Iona Y. Millwood

Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.

An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, pu200a=u200a10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (pu200a=u200a10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), pu200a=u200a0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), pu200a=u200a0.01), and earlier AR (−4.72% (−5.81, −3.63), pu200a=u200a10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966

Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of Nu200a=u200a3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0–20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (pu200a=u200a0.0030) and for the SNP in HHIP (pu200a=u200a0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.

Association of the TNF-α-308 (G→A) polymorphism with self-reported history of childhood asthma

Asthma is a complex disease involving genetic and environmental aetiology. The tumour necrosis factor-alpha (TNF- α) and angiotensin-converting enzyme (ACE) genes have been implicated in asthma pathogenesis. This study investigated the association of a G-308A variant of TNF- α and an insertion/deletion (I/D) variant of ACE with a self-reported history of childhood asthma, in two population groups. At Northwick Park Hospital, London, 1,811 pregnant women attending for antenatal care were recruited. Participants with a self-reported history of childhood asthma, determined by a researcher-administered questionnaire, and controls with no personal or family history of asthma, of UK/Irish (cases n=20; controls n=416) and South Asian (cases n=6; controls n=275) origin were used in this study. Participants were genotyped for the TNF-α-308 and ACE I/D variants by a PCR-RFLP and PCR approach. The TNF-α-308 allele 2 (−308A) was significantly associated with self-reported childhood asthma in the UK/Irish (Odds ratios (OR): 2.6; 95% confidence intervals (CI): 1.1–6.2; P=0.03) but not in the South Asian population. The ACE DD genotype was not associated with childhood asthma in either population group. Gametic phase disequilibrium between the TNF-α-308 and ACE I/D variants was significantly different from zero in UK/Irish cases (Δ=0.09; P=0.034). The TNF-α-308 allele 2 or a linked major histocompatibility complex (MHC) variant may be a genetic risk factor for childhood asthma in the UK/Irish sample.

Safety, tolerability, and pharmacokinetics of SPL7013 gel (VivaGel): a dose ranging, phase I study.

Objectives: To evaluate safety, tolerability and systemic pharmacokinetics of escalating doses of SPL7013 Gel in healthy women. Design: Randomized, double-blind, placebo-controlled dose-escalation trial. Methods: Thirty-seven healthy women were randomized to receive 3.5 g of 0.5% (N = 8), 1% (N = 8), or 3% (N = 9) SPL7013 Gel or placebo gel (N = 12), applied vaginally once daily for 7 consecutive days. Genital toxicity was determined by interview, physical examination, assessment of vaginal microflora and colposcopy. Systemic toxicity was determined by nongenital adverse events (AEs) and laboratory assessments. Plasma was collected for pharmacokinetic analysis. Results: Genital AEs considered potentially product-related were all mild and reported by 5 (20%) women receiving SPL7013 Gel and 2 (17%) women receiving placebo gel. The most common were abdominal pain or discomfort, with no reports of vaginal burning or malodour, or genital-tract pain. There were no clinically significant colposcopic findings, including of genital inflammation or epithelial disruption. Lower concentrations of normal lactobacillary flora occurred during SPL7013 Gel and placebo gel use, with a decrease in anaerobes in the SPL7013 Gel groups. There were no reported cases of bacterial vaginosis, and lactobacilli returned to predose levels in most women after treatment. All nongenital AEs were of mild or moderate severity, expect for a severe tension headache in a woman receiving placebo. There was no absorption of SPL7013 into the systemic circulation. Conclusions: SPL7013 Gel applied vaginally once daily for 7 days at concentrations of 0.5% to 3% was safe and well tolerated in healthy, sexually abstinent women, with no evidence of systemic toxicity or absorption.

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

A randomized controlled trial of the safety of candidate microbicide SPL7013 gel when applied to the penis.

Objectives:To determine the safety of the candidate vaginal microbicide SPL7013 gel (VivaGel) when applied to the penis. Methods:A randomized, double-blind, placebo-controlled study. Thirty-six healthy men (18 circumcised, 18 uncircumcised) were randomized in a 2:1 ratio and treated with 3% SPL7013 gel (n = 24) or placebo gel (n = 12), applied once daily for 7 days. Genital toxicity was determined by interview, diary, and examination. Results:There were 10 genital adverse events (AEs) in 6 men (25%) receiving SPL7013 gel and 5 genital AEs in 4 men (33%) receiving the placebo that were possibly or probably related to the study product (difference of −8%, 95% confidence interval: −40% to 23%, P = 0.70). The most common genital AEs were genital pruritus and application site erythema. All genital AEs were mild (grade 1), and all but 1 in the placebo group were transient. Analysis of vital signs, nongenital AEs, and laboratory results indicated no safety or tolerability issues with SPL7013 gel, irrespective of circumcision status. There was no detectable absorption of SPL7013 into the plasma. Conclusions:Three percent SPL7013 gel was safe and well tolerated, and comparable with placebo, when administered to the penis of both circumcised and uncircumcised men once daily for 7 days, with no evidence of systemic absorption or toxicity.

