Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi.

BACKGROUND: The mechanism of mother-to-child transmission (MTCT) of HIV-1 is not well described. METHODS: Of 328 HIV-infected mother-infant pairs, we identified 91 that had discordant angiotensin I-converting enzyme and glutathione S-transferase M1 alleles. Maternal alleles in cord blood were quantified with real-time polymerase chain reaction, as indicators of microtransfusions. RESULTS: HIV-1 infected infants had more maternal DNA in cord blood than their uninfected counterparts. Increased maternal DNA in cord blood was associated with preterm delivery, low birth weight, and maternal immunosuppression. CONCLUSION: Intrapartum MTCT was associated with placental microtransfusions. The associations among placental microtransfusion, in-utero MTCT, maternal immunosuppression, and poor birth outcome should be further investigated.

CCR5 haplotypes and mother-to-child HIV transmission in Malawi.

BACKGROUND: CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL. CONCLUSIONS/SIGNIFICANCE: Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability.

Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials.

OBJECTIVE: We conducted a meta-analysis of 25 randomized controlled trials published in English-language journals before February 2004, to assess the effect of dietary fiber intake on blood pressure (BP). DESIGN: Using a standardized protocol, information on study design, sample size, participant characteristics, duration of follow-up and change in mean BP, was abstracted. The data from each study were pooled using a random effects model to provide an overall estimate of dietary fiber intake on BP. INTERVENTION: Dietary fiber intake was the only significant intervention difference between the active and control groups. RESULTS: Overall, dietary fiber intake was associated with a significant -1.65 mmHg [95% confidence interval (CI), -2.70 to -0.61] reduction in diastolic BP (DBP) and a non-significant -1.15 mmHg (95% CI, -2.68 to 0.39) reduction in systolic BP (SBP). A significant reduction in both SBP and DBP was observed in trials conducted among patients with hypertension (SBP -5.95 mmHg, 95% CI, -9.50 to -2.40; DBP -4.20 mmHg, 95% CI, -6.55 to -1.85) and in trials with a duration of intervention > or = 8 weeks (SBP -3.12 mmHg, 95% CI, -5.68 to -0.56; DBP -2.57 mmHg, 95% CI, -4.01 to -1.14). CONCLUSIONS: Our results indicate that increased intake of dietary fiber may reduce BP in patients with hypertension and suggests a smaller, non-conclusive, reduction in normotensives. An intervention period of at least 8 weeks may be necessary to achieve the maximum reduction in BP. Our findings warrant conduct of additional clinical trials with a larger sample size and longer period of intervention to examine the effect of dietary fiber intake on BP.

Cardiac risk underestimation in urban, black women.

BACKGROUND: Black women have a disproportionately higher incidence of cardiovascular disease mortality than other groups and the reason for this health disparity is incompletely understood. Underestimation of personal cardiac risk may play a role. OBJECTIVE: We investigated the personal characteristics associated with underestimating cardiovascular disease in black women. DESIGN, SETTING, PARTICIPANTS: Trained surveyors interviewed 128 black women during the baseline evaluation for a randomized controlled trial in an urban, academic continuity clinic affiliated with a public hospital system. They provided information on the presence of cardiac risk factors and demographic and psychosocial characteristics. These self-report data were supplemented with medical record abstraction for weight. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was the accurate perception of cardiac risk. Objective risk was determined by a simple count of major cardiac risk factors and perceived risk by respondent's answer to a survey question about personal cardiac risk. The burden of cardiac risk factors was high in this population: 77% were obese; 72% had hypertension; 48% had high cholesterol; 49% had a family history of heart disease; 31% had diabetes, and 22% currently used tobacco. Seventy-nine percent had 3 or more cardiac risk factors. Among those with 3 or more risk factors ("high risk"), 63% did not perceive themselves to be at risk for heart disease. Among all patients, objective and perceived cardiac risk was poorly correlated (kappa=0.026). In a multivariable model, increased perceived personal stress and lower income were significant correlates of underestimating cardiac risk. CONCLUSIONS: Urban, disadvantaged black women in this study had many cardiac risk factors, yet routinely underestimated their risk of heart disease. We found that the strongest correlates of underestimation were perceived stress and lower personal income.

Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa.

OBJECTIVES: Major risk factors for hepatocellular carcinoma (HCC) are hepatitis viruses and exposure to aflatoxins, including aflatoxin B1 (AFB1). The mutagenic effect of AFB1 results from hepatic bioactivation to AFB1-exo-8,9-epoxide. This is in part catalysed by CYP3A5, an enzyme expressed polymorphically. We investigated the role of CYP3A5 polymorphisms in the formation of AFB1-exo-8,9-epoxide in The Gambia, a population exposed to high aflatoxin levels. METHODS: Common CYP3A5 polymorphisms were identified in an African-American population. Subsequently, 288 Gambian subjects were genotyped and CYP3A5 activity predicted using haplotypes of the three variant loci (CYP3A5*3, *6 and *7) associated with decreases in protein expression. CYP3A5 expression was then compared to aflatoxin-albumin (AF-alb) adduct, a biomarker of AFB1 bioactivation; data were also analysed in relation to expression of other aflatoxin-metabolizing enzymes. RESULTS: CYP3A5 haplotypes reflecting high CYP3A5 protein expression were associated with increased AF-alb. Compared to individuals with predicted low expression those predicted to express CYP3A5 from one allele displayed 16.1% higher AF-alb (95% CI: -2.5, 38.2, P = 0.093) and homozygous expressers displayed 23.2% higher AF-alb levels (95% CI: -0.01, 52.0, P = 0.051). The effect of the CYP3A5 polymorphism was strongest in individuals with low CYP3A4 activity with a 70.1% increase in AF-alb (95% CI: 11.8, 158.7, P < 0.05) in high compared to low expressers. A similar effect was observed for individuals with null alleles of GSTM1, which conjugates the AFB1-exo-8,9-epoxide to reduced glutathione. CONCLUSIONS: The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1-exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC.

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.