Nanette R. Lee

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Size at birth, weight gain in infancy and childhood, and adult blood pressure in 5 low- and middle-income-country cohorts: when does weight gain matter?

Background: Promoting catch-up growth in malnourished children has health benefits, but recent evidence suggests that accelerated child weight gain increases adult chronic disease risk. Objective: We aimed to determine how birth weight (BW) and weight gain to midchildhood relate to blood pressure (BP) in young adults. Design: We pooled data from birth cohorts in Brazil, Guatemala, India, the Philippines, and South Africa. We used conditional weight (CW), a residual of current weight regressed on prior weights, to represent deviations from expected weight gain from 0 to 12, 12 to 24, 24 to 48 mo, and 48 mo to adulthood. Adult BP and risk of prehypertension or hypertension (P/HTN) were modeled before and after adjustment for adult body mass index (BMI) and height. Interactions of CWs with small size-for-gestational age (SGA) at birth were tested. Results: Higher CWs were associated with increased BP and odds of P/HTN, with coefficients proportional to the contribution of each CW to adult BMI. Adjusted for adult height and BMI, no child CW was associated with adult BP, but 1 SD of BW was related to a 0.5-mm Hg lower systolic BP and a 9% lower odds of P/HTN. BW and CW associations with systolic BP and P/HTN were not different between adults born SGA and those with normal BW, but higher CW at 48 mo was associated with higher diastolic BP in those born SGA. Conclusions: Greater weight gain at any age relates to elevated adult BP, but faster weight gains in infancy and young childhood do not pose a higher risk than do gains at other ages.

Size at Birth, Weight Gain in Infancy and Childhood, and Adult Diabetes Risk in Five Low- or Middle-Income Country Birth Cohorts

OBJECTIVE We examined associations of birth weight and weight gain in infancy and early childhood with type 2 diabetes (DM) risk in five cohorts from low- and middle-income countries. RESEARCH DESIGN AND METHODS Participants were 6,511 young adults from Brazil, Guatemala, India, the Philippines, and South Africa. Exposures were weight at birth, at 24 and 48 months, and adult weight, and conditional weight gain (CWG, deviation from expected weight gain) between these ages. Outcomes were adult fasting glucose, impaired fasting glucose or DM (IFG/DM), and insulin resistance homeostasis model assessment (IR-HOMA, three cohorts). RESULTS Birth weight was inversely associated with adult glucose and risk of IFG/DM (odds ratio 0.91[95% CI 0.84–0.99] per SD). Weight at 24 and 48 months and CWG 0–24 and 24–48 months were unrelated to glucose and IFG/DM; however, CWG 48 months–adulthood was positively related to IFG/DM (1.32 [1.22–1.43] per SD). After adjusting for adult waist circumference, birth weight, weight at 24 and 48 months and CWG 0–24 months were inversely associated with glucose and IFG/DM. Birth weight was unrelated to IR-HOMA, whereas greater CWG at 0–24 and 24–48 months and 48 months–adulthood predicted higher IR-HOMA (all P < 0.001). After adjusting for adult waist circumference, birth weight was inversely related to IR-HOMA. CONCLUSIONS Lower birth weight and accelerated weight gain after 48 months are risk factors for adult glucose intolerance. Accelerated weight gain between 0 and 24 months did not predict glucose intolerance but did predict higher insulin resistance.

Rapid weight gain after birth predicts life history and reproductive strategy in Filipino males

Ecological cues during prenatal and postnatal development may allow organisms to adjust reproductive strategy. The hypothalamic-pituitary-gonadal (HPG) axis is a prime candidate for adaptive plasticity as a result of its critical period of birth to 6 mo (B6M) in humans and the role of testosterone in the development and maintenance of costly sexually dimorphic somatic and behavioral traits. We hypothesized that weight velocity specific to B6M would predict male life history characteristics, including maturational timing, reproductive hormones, adult size, strength, and sexual activity. Data come from 770 Filipino men (age 20.5–22.5 y) followed since birth, with predictor variables including birth weight and weight velocities calculated at 6-mo intervals during the first 2 y of life. As expected, infants who were breastfed experienced less diarrhea, lived in wealthier households with better hygiene, and grew faster from B6M. Males with rapid B6M growth reached puberty earlier and, as young adults, had higher testosterone levels, were taller, more muscular, and had higher grip strength. They also had sex earlier and were more likely to report having had sex in the past month, resulting in more lifetime sex partners. Relationships between B6M weight gain and physical outcomes were generally not present or weaker in female subjects. We conclude that rapid weight gain specific to the brief postnatal hypothalamic-pituitary-gonadal critical period predicts early maturation and sexual activity, elevated hormone production, and more costly adult somatic characteristics among the male subjects in this sample. These findings provide evidence for early life developmental plasticity in male life history and reproductive strategy in humans.

