Effect of angiotensin converting enzyme gene I/D polymorphism in South Indian children with nephrotic syndrome

Nephrotic syndrome is one of the most common childhood kidney diseases. It is mostly found in the age group of 2 to 8 years. Around 10%–15% of nephrotic syndrome cases are non-responders of steroid treatment (SRNS). Angiotensin converting enzyme (ACE) (I/D) gene association studies are important for detecting kidney disease and herein we assessed the association of ACE (I/D) polymorphism with nephrotic syndrome in South Indian children. We recruited 260 nephrotic syndrome (162 boys and 98 girls) and 218 (140 boys and 78 girls) control subjects. ACE I/D polymorphism was analyzed by PCR using genotype allele specific primers. In ACE (I/D), we did not find significant association for the ungrouped data of nephrotic syndrome children and the control subjects. Kidney biopsies were done in 86 nephrotic syndrome cases (minimal change disease, n = 51; focal segmental glomerulosclerosis, n = 27; diffuse mesangial proliferation, n = 8). We segregated them into the minimal change disease / focal segmental glomerulosclerosis groups and observed that the ACE 'D' allele was identified with borderline significance in cases of focal segmental glomerulosclerosis and the 'Ⅰ' allele was assessed as having very weak association in cases of minimal change disease. 'Ⅱ' genotype was weakly associated with minimal change disease. Gender specific analysis revealed weak association of 'ID' genotype with female nephrotic syndrome in females. Dominant expression of DD genotype was observed in males with nephrotic syndrome. Our finding indicated that ACE (I/D) has moderate association with focal segmental glomerulosclerosis. However, due to the limited number of biopsy proven focal segmental glomerulosclerosis subjects enrolled, further studies are required to confirm these results.     

Association between the angiotensin I-converting enzyme gene insertion/deletion polymorphism and endurance running speed in Japanese runners

We investigated the association between the angiotensin I-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism and endurance running performance in Japanese elite runners, including several Olympic athletes. The frequency of the I/I genotype was not significantly higher and the frequency of the D/D genotype was not significantly lower in elite runners compared with non-athletes. However, the frequency of the I/D genotype tended to be lower in elite runners than in non-athletes. The best performance was significantly higher for runners with the D/D genotype than for those with the I/I genotype, and the average running speed was significantly higher for those with the combined D/D + I/D genotypes than for those with the I/I genotype. There were no I/I genotypes among the five fastest marathon runners. These results suggest that the D allele of the ACE gene I/D polymorphism is associated with a high level of human endurance.     

Does the ACE I/D polymorphism, alone or in combination with the ACTN3 R577X polymorphism, influence muscle power phenotypes in young, non-athletic adults?

We investigated the association of the angiotensin converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism, alone or in combination with the α-actinin-3 gene (ACTN3) R577X polymorphism, with jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N = 281 (214 male), mean (SD) age 21 (2) years]. We did not observe any effect of the ACE I/D polymorphism on study phenotypes. We repeated the analyses separately in men and women and the results did not materially change. Likewise, the mean estimates of the study phenotypes were similar in subjects with the genotype combinations ACE II + ID and ACTN3 XX or ACE DD and ACTN3 RR + RX. We found no association between the ACE DD and ACTN3 RR + RX genotype combination and performance (≥90th of the sex-specific percentile). In summary, though the ACE I/D polymorphism is a strong candidate to modulate some exercise-related phenotypes or athletic performance status, this polymorphism, alone or in combination with the ACTN3 R577X polymorphism, does not seem to exert a major influence in the muscle ‘explosive’ power of young healthy adults, as assessed during multi-joint exercise tests.     

Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3–7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM. Received: December 10, 2001 / Accepted: January 25, 2002     

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electro-cardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4–5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1–3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0–2.2) or the D/D genotype patients (OR 1.7; CI 1.1–2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138±19 mmHg) than in those with the genotype I/D (149±22 mmHg) or D/D (150±21 mmHg; P<0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.Abbreviations ACE Angiotensin-converting enzyme - CHD Coronary heart disease - NIDDM Non-insulin-dependent diabetes mellitus     

Relationship between ace genotype and short duration aerobic performance development

We have previously demonstrated that, ACE D allele may be related with a better performance in short duration aerobic endurance in a homogeneous cohort with similar training backgrounds. We aimed to study the variation in the short-duration aerobic performance development amongst ACE genotypes in response to identical training programs in homogeneous populations. The study group consisted of 186 male Caucasian non-elite Turkish army recruits. All subjects had undergone an identical training program with double training session per day and 6 days a week for 6 months. Performances for middle distance runs (2,400 m) were evaluated on an athletics track before and after the training period. ACE gene polymorphisms were studied by PCR analysis. The distribution of genotypes in the whole group was 16.7% II, n = 31; 46.2% ID, n = 86; 37.1% DD, n = 69. Subjects with ACE DD genotype had significantly higher enhancement than the ID (P < 0.01) and II (P < 0.05) genotype groups. Around 2,400 m performance enhancement ratios showed a linear trend as ACE DD > ACE ID > ACE II (P value for Pearson χ² = 0.461 and P value for linear by linear association = 0.001). ACE DD genotype seems to have an advantage in development in short-duration aerobic performance. This data in unison with the data that we have obtained from homogenous cohorts previously is considered as an existence of threshold for initiation of ACE I allele effectiveness in endurance performance. This threshold may be anywhere between 10 and 30 min with lasting maximal exercises.     

ACE polymorphism and response to electroconvulsive therapy in major depression

The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery–Åsberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD.     

Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits

Background: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated.

Method: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits.

Results: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant.

Conclusions: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.

     

Association of essential hypertension in elderly Japanese with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene

Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population. Received: April 18, 2000 / Accepted: July 25, 2000     

Maternal vitamin D status and infant anthropometry in a US multi-centre cohort study

Background: Maternal vitamin D status in pregnancy is linked to foetal growth and may impact infant growth.

Aim: This study examined the association between maternal vitamin D status and infant anthropometry.

Subjects and methods: Data came from n?=?2473 mother–child pairs from the 12-site US Collaborative Perinatal Project (1959–1965). Maternal serum 25-hydroxyvitamin D (25(OH)D) was measured at?≤?26 weeks gestation. Multivariate-adjusted linear mixed models were used to relate maternal vitamin D status to infant z-scores for length (LAZ), head circumference (HCZ), weight (WAZ) and BMI (BMIZ), measured at birth and 4, 8 and 12 months.

Results: Infants with maternal 25(OH)D ≥30?nmol/L vs <30?nmol/L had LAZ and HCZ measures 0.13 (95% CI?=?0.03–0.23) and 0.20 (95% CI?=?0.11–0.28) units higher, respectively, across the first year of life. Similar differences in WAZ and BMIZ at birth were resolved by 12 months of age due to interactions indicating steeper age slopes in infants with maternal 25(OH)D <30?nmol/L.

Conclusion: Low maternal vitamin D status was associated with deficits at birth in infant weight and BMI that were recouped across the first year of life; associations with reduced measures of linear and skeletal growth were sustained from birth to 12 months.     

Serum insulin‐like growth factor‐I concentrations in late middle age: no association with birthweight in three UK cohorts

Background: Small body size at birth and during infancy is associated with an increased risk of adult osteoporosis and cardiovascular disease. Fetal programming of the growth hormone–insulin‐like growth factor (GH‐IGF) axis may provide a mechanism for these epidemiological findings. Aims: To determine whether measurements of GH and IGF‐I in late middle age were related to size at birth and in infancy. Methods: Overnight urinary GH excretion and fasting serum IGF‐I were measured in 309 men and 193 women from Hertfordshire (born 1920–1930) for whom birthweight and weight at 1 year were recorded. Serum IGF‐I was measured in men and women from Preston (n = 254, born 1935–1943) and Sheffield (n = 215, born 1939–1940) whose birthweight and other birth measurements were recorded. Results: Urinary GH and serum IGF‐I were not related to birthweight, other measurements at birth, or weight at 1 year. Conclusion: In contrast to previous studies in children or young adults, these data do not support the hypothesis that IGF‐I concentrations are programmed by intra‐uterine events, as assessed by birthweight, in late middle age.     

