Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Continued increases in blood pressure over two decades in Samoa (1991–2013); around one-third of the increase explained by rising obesity levels

Abstract Background To analyse trends over the period 1991–2013 in systolic blood pressure (SBP), diastolic blood pressure (DBP) and the prevalence of hypertension in adults aged 25–64 years in Samoa; and to assess the contribution of rising obesity levels to period trends. Methods Unit record data from seven population-based surveys (n = 10,881) conducted between 1991 and 2013 were included for analysis. Surveys were adjusted to the nearest previous census to improve national representativeness. Hypertension was defined as SBP ≥140 mmHg and/or DBP ≥90 mmHg and/or on medication for hypertension. Obesity was measured by body mass index (BMI). Poisson, linear and meta-regression were used to assess period trends. Results Over 1991–2013 mean SBP and DBP (mmHg), and the prevalence of hypertension (%) increased in both sexes. Increases in hypertension were: from 18.3 to 33.9% (p < 0.001) in men (mean BP from 122/74 to 132/78); and from 14.3 to 26.4% (p < 0.001) in women (mean BP from 118/73 to 126/78). The estimate of the age-adjusted mean SBP and DBP over 1991–2013, and the relative risk for hypertension in 2013 compared to 1991, were attenuated after adjusting for BMI: by 22% (men) and 32% (women) for mean SBP; 37% (men) and 32% (women) for mean DBP; and 19% in both sexes for hypertension. Conclusions Significant increases have occurred in SBP/DBP and hypertension prevalence in both sexes in Samoa during 1991–2013, which would contribute significantly to premature mortality from cardiovascular disease. Obesity accounts for around one-third of the rising trend in blood pressure in the Samoan population. Strengthening of population control of hypertension through reduction in obesity and salt intake, and case detection and treatment through primary care, is required to reduce premature mortality from cardiovascular disease in Samoa

Tobacco smoking trends in Samoa over four decades: can continued globalization rectify that which it has wrought?

Abstract Background The island country of Samoa (population 188,000 in 2011) forms part of Polynesia in the South Pacific. Over the past several decades Samoa has experienced exceptional modernization and globalization of many sectors of society, with noncommunicable diseases (NCD) now the leading cause of morbidity and mortality. The evolution of risk factor prevalence underpinning the increase in NCDs, however, has not been well described, including tobacco smoking which is related to cardiovascular disease, lung cancer, and chronic obstructive pulmonary disease. Methods The present study examines tobacco smoking in relation to different forms and effects of globalization in Samoa using 7 population-based surveys (n = 9223) over 1978–2013. Results The prevalence of daily tobacco smoking steadily decreased over 1978–2013 from 76% to 36% in men, and from 27% to 15% in women (p < 0.0001 both sexes). During 1991–2013, current tobacco smoking also steadily decreased from 64% to 40% in men (p < 0.0001), and from 21% to 17% in women (p < 0.05). Declines were similar in younger (25–44 years) and older (45–64 years) men and women. Colonial globalization facilitated the introduction and prolific spread of tobacco trade and consumption in the Pacific Islands from the sixteenth century, with many populations inexorably pulled into trade relations and links to the global economy. It has also been a different globalization which may have led to the decline in smoking prevalence in Samoa in recent decades, through global dissemination since the 1950s of information on the harmful effects of tobacco smoking derived from research studies in the USA and Europe. Conclusions Over the past 35 years tobacco smoking has steadily declined among Samoan adults; the only NCD risk factor to demonstrate marked declines during this period. By 2013 tobacco smoking in women had decreased to levels similar to Australia and New Zealand (ANZ), however in men smoking prevalence remained more than three times higher than ANZ. The impact on smoking prevalence of the variety of tobacco control interventions that have been implemented so far in Samoa need to be evaluated in order to determine the most effective initiatives that should be prioritized and strengthened

Effect of maternal nutrient intake during 31–37 weeks gestation on offspring body composition in Samoa

Background Pregnancy dietary intake may be associated with newborn body composition, a predictor of future obesity. In Samoa, an energy-dense diet contributes to an alarming prevalence of adult obesity. Identifying associations between pregnancy nutrition and infant body composition in this setting may guide strategies to mitigate intergenerational transmission of obesity risk. Aim To examine dietary macro- and micronutrient intake of Samoan women during the third trimester of pregnancy and associations with infant body composition. Subjects and methods At 34–41 weeks of gestation, we measured dietary intake from the prior month using a Food Frequency Questionnaire (FFQ). Dual-energy X-ray absorptiometry (DXA) measured infant body composition at 1–14 days. We used multivariable linear regression models accounting for confounders to identify independent effects of nutrient intake on infant body composition. Results After adjusting for maternal body mass index, age, gravidity, infant age, and sex, a respective 0.2 g increase and 0.2 g decrease in infant bone mass was associated with fibre and saturated fat intake. Increased protein intake was associated with 0.02 g decrease in bone mass. Conclusions While maternal dietary intake was not associated with infant adiposity or lean mass, we observed an effect on bone mass whose role in regulating metabolic health is overlooked

Feasibility of using infrared thermal imaging to examine brown adipose tissue in infants aged 18 to 25 months

