Mental health and neurocognitive disorder-related hospitalization rates in immigrants and Canadian-born population: a linkage study.

OBJECTIVES: Mental health and neurocognitive conditions are important causes of hospitalization among immigrants, though patterns may vary by immigrant category, world region of origin, and time since arrival in Canada. This study uses linked administrative data to explore differences in mental health hospitalization rates between immigrants and individuals born in Canada. METHODS: Hospital records from the Discharge Abstract Database and the Ontario Mental Health Reporting System for 2011 to 2017 were linked to the 2016 Longitudinal Immigrant Database and to Statistics Canada's 2011 Canadian Census Health and Environment Cohort. Age-standardized hospitalization rates for mental health-related conditions (ASHR-MHs) were derived for immigrants and the Canadian-born population. ASHR-MHs overall and for leading mental health conditions were compared between immigrants and the Canadian-born population, stratified by sex and selected immigration characteristics. Quebec hospitalization data were not available. RESULTS: Overall, immigrants had lower ASHR-MHs compared to the Canadian-born population. Mood disorders were leading causes of mental health hospitalization for both cohorts. Psychotic, substance-related, and neurocognitive disorders were also leading causes of mental health hospitalization, although there was variation in their relative importance between subgroups. Among immigrants, ASHR-MHs were higher among refugees and lower among economic immigrants, those from East Asia, and those who arrived in Canada most recently. CONCLUSION: Differences in hospitalization rates among immigrants from various immigration streams and world regions, particularly for specific types of mental health conditions, highlight the importance of future research that incorporates both inpatient and outpatient mental health services to further understand these relationships.

RéSUMé: OBJECTIFS: Les problèmes de santé mentale et les troubles neurocognitifs sont des causes importantes d'hospitalisation chez les immigrants, bien que les tendances puissent varier selon la catégorie d'immigrants, la région d'origine mondiale et le temps écoulé depuis l'arrivée au Canada. Cette étude utilise des données administratives couplées afin d'explorer les différences dans les taux d'hospitalisation en santé mentale entre les immigrants et les personnes nées au Canada. MéTHODES: Les dossiers hospitaliers de la Base de données sur les congés des patients et du Système d'information ontarien sur la santé mentale de 2011 à 2017 ont été couplés à la Base de données longitudinales sur l'immigration de 2016 et aux cohortes santé et environnement du Recensement canadien de 2011 de Statistique Canada. Les taux d'hospitalisation normalisés selon l'âge pour les problèmes de santé mentale (THNA-SM) ont été comparés entre les immigrants et la population née au Canada, stratifiés selon le sexe et certaines caractéristiques d'immigration. Les données sur les hospitalisations au Québec n'étaient pas disponibles. RéSULTATS: Dans l'ensemble, les immigrants avaient des THNA-SM plus faibles que la population née au Canada. Les troubles de l'humeur étaient les principales causes d'hospitalisation en santé mentale pour les deux cohortes. Les troubles psychotiques, liés aux substances et neurocognitifs étaient également les principales causes d'hospitalisation en santé mentale, bien que leur importance relative varie entre les sous-groupes. Chez les immigrants, les THNA-SM étaient plus élevés chez les réfugiés et plus faibles chez les immigrants économiques, ceux de l'Asie de l'Est et ceux qui sont arrivés au Canada plus récemment. CONCLUSION: Les différences dans les taux d'hospitalisation chez les immigrants des divers groupes d'immigration et régions du monde, plus particulièrement pour certains types de problèmes de santé mentale, soulignent l'importance de recherches futures qui intègrent les services de santé mentale aux patients hospitalisés ainsi qu'aux patients externes afin de mieux comprendre ces relations.

Hospitalization related to chronic hepatitis B and C in recent immigrants in Canada: An immigration administrative data-linked, population-based cohort study.

