A genome-wide search replicates evidence of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE) unlinked to the ACE gene.

BACKGROUND: Angiotensin I-converting enzyme (ACE) plays an important role in cardiovascular homeostasis. There is evidence from different ethnic groups that circulating ACE levels are influenced by a quantitative trait locus (QTL) at the ACE gene on chromosome 17. The finding of significant residual familial correlations in different ethnic groups, after accounting for this QTL, and the finding of support for linkage to a locus on chromosome 4 in Mexican-American families strongly suggest that there may well be QTLs for ACE unlinked to the ACE gene. METHODS: A genome-wide panel of microsatellite markers, and a panel of biallelic polymorphisms in the ACE gene were typed in Nigerian families. Single locus models with fixed parameters were used to test for linkage to circulating ACE with and without adjustment for the effects of the ACE gene polymorphisms. RESULTS: Strong evidence was found for D17S2193 (Zmax = 3.5); other nearby markers on chromosome 17 also showed modest support. After adjustment for the effects of the ACE gene locus, evidence of "suggestive linkage" to circulating ACE was found for D4S1629 (Zmax = 2.2); this marker is very close to a locus previously shown to be linked to circulating ACE levels in Mexican-American families. CONCLUSION: In this report we have provided further support for the notion that there are QTLs for ACE unlinked to the ACE gene; our findings for chromosome 4, which appear to replicate the findings of a previous independent study, should be considered strong grounds for a more detailed examination of this region in the search for genes/variants which influence ACE levels.The poor yields, thus far, in defining the genetic determinants of hypertension risk suggest a need to look beyond simple relationships between genotypes and the ultimate phenotype. In addition to incorporating information on important environmental exposures, a better understanding of the factors which influence the building blocks of the blood pressure homeostatic network is also required. Detailed studies of the genetic determinants of ACE, an important component of the renin-angiotensin system, have the potential to contribute to this strategic objective.

Genetic evidence in support of a shared Eurasian-North African dairying origin.

The process by which pastoralism and agriculture spread from the Fertile Crescent over the past 10,000 years has been the subject of intense investigation by geneticists, linguists and archaeologists. However, no consensus has been reached as to whether this Neolithic transition is best characterized by a demic diffusion (with a significant genetic input from migrating farmers) or a cultural diffusion (without substantial migration of farmers). Milk consumption and thus lactose tolerance are assumed to have spread with pastoralism and we propose that by looking at the relevant mutations in and around the lactase gene in human populations, we can gain insight into the origin(s) and spread of dairying. We genotyped the putatively causal allele for lactose tolerance (-13910T) and constructed haplotypes from several polymorphisms in and around the lactase gene (LCT) in three North African Berber populations and compared our results with previously published data. We found that the frequency of the -13910T allele predicts the frequency of lactose tolerance in several Eurasian and North African Berber populations but not in most sub-Saharan African populations. Our analyses suggest that contemporary Berber populations possess the genetic signature of a past migration of pastoralists from the Middle East and that they share a dairying origin with Europeans and Asians, but not with sub-Saharan Africans.

UGT1A1 variation and gallstone formation in sickle cell disease.

Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease. Subjects were from the Jamaican Sickle Cell Cohort Study (cohort sample, n = 209) and the Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica (clinic sample, n = 357). The UGT1A1 (TA)(n) promoter region was sequenced in 541 SS disease subjects and 111 healthy controls (control sample). Indirect bilirubin levels for (TA)(7)/(TA)(7) and (TA)(7)/(TA)(8) genotypes were elevated compared with (TA)(6)/(TA)(6) (clinic sample, P < 10(-5); cohort sample, P < 10(-3)). The (TA)(7)/(TA)(7) genotype was also associated with symptomatic presentation and gallstones in the clinic sample (odds ratio [OR] = 11.3; P = 7.0 x 10(-4)) but not in the younger cohort sample. These unexpected findings indicate that the temporal evolution of symptomatic gallstones may involve factors other than the bilirubin level. Although further studies of the pathogenesis of gallstones in SS disease are required, the (TA)(7)/(TA)(7) genotype may be a risk factor for symptomatic gallstones in older people with SS disease.

Association between evolutionary history of angiotensinogen haplotypes and plasma levels.

