The distribution of CY2PC19*2 allele in a Trinidadian population. Is Clopidogrel the right choice?

OBJECTIVE: To determine the distribution of the CYP2C19*2 allele among Trinidadians. DESIGN AND METHODS: This is a cross sectional study among 100 patients attending primary health centers within the North Central Region of Trinidad. A stratified sampling technique was used in which there were three mutually exclusive subgroups: those of South Asian descent (Indo-Trinidadians), African descent (Afro-Trinidadians) and mixed ethnicity. Subsequently, systematic sampling was applied to each stratum to improve the representativeness of the sample. Hence, the 100 subjects recruited for the study were 40 Indo-Trinidadians, 40 Afro-Trinidadians and 20 of mixed descent. Apart from baseline data which included age, gender and ethnicity, DNA was assessed for the CYP2C19*2 allelic variant using a PCR method. RESULTS: There was a high allelic frequency (37%) for CYP2C19*2 which was found to be more common among Indo-Trinidadians (47.5%, 95% CI 32.0-63.0) compared to Afro-Trinidadians (22.5%, 95% CI 9.6-35.4) or people of mixed origin (45%, 95% CI 23.2-66.8). There was a significant difference (p=0.019) between CYP2C19*2 frequencies for Indo-Trinidadians and Afro-Trinidadians. CONCLUSION: We provided evidence that the prevalence of CYP2C19*2 mutation was high in our setting.

Population data on the thirteen CODIS core short tandem repeat loci in African Americans, U.S. Caucasians, Hispanics, Bahamians, Jamaicans, and Trinidadians

Allele distributions for 13 tetrameric short tandem repeat (STR) loci, CSF1PO, FGA, TH01, TPOX, VWA, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, and D21S11, were determined in African-American, United States Caucasian, Hispanic, Bahamian, Jamaican, and Trinidadian sample populations. There was little evidence for departure from Hardy-Weinberg expectations (HWE) in any of the populations. Based on the exact test, the loci that departed significantly from HWE are: D21S11 (p=0.010, Bahamians); CSF1PO (p=0.014, Trinidadians); TPOX (p=0.011, Jamaicans and p= 0.035, U.S. Caucasians); and D16S539 (p=0.043, Bahamians). After employing the Bonferroni correction for the number of loci analyzed (i.e., 13 loci per database), these observations are not likely to be significant. There is little evidence for association of alleles between the loci in these databases. The allelic frequency data are similar to other comparable data within the same major population group. (AU)

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)

Association of PON2 variation with birth weight in Trinidadian neonates of South Asian ancestry

Variation in the PON1 and PON2 genes has been shown to be associated with coronary heart disease risk in adults of South Asian origin. In this group, low birth weight is also associated with coronary heart disease risk. We therefore hypothesized that variation in PON1 and PON2 genes may be associated with variation in birth weight. This relationship was examined in 90 consecutive Trinidadian neonates of different ethnic origins. We found that variation in PON2 was significantly associated with variation in birth weight in Trinidadian neonates of south Asian origin. Among the neonates of South Asian origin, those who were homozygous for PON A148/A148 had significantly lower birth weight, by approximately 00 g, compared with those with the other two genotypes (P < 0.05). For neonates of south Asian origin, PON2 A148/A148 homozygotes were significantly more prevalent in those comprising the lowest tertile for birth weight than those comprising the highest tertile (0.41 versus 0.24, P < 0.05). There were no significant associations of PON variation with any phenotype in other ethnic groups. We conclude that among neonates of South Asian origin, homozygosity for PON2 A148/A148, is associated with significantly lower birth weight. This suggests that genetic factors in the fetus may be important determinants of neonatal birth weight and possibly of more distal adult phenotypes, such as coronary heart disease.(AU)

Estimating African American admixture proportions by use of population-specific alleles