Background Recent studies in adults indicate that cold-induced temperature change of supraclavicular skin corresponds with brown adipose tissue (BAT) thermogenesis. Aim This study examined the feasibility of using thermography to assess temperature changes in infants aged 18–25 months after mild cooling. Further, this study sought to evaluate whether cold exposure induces a thermal response suggestive of BAT activity underlying the supraclavicular region. Subjects and Methods Changes in maximum skin temperature at the supraclavicular and interscapular regions were determined using thermal imaging following a mild 5-minute cooling condition (by removal of clothes in a climate-controlled room) in 67 Samoan infants. Temperature changes of the forehead and hand, known BAT-free regions, served as indicators of cooling efficacy. Results Infants with increased hand and forehead temperatures after cold exposure were excluded from analysis, reducing the effective sample size to 19 infants. On average, forehead (p < 0.001), hand (p < 0.001) and back (0.029) temperatures dropped significantly while supraclavicular temperatures remained constant. Participants with greater decreases in forehead temperature tended to exhibit greater supraclavicular thermogenesis (p = 0.084), suggesting potential BAT activity in this region. Conclusions While further work is necessary to develop a reliable cooling condition, this study provides proof-of-concept for non-invasive assessment of BAT activity in infants

Assessing the impact of high blood pressure referrals on hypertension awareness and management, BMI, and blood pressure values in adult Samoans 2010–2019

The Samoan population has experienced rapid increases in the prevalence of non-communicable diseases (NCDs) and NCD risk factors over the last 30 years. However, understanding how increased awareness and treatment of these conditions in reducing disease burden remains understudied. Using data from a longitudinal study (2010–2019) of cardiometabolic health among Samoan adults, we assess the impact of a referral for elevated blood pressure (BP) on changes in BP, physician’s diagnoses of hypertension and medication use, body mass index (BMI), and other risk factors for elevated BP. Analyses compared adult Samoans (n = 328) who in 2010 either (1) received a referral for elevated BP (BP ≥ 140/90 mmHg) or (2) had measured BP indicative of pre-hypertension (BP ≥ 120/80 mmHg) but were not referred. Data were analysed using linear and logistic regression, paired T- and McNemar’s tests, and Wilcoxon Rank Sum assessments. Referrals in 2010 significantly increased the odds of reporting a physician’s diagnosis of hypertension (OR 2.16; 1.18, 3.95) and hypertension medication use (OR 3.52; 1.86, 6.73) in 2018; however, referrals, medication use, and diagnoses were not associated with BP values or reduced odds of having elevated BP. Despite the referral having positive effects on hypertension-related health care, our results demonstrate that other factors are influencing effective BP/hypertension control. We advocate for greater engagement of health researchers with local health sector actors to improve the probability that researcher-provided health referrals will result in long-term health improvements

Prediction of fat mass from anthropometry at ages 7 to 9 years in Samoans: a cross-sectional study in the Ola Tuputupua’e cohort

Background/Objective: With increasing obesity prevalence in children globally, accurate and practical methods for quantifying body fat are critical for effective monitoring and prevention, particularly in high risk settings. No population is at higher risk of obesity than Pacific Islanders, including children living in the independent nation of Samoa. We developed and validated sex-specific prediction models for fat mass in Samoan children. Subjects/Methods: Dual x-ray absorptiometry (DXA) assessments of fat mass and weight, height, circumferences, and skinfolds were obtained from 356 children aged 7-9 years old in the Ola Tuputupua’e “Growing Up” study. Sex-specific models were developed from a randomly selected model development sample (n=118 females, n=120 males) using generalized linear regressions. In a validation sample (n=59 females; n=59 males), Lin’s concordance and Bland-Altman limits-of-agreement (LoA) of DXA-derived and predicted fat mass from this study and other published models were examined to assess precision and accuracy. Results:  Models to predict fat mass in kilograms were: e^[(-0.0034355*Age8-0.0059041*Age9+1.660441*l n⁡(Weight(kg))-0.0087281 *Height(cm)+0.1393258 *ln⁡[Suprailiac(mm)]-2.661793)]  for females and e^[-0.0409724 *Age8-0.0549923*Age9+336.8575*[Weight(kg)]^(-2)-22.34261 *l n⁡(Weight(kg)) [Weight(kg)]^(-1)+0.0108696*Abdomen(cm)+ 6.811015 *〖Subscapular (mm)〗^(-2)-8.642559 *l n⁡(Subscapular(mm)) 〖Subscapular(mm)〗^(-2)-1.663095 *Tricep(mm)^(-1)  +3.849035]  for males, where Age8=Age9=0 for children at age 7 years, Age8 =1 and Age9=0 at 8 years, Age8 =0  and Age9 = 1 at 9 years. Models showed high predictive ability, with substantial concordance (ρ_C>0.96), and agreement between DXA-derived and model-predicted fat mass (LoA female= -0.235, 95% CI:-2.924-2.453; male= -0.202, 95% CI:-1.977-1.572). Only one of four existing models, developed in a non-Samoan sample, accurately predicted fat mass among Samoan children. Conclusions: We developed models that predicted fat mass in Samoans aged 7-9 years old with greater precision and accuracy than the majority of existing models that were tested. Monitoring adiposity in children with these models may inform future obesity prevention and interventions.</p