Africa↗
PubMed2001

Changes in physical activity are associated with changes in metabolic cardiovascular risk factors.

AIMS/HYPOTHESIS: To investigate the effect of changes in physical activity on changes in metabolic cardiovascular risk factors and to investigate what factors affect the association between physical activity and cardiovascular mortality. METHODS: Of the 1860 men who were 50 years of age and who were without pre-existing cardiovascular disease participating in a population-based study, 898 were re-examined 20 years later. Altogether 231 died from cardiovascular diseases during the follow-up (mean = 22.6 years). The examinations which the men underwent at 50 and 70 years of age included assessment of physical activity (self-reported at four alternative levels), anthropometry, measurements of fasting concentrations of glucose, specific insulin, proinsulin, split proinsulin and lipids. RESULTS: During the 20 years, 31 % increased their amount of physical activity while 51 % continued the same amount of exercise. Increased physical activity was associated with significant changes in several important metabolic variables, including fasting glucose, proinsulin and HDL cholesterol, independent of body weight changes. The risk of cardiovascular disease for men performing moderate, regular and athletic physical activity was 25 % (p = 0.127), 34 % (p = 0.022) and 71 % (p = 0.009) lower, respectively, compared with sedentary men. The association was attenuated by adjustment for baseline measurements of insulin, proinsulin and split proinsulin. Additional adjustment for other cardiovascular risk factors did not further attenuate the association. CONCLUSION/INTERPRETATION: Increased leisure time physical activity between the ages of 50 and 70 years, in the absence of active intervention, is associated with improved glucose, insulin and lipid metabolism in men. The concentrations of insulin, proinsulin and split proinsulin could mediate much of the association between a sedentary lifestyle and increased risk of cardiovascular mortality.

Aged↗
PubMed2001

Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians.

OBJECTIVE: To investigate the association between circulating C-reactive protein (CRP) concentrations and indices of body fat distribution and the insulin resistance syndrome in South Asians and Europeans. DESIGN: : Cross-sectional study. SUBJECTS: A total of 113 healthy South Asian and European men and women in West London (age 40-55 y, body mass index (BMI) 17-34 kg/m(2)). MEASUREMENTS: Fatness and fat distribution parameters (by anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan); oral glucose tolerance test with insulin response; modified fat tolerance test; and CRP concentration by sensitive ELISA. RESULTS: Median CRP level in South Asian women was nearly double that in European women (1.35 vs 0.70 mg/1, P=0.05). Measures of obesity and CRP concentration were significantly associated in both ethnic groups. The correlation to CRP was especially strong among South Asians (P<0.01) for measures of central obesity (waist girth and visceral fat area), whereas BMI and percentage fat were more significantly associated with CRP in Europeans (P<0.05). In South Asians the associations of CRP with visceral fat area and waist girth persisted after adjustment for either BMI or percent fat (all, P<0.05). In age-, sex- and smoking-adjusted regression analyses CRP concentrations were significantly associated with fasting and 2 h insulin and lipid levels in both ethnic groups (P<0.05). When further statistical adjustment was made for visceral fat area these associations were abolished (P>0.15). CONCLUSION: We suggest that adiposity and in particular visceral adipose tissue is a key promoter of low-grade chronic inflammation. This observation may in part account for the association of CRP with markers of the metabolic syndrome. Future studies should confirm whether CRP concentrations are elevated in South Asians and whether losing weight by exercise or diet, or reduction in visceral fat mass, is associated with reduction in plasma CRP concentrations.

Adipose Tissue↗
PubMed2001

A comparison of left ventricular abnormalities associated with glucose intolerance in African Caribbeans and Europeans in the UK.