The ACE gene and Alzheimer's disease susceptibility

A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE ε4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33, 95% CI=1.14-1.53, p=0.0002).


Keywords: Alzheimer's disease; ACE gene; I allele     

A study of gene--environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach

Introduction: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene–environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness.

Methods: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products.

Results: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r² = 0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers.

Discussion: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis.

     

Comparative analysis of associations between polymorphic variants of the F2, F5, GP1BA, and ACE genes and the risk of developing stroke in Russian and Ukrainian populations

We performed comparative analysis of associations between the F2 gene G20210A polymorphism, the F5 gene G1691A polymorphism, the GP1BA gene -5T/C polymorphism, the ACE gene insertion/deletion (I/D) polymorphism and the risk of developing stroke in two samples drawn from ethnic Russian and ethnic Ukrainian populations. It has been shown, that among the Russian population, the risk of developing ischemic stroke is increased in DD genotype individuals (odds ratio (OR) = 1.4, 95% confidence interval (CI) [1.05; 1.78], p = 0.02), whereas the I/I and I/D genotypes are associated with a decreased risk of developing stroke (OR = 0.7, 95% CI [0.56; 0.95], p = 0.02). In the ethnic Ukrainian sample, differences in the distribution of genotypes and allele frequencies between stroke patients and the control group of subjects with regard to this polymorphic locus are statistically unreliable and the ACE gene I/D polymorphism is unassociated with the risk of developing stroke in the Ukrainian population (OR = 0.8, 95% DI[0.48; 1.32], p = 0.45). The F2 gene G20210A polymorphism, the F5 gene G1691A polymorphism, and the GP1BA gene -5T/C polymorphism are unassociated with stroke risk factor across both ethnic samples.     

Polymorphism of genes of the renin-angiotensin system ACE, ATIR, and AT2R in patients with pulmonary tuberculosis

The investigation was aimed at testing the hypothesis on the possible role of some genes of the renin-angiotensin system in the formation of innate immunity to tuberculosis. It is known that insertion-deletion (I/D) polymorphism of the gene encoding the angiotensin-converting enzyme (ACE) influences the concentration of angiotensin II in the human organism and, indirectly, many stages of metabolism. On one hand, homozygotes of deletion in the ACE gene (DD genotype) are characterized with obesity, arterial hypertension, hypocholesterolemia, and some other pathological conditions. On the other hand, it was demonstrated that hypercholesterolemia is common pathology for patients with pulmonary tuberculosis (C. Perez-Guzman et al., 2005). The investigation of insertion-deletion polymorphism of the ACE gene (genotypes DD, ID and II), single nucleotide polymorphism at position 1166 of the AT1R gene (1166 A/C), and analogous transversion at position 3123 of the AT2R gene (3123 A/C) was carried out. A group of 200 patients with tuberculosis 202 patients with essential hypertension and 208 healthy individuals were analyzed. A group of patients with essential hypertension was used as a contrast sample. According to hypothesis, a statistically significant excess number was found of carriers of genotype DD (ACE) in patients with hypertension as compared to the group of patients with tuberculosis (χ² = 9.64; ρ = 0.0019; OR = 2.0; CI 1.2, 3.3). The tendency toward an increase in the amount of DD genotypes was observed in comparisons of patients with tuberculosis and healthy patients with hypertension, although these differences did not reach significant values in the given study. A comparison of genotypes and allelotypes in group of patients with tuberculosis and both control groups (healthy and patients with hypertension) was performed. A significant difference was observed in the group of male patients with tuberculosis, though not female, when comparing with control groups. It had been demonstrated that the most important contribution is made by the ACE and AT2R genes. Genotype ID + 3123C (genes ACE and AT2R) was found significantly more often in male patients with tuberculosis than in the control group of healthy individuals (χ² = 9.70; ρ = 0.002; OR = 2.3; CI 1.2s-4.3). The obtained results were discussed.     