The safety of candidate vaginal microbicides since nonoxynol-9: a systematic review of published studies.

Objective:To gain a greater understanding of published safety data for candidate vaginal microbicides. Design:A systematic review of human safety trials of candidate vaginal microbicides – agents designed to protect women against HIV and other sexually transmitted infections. Methods:Trials were published in peer-reviewed journals, and publication cut-off was August week 4, 2008. Trials of nonoxynol-9 were excluded, as were trials without a control group, trials that enrolled only male participants or reported on the investigation of a product for the treatment of a genital infection. Results:Twenty-one trials of 11 products, involving 1465 women, satisfied review criteria. Most trials reported on genital epithelial findings and urogenital symptoms and a number reported a range of other local and systemic toxicity endpoints. Trials were generally of short duration (2 weeks or less) with small sample sizes. There were few findings of significant difference between women in active and control arms. Among the products assessed in more than one study, there were significantly more genital findings with intact epithelium in recipients of PRO2000 [relative risk (RR) 1.68, 95% confidence interval (CI) 1.08–2.60] and a lower incidence of bacterial vaginosis in dextrin sulphate recipients (RR 0.61, 95% CI 0.42–0.88). CIs were generally very wide, and most studies were unable to exclude differences of a substantial magnitude between treated and control women. Conclusion:Larger and longer safety studies are necessary to detect clinically important toxicities, including those that indicate a potential increase in HIV risk, and provide assurance that agents are ready for large-scale effectiveness trials.

Multiple measures of adiposity are associated with mean leukocyte telomere length in the Northern Finland birth cohort 1966

Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (Pu200a=u200a0.041). Adult BMI and WHR in both men (Pu200a=u200a0.025 and Pu200a=u200a0.049, respectively) and women (Pu200a=u200a0.029 and Pu200a=u200a0.008, respectively), and BAI in women (Pu200a=u200a0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (Pu200a=u200a0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.

The Evolving Design and Methods for Trials Evaluating the Safety of Candidate Vaginal Microbicides: A Systematic Review

Abstract Vaginal preexposure prophylaxis is a promising biomedical tool for HIV prevention. Although guidelines for the clinical assessment of microbicides are available, validated markers for product safety are lacking. To inform future microbicide and multipurpose vaginal product research, we reviewed the current and past safety methods used. We searched the Cochrane, EMBASE, and Ovid MEDLINE databases for clinical studies of vaginal products for the prevention of HIV that included safety evaluations. Ninety-seven clinical studies involving 21 products were identified: 63 lasted 14 days or less, 19 were longer in duration, and 15 were effectivess studies that included also safety as an outcome. Median sample size in the safety studies was 48 participants (range, 10–799). All studies reported on urogenital endpoint, 71% included colposcopy, and 67% assessed the vaginal microflora. Markers of vaginal epithelial inflammation, systemic absorption, and systemic toxicology assessments were evaluated in 29%, 26%, and 43% of studies, respectively. Excluding the effectiveness studies, these same assessments were done before 1998 in 33%, 7%, and 27% and after 2001 in 38%, 44%, and 60% of studies, respectively. Soluble inflammatory markers were introduced after 2001. Adverse event collection was reported in 73% of studies before 1998 and in 98% after 2001. In a previous review, we recommended that larger and longer safety studies were necessary to detect clinically important toxicities and to provide assurance that agents are ready for large-scale effectiveness trials. Here, we propose a stepwise clinical assessment that can be used for future guidance.

Microbicide safety and effectiveness: an overview of recent clinical trials.

Purpose of reviewThis review summarizes findings from recent vaginal microbicide safety and effectiveness trials and discusses the challenges associated with undertaking these trials. Recent findingsIn safety trials, there has been a focus on the development of biomarkers of genital irritation. Recent safety studies have expanded the range of genital toxicity measures to include biomarkers of mucosal immunity, detection of haemoglobin in cervicovaginal lavage specimens and microbicide-induced vaginal flora changes. Four effectiveness trials have been stopped prematurely, two due to a lower than estimated HIV incidence rate, one as a result of an interim analysis suggesting increased risk of HIV acquisition among participants receiving active product, and one as a safety precaution. One effectiveness trial was completed and showed no reduction in HIV acquisition among participants receiving active product, and one ongoing effectiveness trial was modified by discontinuing a trial arm. Methodological challenges faced by these trials have included accurately estimating HIV incidence and pregnancy rates in trial populations, and improving adherence to and measurement of study product use. SummaryValidated safety and surrogate efficacy endpoints and standard ways of reporting them are being pursued. Focus has shifted to antiretrovirals containing microbicides, some of which may be used independent of coitus. Research on how to improve and measure adherence should continue.