Background: Canadian immigrants from countries where the hepatitis B virus (HBV) and hepatitis C virus (HCV) are endemic may be at higher risk of liver-related disease than Canadian-born residents. This study compared HBV- and HCV-related hospitalizations in Canadian immigrants (arriving from 1980 to 2013) and long-term residents (Canadian-born population and pre-1980 immigrants) and aimed to describe the burden of disease in both groups. Methods: Based on the 2004/2005-to-2013/2014 hospital Discharge Abstract Database linked to the 1980-to-2013 Longitudinal Immigration Database, this descriptive cross-sectional study examined the distribution of HBV- and HCV-related hospitalizations, lengths of stay, comorbidities, and sequelae incurred by immigrants and long-term residents in Canada. With a linkage rate of 85%, 5,854,949 immigrants were included in the study. Proportions of HBV- and HCV-related hospitalizations attributable to immigrants were calculated. Results: By birth country risk level, 22% of HBV-related hospital events among recent immigrants, and 20% of those related to HCV, were among people from high-risk countries. Proportionally, fewer immigrants had comorbidities than long-term residents. The top two hospital-related sequelae in both groups were cirrhosis and ascites, and liver cancer. While immigrants made up 16% of the Canadian population, they incurred 37% of HBV-related hospitalizations and 9% of HCV-related hospitalizations, giving ratios of hepatitis-related hospitalizations relative to the population share of 2.3 (95% confidence interval [CI]: 2.2 to 2.5) and 0.5 (95% CI: 0.5 to 0.6) respectively. These ratios were higher among seniors, at 4.4 (95% CI: 3.9 to 4.9) and 2.3 (95% CI: 1.9 to 2.6), respectively. Interpretation: Immigrants can require hospitalization for hepatitis in Canada, especially for HBV. These results may inform health screening for HBV or HCV in the Canadian immigration context.

All-cause acute care hospitalization rates of immigrants and the Canadian-born population: A linkage study.

BACKGROUND: As Canadian immigration levels increase, knowledge concerning immigrant health becomes increasingly important for health system policy and planning. This study compares the rate of all-cause hospitalization among immigrants with that of their Canadian-born counterparts. DATA AND METHODS: Using records from the Discharge Abstract Database (2004/2005 to 2016/2017) and the Ontario Mental Health Reporting System (2006/2007 to 2017/2018) linked to the 2016 Longitudinal Immigration Database, this study compared the age-standardized hospitalization rates (ASHRs) among immigrants with those of the Canadian-born population; the latter were obtained from a linkage based on the 2011 National Household Survey. Comparisons were made at the International Classification of Diseases chapter level by immigrant landing year, admission category and world region of birth. Quebec data were not available. RESULTS: Overall, ASHRs among immigrants were lower than for the Canadian-born population. Immigrants in the economic class had the lowest ASHR, followed by those in the family class and among refugees. After pregnancy was excluded, leading hospitalization causes were similar for immigrants and the Canadian-born population, where top causes included digestive system and circulatory diseases, injuries, and cancer. In male and female immigrants, the ASHRs were lowest among those from East Asia. By landing year, males arriving earlier had the highest ASHR compared with the most recent arrivals. When pregnancy was excluded and while the differential in ASHRs among females by landing year remained, the magnitude was smaller. INTERPRETATION: These results corroborate those from previous studies suggesting a healthy immigrant effect, but also reveal heterogeneity in ASHRs within the immigrant population. They provide a baseline for comparison of health status between populations, which enables further monitoring and informs health-system policy and planning.