Over the last decade, considerable effort has been invested in studying the associations between angiotensinogen (AGT) variants, AGT plasma levels and high blood pressure. Evidence accumulated to date consistently supports the relationship between the AGT locus and the protein level, while an influence on blood pressure has been difficult to establish; in both instances the predisposing molecular variants are not fully defined. An evolutionary approach, taking into account the phylogenetic relationship between all the polymorphisms at this locus, may improve our understanding of the genetic nature of these quantitative phenotypes. Accordingly we sequenced a 6.8 kb region of the AGT gene in 57 Nigerian individuals (29 with high AGT plasma levels and 28 with low AGT plasma levels). Haplotypes were grouped into seven major haplogroups and their phylogenetic relationship was established. The association between haplogroups and AGT plasma levels was investigated. A significant linear correlation was detected between haplogroup genetic distance and AGT levels, suggesting a nonrandom accumulation of risk-associated mutations during the evolutionary history of the AGT gene.

Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans.

The genes in the renin-angiotensin system are important physiologic candidates in studies of the genetic susceptibility to hypertension. Limited information has been available in most studies on the extent of variation in the candidate loci or the modifying effects of different environmental settings. We consequently genotyped 13 polymorphisms at the angiotensin I-converting enzyme (ACE) locus at an average distance of 2 kb in 2776 family members from Nigeria, Jamaica and an African-American community in the US. Allele and haplotype frequencies were similar in the three populations, with modest evidence of European admixture in the US. Two markers were consistently associated with ACE level in the three samples and the proportion of variance accounted for by ACE8 was similar in the three groups. No evidence of consistent association of single markers was noted with blood pressure across the three population samples, however. Likewise, in a haplotype-based analysis, despite significant associations within each population, the findings were not replicated consistently across all three samples. We did observe, however, that the overtransmitted haplotypes among hypertensives were drawn from a single clade, suggesting that susceptibility may cluster in patterns not captured directly by our markers.

A genome-wide scan for body mass index among Nigerian families.

OBJECTIVE: Interest in mapping genetic variants that are associated with obesity remains high because of the increasing prevalence of obesity and its complications worldwide. Data on genetic determinants of obesity in African populations are rare. RESEARCH METHODS AND PROCEDURES: We have undertaken a genome-wide scan for body mass index (BMI) in 182 Nigerian families that included 769 individuals. RESULTS: The prevalence of obesity was only 5%, yet polygenic heritability for BMI was in the expected range (0.46 +/- 0.07). Tandem repeat markers (402) were typed across the genome with an average map density of 9 cM. Pedigree-based analysis using a variance components linkage model demonstrated evidence for linkage on chromosome 7 (near marker D7S817 at 7p14) with a logarithm of odds (LOD) score of 3.8 and on chromosome 11 (marker D11S2000 at 11q22) with an LOD score of 3.3. Weaker evidence for linkage was found on chromosomes 1 (1q21, LOD = 2.2) and 8 (8p22, LOD = 2.3). Several candidate genes, including neuropeptide Y, DRD2, APOA4, lamin A/C, and lipoprotein lipase, lie in or close to the chromosomal regions where strong linkage signals were found. DISCUSSION: The findings of this study suggest that, as in other populations with higher prevalences of obesity, positive linkage signals can be found on genome scans for obesity-related traits. Follow-up studies may be warranted to investigate these linkages, especially the one on chromosome 11, which has been reported in a population at the opposite end of the BMI distribution.

Genome scan among Nigerians linking blood pressure to chromosomes 2, 3, and 19.

An understanding of the genetic influences on hypertension would help unravel the pathophysiology of this complex disorder and improve our understanding of causal mechanisms. Contemporary technology makes it possible to examine enough genetic markers to support a generalized search across the entire genome for candidate regions. In the present study, a family set was recruited from southwest Nigeria, and 378 microsatellite markers were typed on 792 individuals in 196 families. Multipoint variance component analysis identified linkage signals (logarithm of the odds [LOD] 1.74, P<0.0023) for systolic blood pressure on 19p (D19S714) and 19q (D19S246), whereas for diastolic blood pressure, linkage was observed on 2p (D2S1790), 3p (D3S1304), 5q (D5S1462), 7p (D7S3046), 7q (D7S821), and 10q (D10S1221). Other regions of interest (1.18

Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides.

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.