Maternal height and child growth patterns

Objective To examine associations between maternal height and child growth during 4 developmental periods: intrauterine, birth to age 2 years, age 2 years to mid-childhood (MC), and MC to adulthood. Study design Pooled analysis of maternal height and offspring growth using 7630 mother–child pairs from 5 birth cohorts (Brazil, Guatemala, India, the Philippines, and South Africa). We used conditional height measures that control for collinearity in height across periods. We estimated associations between maternal height and offspring growth using multivariate regression models adjusted for household income, child sex, birth order, and study site. Results Maternal height was associated with birth weight and with both height and conditional height at each age examined. The strongest associations with conditional heights were for adulthood and 2 years of age. A 1-cm increase in maternal height predicted a 0.024 (95% CI: 0.021-0.028) SD increase in offspring birth weight, a 0.037 (95% CI: 0.033-0.040) SD increase in conditional height at 2 years, a 0.025 (95% CI: 0.021-0.029 SD increase in conditional height in MC, and a 0.044 (95% CI: 0.040-0.048) SD increase in conditional height in adulthood. Short mothers (<150.1 cm) were more likely to have a child who was stunted at 2 years (prevalence ratio = 3.20 (95% CI: 2.80-3.60) and as an adult (prevalence ratio = 4.74, (95% CI: 4.13-5.44). There was no evidence of heterogeneity by site or sex. Conclusion Maternal height influences offspring linear growth over the growing period. These influences likely include genetic and non-genetic factors, including nutrition-related intergenerational influences on growth that prevent the attainment of genetic height potential in low- and middle-income countries.

Birth weight, postnatal weight gain, and adult body composition in five low and middle income countries.

To evaluate the associations between birth weight (BW), infancy, and childhood weight gain and adult body composition.

Genome‐Wide Association Study of Anthropometric Traits and Evidence of Interactions With Age and Study Year in Filipino Women

Increased values of multiple adiposity‐related anthropometric traits are important risk factors for many common complex diseases. We performed a genome‐wide association (GWA) study for four quantitative traits related to body size and adiposity (BMI, weight, waist circumference, and height) in a cohort of 1,792 adult Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This is the first GWA study of anthropometric traits in Filipinos, a population experiencing a rapid transition into a more obesogenic environment. In addition to identifying suggestive evidence of additional single‐nucleotide polymorphism (SNP) association signals (P < 10−5), we replicated (P < 0.05, same direction of additive effect) associations previously reported in European populations of both BMI and weight with MC4R and FTO, of BMI with BDNF, and of height with EFEMP1, ZBTB38, and NPPC, but none with waist circumference. We also replicated loci reported in Japanese or Korean populations as associated with BMI (OTOL1) and height (HIST1H1PS2, C14orf145, GPC5). A difference in local linkage disequilibrium (LD) between European and Asian populations suggests a narrowed association region for BDNF, while still including a proposed functional nonsynonymous amino acid substitution variant (rs6265, Val66Met). Finally, we observed significant evidence (P < 0.0042) for age‐by‐genotype interactions influencing BMI for rs17782313 (MC4R) and rs9939609 (FTO), and for a study year‐by‐genotype interaction for rs4923461 (BDNF). Our results show that several genetic risk factors are associated with anthropometric traits in Filipinos and provide further insight into the effects of BDNF, FTO, and MC4R on BMI.

Cohort Profile: The Consortium of Health-Orientated Research in Transitioning Societies

Human Sciences Research Council and the Birth to Twenty Research Programme, University of the Witwatersrand, South Africa, Universidade Federal de Pelotas, Pelotas, Brazil, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, S.L. Jain Hospital, New Delhi, India, MRC Lifecourse Epidemiology Unit, University of Southampton, UK, Office of Population Studies, University of San Carlos, Cebu City, Philippines, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA, Birth to Twenty Research Programme and the Department of Paediatrics, University of the Witwatersrand, South Africa, Sitaram Bhartia Institute of Science and Research, New Delhi, India and Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA

Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10–8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10–3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10–15), rs2681492 at ATP2B1 (P=3.4×10–7), rs11191593 at NT5C2 (1.1×10–6), rs3824755 at CYP17A1 (P=1.2×10–6), and rs13149993 at FGF5 (P=2.4×10–4). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10–5) and rs11191593 at NT5C2 (P=1.1×10–3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10–3) and rs2681492 at ATP2B1 (P=9.0×10–3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci

Human height is associated with risk of multiple diseases and is profoundly determined by an individuals genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.