Prevalence, short term outcome and factors associated with survival in patients suffering from upper gastrointestinal bleeding in a resource limited-setting, the case of Mulago hospital in Kampala, Uganda.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common cause of admission and death in the gastroenterology service. The prevalence, risk factors and the case fatality rate of UGIB may differ by settings. OBJECTIVES: Our objective was to determine the prevalence of symptoms and the case fatality rate of UGIB among patients at the gastroenterology service of Mulago Hospital in Kampala, Uganda and to describe the clinical and laboratory risk factors associated with the survival of these patients. METHODS: In a cross-sectional study performed between September 2013 and April 2014, patients were screened for UGIB symptoms. Data was collected on socio-demographic characteristics, clinical presentation and patient's outcome within one week of admission. Bivariate, multivariate, and survival analysis were performed to identify variables that were significantly associated with mortality. RESULTS: Out of 1085 patients screened, we identified the prevalence of UGIB symptoms in 220 patients (20.3%). Among these, 150 met the inclusion criteria for our study. The majority were males (70.7%) and 40 years of age or less (60%). The most prevalent clinical diagnosis were gastritis (39.3%), esophageal varices (17.3%) and peptic ulcer disease (PUD) (16%). Among patients who underwent endoscopy, esophageal varices (42.2%), PUD (26.3%) and gastritis (15.8%) were the leading causes of bleeding. The overall case fatality rate was 16.7% (25/150). Uremia remained associated with mortality after controlling for confounders.Survival was significantly reduced for males as well as for patients with uremia and malignancy. CONCLUSION: the prevalence of symptoms and the case fatality rate of UGIB among patients admitted to the gastroenterology ward in Mulago hospital were higher than in developed countries and similar to other resource-limited setting. The majority of patients were young men and presented with both hematemesis and melena. The most common causes of UGIB were esophageal varices, gastritis and PUD. Survival analysis indicate that male gender, uremia, and malignancy are associated with reduced survival.

Association of MAOA genetic variants and resilience with psychosocial stress: A longitudinal study of Syrian refugees.

Early childhood trauma can have profound and lifelong effects on adult mental health and psychosocial wellbeing. Nevertheless, responses to trauma are highly variable. Genetic variants may help explain variation in responses to trauma by identifying alleles that associate with changes in mental health measures. Protective factors, such as resilience, likely also play an important role in responses to trauma. The effects of genetic variants, in combination with protective factors, on psychosocial health are not well understood, particularly in non-Western contexts. In this study, we test the relative influence of genetic variants of monoamine oxidase A (MAOA, a gene proposed to influence the impact of childhood trauma on adult violence and antisocial behavior), levels of resilience, and exposure to traumatic events on psychosocial stress and mental health trajectories over time. We use data from a cohort of 12-18-year-old Syrian refugees who were forcibly displaced to neighboring Jordan (n = 399). DNA samples and survey data on trauma exposure, resilience (CYRM-12), and psychosocial stress were collected at three time points: baseline, ~13 weeks, and ~48 weeks. Using multilevel models, we identified an association of MAOA variant, in males only, with symptom scores of psychosocial stress on the Perceived Stress Scale (PSS) over time (p = 8.1 x 10-4). We also found that resilience is strongly associated with PSS (p = 7.9 x 10-9), underscoring the importance of protective factors in influencing levels of psychosocial stress. Furthermore, there was an additive effect wherein the sharpest reductions in perceived psychosocial stress are seen in low-activity MAOA males with low trauma exposure or high resilience levels. Our results highlight the value of studies that integrate genetic and psychosocial factors to better understand complex phenotypes, such as responses to trauma in contexts of high trauma exposure.

Congenital Malaria in Newborns Presented at Tororo General Hospital in Uganda: A Cross-Sectional Study.

Despite recent large-scale investments, malaria remains a major public health concern. Few studies have examined congenital malaria, defined as the presence of malaria parasitemia within the first 7 days of life, in endemic areas. This study aimed to determine the prevalence, to describe the clinical presentation, and to examine factors associated with congenital malaria in newborns aged up to 7 days attending Tororo General Hospital in Uganda. A total of 261 mother/baby pairs were recruited in this cross-sectional study. Giemsa-stained thick blood smears for malaria parasites and rapid malaria diagnostic tests were performed on capillary blood samples from all newborns and mothers, as well as on placental and cord samples from newborns delivered in the hospital. The prevalence of congenital malaria in the newborns was 16/261 (6.1%). No single clinical feature was associated with congenital malaria. However, there were associations between congenital malaria and maternal parasitemia (P < 0.001), gravidity of one (P = 0.03), maternal age < 19 years (P = 0.01), cord blood parasitemia (P = 0.01), and placental malaria (P = 0.02). In conclusion, congenital malaria is not rare in Uganda and there are no obvious clinical features associated with it in the newborn. Based on these findings, we recommend strengthening malaria prevention during pregnancy to reduce the occurrence of congenital malaria in newborns.