The ACE I allele is associated with increased risk for ruptured intracranial aneurysms

Genetic and environmental factors play roles in the aetiology of ruptured intracranial aneurysms. Hypertension has been reported as a risk factor for intracranial aneurysm haemorrhage. We have tested if genotypes at the angiotensin converting enzyme (ACE) gene locus are associated with ruptured intracranial aneurysms. The insertion/deletion polymorphism in the ACE gene was genotyped in 258 subjects presenting in East Anglia with ruptured intracranial aneurysms (confirmed at surgery or angiographically) and 299 controls from the same region. ACE allele frequencies were significantly different in the cases and the controls (alleles χ²₁=4.67, p=0.03). The I allele was associated with aneurysm risk (odds ratio for I allele v D allele = 1.3 (95% CI=1.02-1-65); odds ratio for II v DD genotype = 1.67 (95% CI=1.04-2.66)). The I allele at the ACE locus is over-represented in subjects with ruptured intracranial aneurysms. These data are supported by non-significant trends in the same direction in two previous smaller studies. Thus, this allele may be associated with risk for ruptured intracranial aneurysms.


Keywords: ACE I allele; ruptured intracranial aneurysms     

Exposure to dogs is associated with a decreased tumour necrosis factor‐α‐producing capacity in early life

Background It appears that contacts with furred animals early in life and already during gestation contribute to the immunological development in humans, but the mechanisms and relevant exposures are not clear. Objective To investigate whether exposure to animals during pregnancy and the first year of life is associated with early immune development, determined as stimulated cytokine responses of children at birth and at age 1 year. Methods Cord blood (n=228) and peripheral venous blood (n=200) samples 1 year after birth were collected and stimulated with Gram‐positive superantigen Staphylococcal enterotoxin B, Gram‐negative bacterial lipopolysaccharide (LPS) and the combination of mitogenic phorbol 12‐myristate 13‐acetate and calcium ionophore ionomycin (P/I) for 24 and 48 h. TNF‐α, IFN‐γ, IL‐5, IL‐8 and IL‐10 responses were measured by ELISA. For each cytokine, the time‐point with the highest response was chosen for further analyses. Animal contacts were surveyed by self‐administered questionnaires. Results Dog ownership was associated with decreased TNF‐α‐producing capacity at birth (P/I: median 841 vs. 881 pg/10⁶ WBC, P=0.05) and 1 year after birth (P/I: 1290 vs. 1530, P=0.01; LPS: 425 vs. 508, P=0.02). Associations remained significant after adjustment for potential confounders. Cat ownership was not associated with cytokine production. Conclusion Having a dog in the household in infancy and already during pregnancy may be associated with reduced innate immune responses in early childhood. The observed attenuation of cytokine production may help in preventing exaggerated immune responses against harmless antigens later in life. Thus, intensive exposure to dogs in early life may be beneficial during normal immune maturation. Cite this as: M. H. J. Lappalainen, K. Huttunen, M. Roponen, S. Remes, M.‐R. Hirvonen and J. Pekkanen, Clinical & Experimental Allergy, 2010 (40) 1498–1506.     

The D-allele of ACE insertion/deletion polymorphism is associated with regional white matter volume changes and cognitive impairment in remitted geriatric depression

Prior studies suggested that angiotensin-converting enzyme (ACE) affected vascular homeostasis and degradation of amyloid β (Aβ). It is associated with the therapeutic outcome in major depression. The aim of this study was to investigate the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and structural abnormalities in remitted geriatric depression (RGD), and test the relationship of neuropsychological performances and regional white matter volumes. 31 RGD patients were recruited and neuropsychological tests, magnetic resonance imaging (MRI) and genotype of ACE I/D were examined for each subject. The differences in regional white matter volume were tested between I homozygotes and D-allele carriers (I/D or D/D genotype) by optimized VBM. D-allele carriers exhibited significantly smaller white matter volumes of right superior frontal gyrus (SFG) and right anterior cingulated gyrus (ACG), but had larger volumes of left middle temporal gyrus (MTG) and right middle occipital gyrus (MOG) than I homozygotes (P < 0.001). Meanwhile, there was a significant positive correlation between white matter volume enlargement of left MTG and Symbol Digit Modalities Test (SDMT) (r = 0.456, P = 0.043), and the reduction of right ACG was negatively related to Clock Drawing Test (CDT) performance (r = −0.445, P = 0.050) in D-allele carriers. The finding suggests that ACE can modulates the pathology of RGD, the left MTG and right ACG might be involved in the pathophysiology of cognitive dysfunction in RGD patients.     