We analyzed the European genetic contribution to 10 populations of Africans descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45 percent between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8 percent (Jamaica) to 22.5 percent (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3 percent -2.7 percent). We also estimated the male and female European contribution to African Americans. on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater that the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resources for mapping traits with different prevalence in two parental populations (AU)

The Trp64 A rg mutation of the B3- Adrenergic Receptor Is associated with hyperglycemia and current body mass index in Jamaican women

The Trp64Arg mutation the the beta3-adrenergic receptor (beta3-AR) has been linked to earlier onset of non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, abdominal obesity, and an increase capacity to gain weight in some European and Japanese populations. We studied the prevalence of the mutation and its association with NIDDM and obesity in our population, in which both rates are high, especially in women. The frequency of the homozygous mutation was 1.53 percent, and of the Arg allele, 10.5 percent. Rates were similar in men and women. Significantly higher body mass index (BMI), weight, hip circumference, and fasting and postchallenge 2 hour blood glucose concentrations were associated with the presence of the Arg allele in women but not in men. The association with weight and hip measurements and with hyperglycemia was present only in women aged less than 55 years. In multivariate analysis, the mutation was associated with the BMI and sex in a model that also included age. The variation in fasting and 2 hour blood glucose levels were predicted by beta3-AR, gender, age and BMI. These results suggest that the presence of the mutation contributes to obesity and hyperglycemia in our female population.(AU)

Human leukocyte antigen class II alleles associated with human T cell lymphotropic virus type I infection and adult T-vell leukemia/lymphoma in a black population

BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T-cell luekemia/lymphoma (ATL) and HTLV-I associated myelopathy (HAM; also known as tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder. Worldwide, several million HTLV-I carriers are at risk for disease, with an estimated lifetime cumulative risk of 1 percent-5 percent. However, the determinants of disease progression are relatively unknown. We studied human leukocyte antigens (HLA class II) that have been implicated in the pathogenesis of HTLV-I related diseases. METHODS: We analyzed HLA class II alleles among asymptomatic HTLV-I carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I seronegative control subjects (n = 51). All participants were of African descent and were enrolled in epidemiologic studies conducted at the University of the West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays for HLA antigen serotyping and polymerase chain reaction-based methods to examine HLA class II DRB1 and DQB1 alleles. RESULTS: Two antigens determined by serotyping DR15 and DQ1, occurred at significantly increased frequency among HTLV-I carriers compared with seronegative control subjects (42 percent versus 22 percent for DR15 [odds ratio [OR] = 2.7; 95 percent confidence interval [CI] - 1.0-7.2] and 78 percent versus 53 percent for DQ1 [OR = 3.1; 95 percent CI= 1.2-8.5]). Asymptomatic carriers were shown to have and HLA class II allele distribution similar to that of patients with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602 were significantly increased among patients with ATL compared with patients with HAM/TSP. CONCLUSIONS: These data suggest that host genetic background is an important factor in determining weather HTLV-I carriers develop either ATL or HAM/TSP.(AU)

Obesity and dysglycaemia in Jamaican women: does the Trp64Arg mutation of B-3 adrenergic receptor play a role?

The Trp64Arg mutation of B3 adrenergic receptor (B3AR) has been linked to earlier onset of non insulin dependent diabetes (NIDDM), insulin resistance, abdominal obesity and increased capacity to gain weight in some European and Japanese populations. We studied the prevalence of the mutation and its association with NIDDM and obesity in our population in which both rates are high, especially in women. The frequency of the homozygous mutation was 1.53 percent and of the Arg allele, 10.5 percent. Rates were similar in males and females. Significantly higher levels of BMI weight, hip circumference, fasting and post challenge 2h blood glucose concentrations were associated with the presence of the Arg allele in women but not in men. The association with weight and hip measurements and with hyperglycaemia was present only in women >55 years. In multivariate analysis the mutation was associated with BMI and gender in a model that also included age. The variation in fasting and 2h blood glucose levels was predicted by B3 Ar, gender, age and MBI. These results suggest that the presence of the mutation contributes to obesity and hyperglycaemia in our female population. (AU)