OBJECTIVE: To determine whether abnormalities of the left ventricle differ by glucose tolerance status, to explore reasons for differences, and to assess ethnic differences in these relations. DESIGN: Population based prevalence study. SETTING: London, UK. PATIENTS: 1152 African Caribbeans and Europeans. METHODS: Echocardiograms, blood pressure, obesity, fasting and two hour blood glucose, insulin and lipids, and urinary albumin excretion rate were measured. MAIN OUTCOME MEASURES: Left ventricular mass index, wall thickness, and early (E) to atrial (A) wave ratio. RESULTS: Left ventricular mass index was greater in diabetic Europeans than in normoglycaemic Europeans (mean (SE), 95.6 (5.0) v 79.7 (0.8) g/m(2), p = 0.001) and in diabetic African Caribbeans than in normoglycaemic African Caribbeans (88.6 (2.5) v 82.4 (0.9) g/m(2), p = 0.02). Similar, but weaker associations were observed for the E:A ratio. beta Coefficients between left ventricular mass index and fasting glucose in the normoglycaemic range, adjusted for age and sex, were 2.43 in Europeans (p = 0.05) and 3.74 in African Caribbeans (p = 0.02). These were attenuated to 1.19 (p = 0.4) and 3.03 (p = 0.08) in Europeans and African Caribbeans, respectively, when adjusted further for blood pressure and obesity. Adjustments for other risk factors made little difference to the coefficients. There were no ethnic differences in risk factor relations. CONCLUSIONS: Abnormalities of the left ventricle occur in response to glucose intolerance and are observable into the normoglycaemic range. These disturbances are largely accounted for by associated obesity and hypertension. African Caribbeans have a greater degree of left ventricular structural impairment, emphasising the importance of tight blood pressure control.

Adult↗
PubMed2000

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium.

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.

Africa↗
PubMed2000

Relation of nocturnal polyuria of the elderly to essential hypertension.

Nocturnal polyuria is common in the elderly. In this condition the normal circadian rhythm of urine production is reversed so that urine flow is higher at night than during the day. Elderly men with nocturnal polyuria are commonly referred for prostate surgery, which, not surprisingly, fails to relieve their symptoms. Compared with controls, patients with nocturnal polyuria have higher nocturnal sodium excretion but not higher nocturnal free-water clearance. Similar results have been obtained in children with nocturnal enuresis. Use of vasopressin analogues to induce water retention in elderly patients with nocturnal polyuria is illogical and potentially hazardous; nocturia can be more safely alleviated by diuretic therapy. Nocturnal polyuria in the elderly is associated with hypertension: this is consistent with studies in younger age groups that show that essential hypertension is associated with nocturia and with increased night/day ratios for sodium excretion. We propose that nocturnal polyuria and essential hypertension share some of the same pathophysiological determinants. Specifically, we suggest that a defect in the nitric-oxide pathway may lead to resetting of the pressure-natriuresis relation in the kidney, sodium retention, and compensatory nocturnal natriuresis. This suggestion is consistent with evidence that ageing and essential hypertension are both associated with defects in the nitric-oxide pathway. Our hypothesis has obvious therapeutic implications. More generally, studying the pathogenesis of nocturnal polyuria in the elderly may advance our understanding of the pathogenesis of essential hypertension.

Aged↗
PubMed2000

Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances.

AIMS/HYPOTHESIS: To distinguish the physiological disturbances related to birth weight from the cluster of disturbances called the insulin resistance syndrome. METHODS: Men participating in a population-based study in Uppsala, Sweden, with recordings of birth weight, were metabolically characterised at age 50 (n = 1268) and re-investigated at age 70 (n = 734). Blood pressure, BMI, glucose and insulin concentrations are associated with birth weight in this cohort. RESULTS: Birth weight was inversely associated (p < 0.03) with subscapular:triceps skinfold ratio (truncal fat), plasminogen activator inhibitor-1 (PAI-1) activity, specific insulin and proinsulin-like molecules when adjusted for BMI. Birth weight was not related (p > 0.10) with waist circumference, serum triglycerides or HDL cholesterol. The insulin resistance syndrome was defined as the combination of hypertension, insulin resistance and dyslipidaemia. The prevalence of this syndrome at age 50 and 70 was inversely related to birth weight with odds ratio 0.66 and 0.71, respectively, per kg increase in birth weight. When the syndrome was defined to include truncal obesity or raised plasminogen activator inhibitor-1 instead of dyslipidaemia, the corresponding odds ratios were 0.51 and 0.66, respectively. CONCLUSIONS/INTERPRETATION: Low birth weight predicts high blood pressure, insulin resistance, truncal obesity and high plasminogen activator inhibitor-1 activity but not the abdominal obesity or dyslipidaemia present in the insulin resistance syndrome. The cluster of disturbances associated with low birth weight is a subset of the disturbances that are clustered in the general population as the insulin resistance syndrome. This subset of physiological disturbances is possibly linked by a specific pathway.

Aged↗