Lifecourse Adversity and Telomere Length in Older Women from Northeast Brazil.

We examined associations between adverse childhood experiences (ACEs) and shorter telomere length (TL) in 83 older women, including 42 women with less than secondary education and 41 with secondary or more education in a city of Northeast Brazil, a region with substantial socioeconomic inequalities. The low education sample was selected from a representative survey at local neighborhood health centers, while the high education group consisted of a convenience sample recruited by advertising in community centers and centers affiliated with the local university. Relative leukocyte TL was measured by quantitative polymerase chain reaction from blood samples. ACEs were self-reported. Spline linear regression was fitted to assess the strength of the associations between ACEs and TL. Among women with low education, median TL was 1.02 compared with 0.64 in the high education group (p = 0.0001). Natural log-transformed T/S ratio as the dependent variable was used in analysis. Women with low education had been exposed to more ACEs, and among them those experiencing two or more ACEs had longer TL than women exposed to ≤1 ACEs (p = 0.03); among women with high education, this difference was not significant (p = 0.49). In analyses adjusted by age, education, and parental abuse of alcohol, the linear trend of higher TL with increasing ACEs was confirmed (p = 0.02), and the mean difference in TL between groups remained significant (p = 0.002). The unexpected positive relationship between low education and ACEs with TL suggests that older adults who have survived harsh conditions prevailing in Northeast Brazil have the longest TL of their birth cohort.

Genetic Loci and Novel Discrimination Measures Associated with Blood Pressure Variation in African Americans Living in Tallahassee.

Sequencing of the human genome and decades of genetic association and linkage studies have dramatically improved our understanding of the etiology of many diseases. However, the multiple causes of complex diseases are still not well understood, in part because genetic and sociocultural risk factors are not typically investigated concurrently. Hypertension is a leading risk factor for cardiovascular disease and afflicts more African Americans than any other racially defined group in the US. Few genetic loci for hypertension have been replicated across populations, which may reflect population-specific differences in genetic variants and/or inattention to relevant sociocultural factors. Discrimination is a salient sociocultural risk factor for poor health and has been associated with hypertension. Here we use a biocultural approach to study blood pressure (BP) variation in African Americans living in Tallahassee, Florida by genotyping over 30,000 single nucleotide polymorphisms (SNPs) and capturing experiences of discrimination using novel measures of unfair treatment of self and others (n = 157). We perform a joint admixture and genetic association analysis for BP that prioritizes regions of the genome with African ancestry. We only report significant SNPs that were confirmed through our simulation analyses, which were performed to determine the false positive rate. We identify eight significant SNPs in five genes that were previously associated with cardiovascular diseases. When we include measures of unfair treatment and test for interactions between SNPs and unfair treatment, we identify a new class of genes involved in multiple phenotypes including psychosocial distress and mood disorders. Our results suggest that inclusion of culturally relevant stress measures, like unfair treatment in African Americans, may reveal new genes and biological pathways relevant to the etiology of hypertension, and may also improve our understanding of the complexity of gene-environment interactions that underlie complex diseases.

Systematic review of the association between chronic social stress and telomere length: A life course perspective.

Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta-analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta-analysis.

Interaction of Alu Polymorphisms and Novel Measures of Discrimination in Association with Blood Pressure in African Americans Living in Tallahassee, Florida.

