Lipoprotein-genotype associations in Trinidadian neonates

OBJECTIVES: We hypothesized that common variation in the angiotensinogen (AGT), beta-3-adrenergic receptor. intestinal fatty acid-binding protein, serum paraoxonase, paraoxonase-2, hepatic lipase, apolipoprotein E (APOE), and Werner helicase (WRN) genes would be associated with variation in biochemical phenotypes in a previously unstudied neonatal sample. DESIGN AND METHODS: We examined associations of both nongenetic and genetic variables with plasma lipoprotein traits in neonates from Trinidad. RESULTS: Among nongenetic variables, we found significant associations between plasma concentrations of 1.) lipoprotein (a) [Lp(a)] and both ethnicity (p=0.037) and birth weight (p=0.001); 2)total cholesterol and gender (p=0.010); 3)triglyceride and birth weight (p=0.035); and 4)apolipoprotein A1 and gender (p=0.016). Among genetic variables, we found that: 1)common variation on chromosome 1q in AGT codon 235 was significantly associated with variation in plasma apolipoproteins Al (p<0.0001); and 3)common variation in APOE at codons 112 and 158 was significantly associated with variation in plasma triglycerides (p=0.013). CONCLUSIONS: The associations with AGT and WRN are novel and may have resulted either from direct influence of the genetic variants or through linkage disequilibrium with other functional loci, such as the familial combined hyperlipidemia locus on chromosome 1q in the case of AGT. Despite the fact that there are some limitations in making determinations from cord blood, the results suggest that there may be genetic determinants of plasma lipoproteins in neonates. (AU)

Angiotensinogen levels and obesity in four black populations. ICSHIB Investigations

BACKGROUND: The relationship between circulating levels of angiotensinogen and hypertension in the epidemiologic setting has not been studied much. Recent findings related to the association between hypertension and polymorphisms of the angiotensinogen gene have generated new interest in this potential pathway to hypertension. OBJECTIVES: To examine environmental factors associated with levels of circulating angiotensinogen as determinants of hypertension in populations of African origin. METHODS: We recruited 1557 participants from communities in Nigeria (n = 611), Zimbabwe (n = 161), Jamaica (n = 476), and Maywood, Illinois, USA (n = 309). RESULTS: Mean angiotensinogen levels varied widely across groups (Nigeria 1381 ng/ml angiotensin I generated, Zimbabwe 1638 ng/ml angiotensin and I generated Jamaica 1801 ng/ml angiotensin I generated, and Maywood 2039 ng/ml angiotensin I generated). Average body mass index was highly correlated to angiotensinogen level across the population samples, accounting for 90 percent of the between-sample variation. At the individual level the correlation between body mass index and angiotensinogen level was substantially smaller, in the range 0.04-0.15, although the association attained statistical significance for all but one of the populations. Women had higher levels of angiotensinogen and mean levels in subjects of both sexes declined in late middle age. Hypertensives also had significantly higher levels of angiotensinogen and we noted correlations to blood pressure for two of the four populations. CONCLUSIONS: Obesity, sex and age would all appear to be important modifiers of circulating angiotensinogen levels. The variation in level across populations was substantially larger than that which has been found previously in association with known genetic polymorphisms within populations, suggesting the possibility that environmental effects are more important than had previously been recognised.(AU)

ACE, angiotensinogen and obesity: a potential pathway leading to hypertension

The renin-angiotensin system (RAS) plays a crucial role in the regulation of fluid volume, thereby influencing blood pressure (BP). Obesity is an important risk factor for hypertension, however the physiologic basis for this relationship has not been clarified. In a population survey we examined the potential relationship between the RAS and obesity. Based on community sampling, 449 individuals were recruited from metropolitan Kingston, Jamaica. Serum angiotensin-converting enzyme (ACE) and circulating angiotensinogen levels were measured and the associated genes were typed for previously described polymorphisms. Obese individuals (body mass index > 31) had significantly higher serum ACE and angiotensinogen levels, this relationship persisted for ACE in multivariate analyses controlling for BP, hypertension status, age and gender. The insertion/deletion polymorphism of the ACE gene was associated with variation in the levels of ACE, but inconsistently with body mass index. Variants of the angiotensinogen gene leading to amino acid substitutions at positions 174 and 235 did not influence levels either of angiotensinogen or obesity. These data suggest that obesity may alter the levels of ACE and angiotensinogen, and provide a potential pathway through which obesity leads to elevation of BP.(AU)

Angiotensinogen and blood pressure among blacks: findings from a community survey in Jamaica

OBJECTIVE: To examine the association between blood pressure, angiotensinogen levels, angiotensin converting enzyme activity and polymorphisms of the angiotensinogen and angiotensin converting enzyme genes in a population-based sample. METHOD: Five hundred participants were recruited in a house-to-house survey of three communities in metropolitan areas of Kingston and St. Andrew, in Jamaica. Demographic data, anthropometric and blood pressure measurements were obtained for each participant during a brief clinic visit. Circulating levels of angiotensinogen and angiotensin converting enzyme genes were determined. RESULTS: A weak association between angiotensinogen level, angiotensin converting enzyme activity and blood pressure was identified in this population, but substantial joint effect of angiotensin converting enzyme activity and agiotensinogen level on blood pressure was apparent. Variants of the angiotensinogen gene had inconsistent effects on blood pressure and on the risk of hypertension. Angiotensinogen level and angiotensin converting enzyme activity were significantly related to several measures of obesity, including body mass index, waist circumference and skin fold thickness. CONCLUSION: The angiotensinogen and angiotensin converting enzyme genetic variants which were studied appear to have only a modest relationship with blood pressure and associated anthropometric risk factors among blacks. (AU)

Polymorphisms of renin-angiotensin genes among Nigerians, Jamaicans, and African Americans

Within the context of an international collaborative study of the evolution of hypertension in the black disapora, we determined the allelic distribution of hypertension candidate genes for the renin-angiotensin system in three populations of African origin. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and the M235T and T174M variants of the angiotensinogen (AGT) gene were examined in individuals from Nigeria, Jamaica, and the United States. Large differences in the prevalence of hypertension were recorded in door-to-door surveys, ranging from 16 percent in Nigeria to 33 percent in the United States. The frequency of the D allele was similar in all groups (54 percent, 59 percent and 63 percent in Nigeria, Jamaica, and the United States, respectively). The 235T allele of the AGT gene was found in 81 percent of US and Jamaican blacks and 91 percent of Nigerians: very little variation was seen for the T174M marker. Despite larger differences in hypertension rates, genetic variation at the index loci among these groups was modest. Overall, the frequency of the ACE D allele was only slightly higher than that reported for European and Japanese populations, whereas the AGT 235T allele was twice as common. Compared with blacks in the western hemisphere. Nigerians had a higher frequency of the 235T allele, which is consistent with 25 percent European admixture in Jamaica and the United States. The results indicate the potential for etiolgic heterogeneity in genetic factors related to hypertension across the ethnic groups while suggested that environmental exposures most likely explain the gradient in risk in the comparison among black populations.(AU)

Linkage of the angiotensin gene locus to human essential hypertension in African Caribbeans

The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within the system has been linked to essential hypertension in white Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among sibling genotyped using an angiotensingogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (Xý = 50.2, 12 degrees of freedom, P ó 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity (AU)