Candidate Molecular Pathway Genes Related to Appetite Regulatory Neural Network,Adipocyte Homeostasis and Obesity: Results from the CARDIA Study

Appetite regulatory neural network and adipocyte homeostasis molecular pathways are critical to long‐term weight maintenance. Associations between obesity‐related phenotypes and four genes in these pathways – leptin (LEP), leptin receptor (LEPR), neuropeptide Y2 receptor (NPY2R) and peptide YY (PYY) were examined in CARDIA Study participants (aged 18–30 at recruitment in 1985–6). Weight, BMI and waist circumference were measured at baseline and at years 2, 5, 7, 10, 15, and 20. Genotyping was conducted using tag SNPs characterising common genetic variations in these genes. Generalized estimating equation (GEE) models estimated associations between SNPs and repeated anthropometric measurements, controlling for sex and age. False discovery rate was used to adjust for multiple testing. In African‐Americans, SNPs across the LEP gene demonstrated significant overall associations with all obesity‐related phenotypes. The associations between LEP rs17151919 with weight tended to strengthen with time – the difference in weight associated with each additional minor allele increased from 2.6 kg at baseline to 4.8 kg at year 20 (SNP*time interaction p = 0.0193). NPY2R gene SNPs were associated with waist circumference among African‐American men (p = 0.0462). In Caucasians, LEP SNPs also tended to be associated with weight (p = 0.0471), and PYY rs11684664 was associated with obesity‐related phenotypes in women only (p = 0.010–0.026). Several LEP, and NPY2R and PYY SNPs were associated with obesity‐related phenotypes in young adults, particularly among African‐Americans.     

Early rapid growth,early birth: Accelerated fetal growth and spontaneous late preterm birth

The past two decades in the United States have seen a 24% rise in spontaneous late preterm delivery (34–36 weeks) of unknown etiology. This study tested the hypothesis that fetal growth was identical prior to spontaneous preterm (n = 221, median gestational age at birth 35.6 weeks) and term (n = 3706) birth among pregnancies followed longitudinally in Santiago, Chile. The hypothesis was not supported: Preterm‐delivered fetuses were significantly larger than their term‐delivered peers by mid‐second trimester in estimated fetal weight, head, limb, and abdominal dimensions, and they followed different growth trajectories. Piecewise regression assessed time‐specific differences in growth rates at 4‐week intervals from 16 weeks. Estimated fetal weight and abdominal circumference growth rates slowed at 20 weeks among the preterm‐delivered, only to match and/or exceed their term‐delivered peers at 24–28 weeks. After an abrupt growth rate decline at 28 weeks, fetuses delivered preterm did so at greater population‐specific sex and age‐adjusted birth weight percentiles than their peers from uncomplicated pregnancies (P < 0.01). Growth rates predicted birth timing: one standard score of estimated fetal weight increased the odds ratio for late preterm birth from 2.8 prior to 23 weeks, to 3.6 (95% confidence interval, 1.82–7.11, P < 0.05) between 23 and 27 weeks. After 27 weeks, increasing size was protective (OR: 0.56, 95% confidence interval, 0.38–0.82, P = 0.003). These data document, for the first time, a distinctive fetal growth pattern across gestation preceding spontaneous late preterm birth, identify the importance of mid‐gestation for alterations in fetal growth, and add perspective on human fetal biological variability. Am. J. Hum. Biol., 2009. © 2008 Wiley‐Liss, Inc.