Evidence for genetic hitchhiking effect associated with insecticide resistance in Aedes aegypti

Information on genetic variation within and between populations is critical for understanding the evolutionary history of mosquito populations and disease epidemiology. Previous studies with Drosophila suggest that genetic variation of selectively neutral loci in a large fraction of genome may be constrained by fixation of advantageous mutations associated with hitchhiking effect. This study examined restriction fragment length polymorphisms of four natural Aedes aegypti mosquito populations from Trinidad and Tobago, at 16 loci. These populations have been subjected to organophosphate (OP) insecticide treatments for more than two decades, while dichlor-diphenyltrichlor (DDT) was the insecticide of choice prior to this period. We predicted that genes closely linked to the OP target loci would exhibit reduced genetic variation as a result of the hitchhiking effect associated with intensive OP insecticide selection. We also predicted that genetic variability of the genes conferring resistance to DDT and loci near the target site would be similar to other unlinkded loci. As predicted, reduced genetic variation was found for loci in the general chromosomal region of a putative OP target site, and these loci generally exhibited larger F (ST) values than other random loci. In contrast, the gene conferring resistance to DDT and its linked loci show polymorphisms and genetic differentiation similar to other random loci. The reduced genetic variability and apparent gene deletion in some regions of chromosome 1 likely to reflect the hitchhiking effect associated with OP insecticide selection(AU)

Lipids, apoliprotein-E genotypes and other risk factors of patients with coronary artery disease in Curacao

We studied lipids, apolipoprotein-E (apo-E) genotypes and other coronary artery disease (CAD) risk factors of 67 CAD patients (male/female ratio 5) in Curacao. Compared with 57 controls, male CAD patients had higher cholesterol, triglycerides, LDL-cholesterol, apo-B and decreased HDL-cholesterol and HDL-cholesterol/cholesterol concentrations. Other CAD risk factors were: increased fasting glucose and Hba concentration, decreased creatinine clearance, and increased prevalences of lipoprotein (a) concentration > 500 mg/l, renal disease, hyperhomcysteinaemia, diabetes mellitus type II (DM-II), positive CAD family history and cigarette smoking. Male CAD patients had higher plasma O-tocopherol. Compared with 29 female controls, female CAD patients had higher fasting plasma glucose with HbA concentrations, and prevalence of DM-II. Predicting factors for CAD development in the whole CAD group were: DM-II, cigarette smoking, apo-E/E and apo-E/E Apo-E was associated with lower HDL-and higher LDL-cholesterol concentrations. There is a need for local studies on improvement of diabetic control, reference values of lipoprotein (a) and homocysteine concentrations, on apolipoprotein (a) phenotypes, causes of hyperhomocysteinaemia, and dietary influences on CAD development in subject who carry the apo-E allele.(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)

Investigation of the renin gene as a putative locus for essential hypertension (EH) in Vincentian African Caribbeans

Epidemiological studies have consistently reported a higher prevalence of essential hypertension in black people. Other data indicate that black people may have salt regulatory systems with low reserves which are unable to cope with moderate quantities of salt and respond to salt loading by increasing their blood pressures. Black people are therefore susceptible to the deleterious effects of salt. As some forms of EH may be related to defects in salt regulatory systems, we investigated association of the renin gene locus (the rate limiting enzyme in an important salt regulatory system) with EH in an ethnically homogenous group of black people of African origin (Summary)

Blood group frequencies of the population of Trinidad and Tobago, West Indies

The results of grouping tests performed on blood samples collected over a five-year period at the Trinidad and Tobago Forensic Science Centre are presented. The samples were tested using the ABO, PGM, EAP and GLO blood group systems. Phenotypic frequencies and allele frequencies for each system were calculated for the two major ethnic groups of the population, the African and East Indian. Matching probabilities, which can be used in the interpretation of physical evidence in forensic cases, were also calculated. (AU)

HLA-DQA1 and DQB1 Alleles associated with genetic susceptibility to IDDM in a black population

Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk[RR] = 25.3, corrected P [Pc]<7.0 x 10 -6). THe DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc<6.5 x 10 -3 and RR = 12.3,Pc = 3.4 x 10 -3, respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc<3.5 x 10 -3 and RR = 0.15, Pc = 2.4 x 10 -2, respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM. (AU)

Population genetics of four hypervariable loci

Populations of white Caucasians, Afro-Caribbeans and Asians residing within the UK have been analysed at 4 different hypervariable loci. A computerised system was used to store and to analysed the data. Simulation experiments were carried out in order to determine whether there was any evidence for population stratification, which would lead to non-independence of allelic distributions. (AU)

Restriction site polymorphisms at the human HepG2 glucose transporter gene locu in Caucasian and West Indian subjects with non-insulin-dependent diabetes mellitus

Digestion of human genomic DNA with the restriction enzyme Stul revealed a 2-allele polymorphism with a human HepG2 glucose transporter probe. Bands of 3.2 kilobases (kb; SI allele) and 2.6 kb (S2 allele) were observed. The genotype frequencies were investigated in 2 non-insulin-dependent diabetic populations. The gene type frequencies of S1S1, S1S2 and S2S2 were 6, 42 and 52 percent among Caucasian diabetic subjects (n=48), and 11, 38 and 51 percent in 47 controls, respectively. In West Indian diabetic patients (n=48), the genotype frequencies were 17, 54 and 29 percent, and for 36 controls they were 25, 33 and 42 percent, respectively. The polymorphism information content of this restriction fragment length polymorphism (RFLP) is 0.32 in Caucasians and 0.37 in West Indians, respectively. There was no significant difference of allele or genotype frequencies between the diabetic patients and non-diabetic controls in either group. Haple type analysis of Stul and Xbal RFPLs showed that there was also no significant difference in the frequencies of the four different haplotypes S1X1, S1X2, S2X1 and S2X2 between the patients and controls. However there was a difference for the frequency of the S1 allele between Caucasians (control 30 percent, patients 27 percent) and West Indians (controls 42 percent, patients 44 percent). There was also a significant difference in the frequency of haplotype S2X2 between these two racial groups (controls 48 percent, cases 51 percent for Caucasians, and controls 33 percent, cases 22 percent for West Indians). (AU)

Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2 percent to 50 percent in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the á- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from ás. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9 percent confidence limits or were alike by t test (Po .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always ó .005 and usually ó 10 to the 4th power. We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of á-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the á-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to á to the s power, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one (AU)

Origin of the beta S-globin gene in blacks: the contribution of recurrent mutation or gene conversion or both

In order to investigate the origin(s) of the mutation(s) leading to the beta S-globin gene in North American populations of African ancestory, we analysed DNA polymorphisms in the beta-globin gene cluster in a large number of both beta A- and beta S-globin gene-bearing chromosomes in U.S. and Jamaican Blacks. We found 16 different haplotypes of polymorphic sites associated with 170 beta S-globin gene-bearing chromosomes. The three most common beta S haplotypes, which account for 151/170 of the beta S-globin gene-bearing chromosomes, are only rarely seen in the chromosomes bearing the beta A-globin gene in these populations (6/47). Two observations suggest multiple origins or interallelic gene conversion, or both, of the beta S mutation. First, the mutation is present in all three beta-globin gene frameworks. Second, the beta S haplotypes can be divided into four groups, each of which cannot be derived from any other by less than two crossing-over events. In summary, our observation of the beta S mutation on 16 different halotypes in African populations can be best explained by (i) a number of simple recombination events 5' to the beta-globin gene and (ii) up to four independent mutations and/or interallelic gene conversions. (AU)