African Americans are 40% more likely to be afflicted with hypertension than are non-Hispanic, white Americans, resulting in a 30% higher instance of mortality due to cardiovascular disease. There is debate about the relative contributions of genetic and sociocultural risk factors to the racial disparity in hypertension. We assayed three Alu insertion polymorphisms located in the ACE (angiotensin 1 converting enzyme), PLAT (plasminogen activator, tissue), and WNK1 (lysine deficient protein kinase 1) genes. We also estimated West African genetic ancestry and developed novel measures of perceived discrimination to create a biocultural model of blood pressure among African American adults in Tallahassee, Florida (n = 158). When tested separately, the ACE Alu noninsertion allele was significantly associated with higher systolic and diastolic blood pressure. In multiple regression analyses, West African genetic ancestry was not associated with blood pressure and reduced the strength of all blood pressure models tested. A gene × environment interaction was identified between the ACE Alu genotype and a new measure of unfair treatment that includes experiences by individuals close to the study participant. Inclusion of the WNK1 Alu genotype further improved this model of blood pressure variation. Our results suggest an association of the ACE and WNK1 genotypes with blood pressure that is consistent with their proposed gene functions. Measures of perceived unfair treatment of others show a threshold effect, with increased blood pressure occurring at higher values. The interaction between the ACE genotype and unfair treatment highlights the benefits of including both genetic and cultural data to investigate complex disease.

Protocol for a systematic review of the association between chronic stress during the life course and telomere length.

BACKGROUND: The effects of stress on ill health have become evident in recent years. Under acute stress situations, a cascade of physiological events helps the body mount an appropriate adaptive response. However, under chronic stress situations, this physiological response may lead to wear and tear on the body that accelerates the decline in physiological functioning and increases the risk of chronic conditions. Recent evidence for social stress experienced during childhood suggests serious consequences many years later, even later life. Telomere length, a marker of cell aging, may provide a link between chronic social stress and age-associated physical and mental decline and risk of chronic conditions. This study examines whether chronic social stress is associated with telomere length throughout the life course. METHODS/DESIGN: We will perform a systematic review of the literature on the relationship between chronic social stress, for example, due to violence, extreme poverty, or caregiving of people with disabling conditions (exposure), and telomere length (outcome) by searching electronic databases in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and gray literature from their start date onwards. We will limit the search to studies performed on human populations. Two reviewers will conduct standardized screening, eligibility assessment, data abstraction, and scientific quality assessment. All study designs investigating the association between chronic social stress and telomere length in healthy or diseased adults and children will be eligible for inclusion in the review. We will extract individual demographic and socioeconomic characteristics, research setting, method of measuring telomere length, reported outcome, and determinants of interest. Studies will also be stratified by 1) age into 3 groups: childhood (0 to 18 years), adulthood (19 to 64 years) and late life (65+); 2) cell type; 3) study design; and 4) telomere length assessment method. Where feasible, study results will be combined through meta-analyses to obtain a pooled measure of associations. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. DISCUSSION: This systematic review will provide knowledge on the existing evidence for chronic social stress and its association with telomere lengths throughout the life course.

Genomic architecture of sickle cell disease in West African children.

Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.

Evidence for additive and interaction effects of host genotype and infection in malaria.

The host mechanisms responsible for protection against malaria remain poorly understood, with only a few protective genetic effects mapped in humans. Here, we characterize a host-specific genome-wide signature in whole-blood transcriptomes of Plasmodium falciparum-infected West African children and report a demonstration of genotype-by-infection interactions in vivo. Several associations involve transcripts sensitive to infection and implicate complement system, antigen processing and presentation, and T-cell activation (i.e., SLC39A8, C3AR1, FCGR3B, RAD21, RETN, LRRC25, SLC3A2, and TAPBP), including one association that validated a genome-wide association candidate gene (SCO1), implicating binding variation within a noncoding regulatory element. Gene expression profiles in mice infected with Plasmodium chabaudi revealed and validated similar responses and highlighted specific pathways and genes that are likely important responders in both hosts. These results suggest that host variation and its interplay with infection affect children's ability to cope with infection and suggest a polygenic model mounted at the transcriptional level for susceptibility.

A population genetic approach to mapping neurological disorder genes using deep resequencing.

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n  =  285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders.

LGL1, a novel branching morphogen in developing kidney, is induced by retinoic acid.

Late-gestation lung protein 1 (LGL1) is a glycoprotein secreted by fetal lung mesenchyme that stimulates branching morphogenesis of the developing lung bud. We show that Lgl1 mRNA and protein are also expressed in mesenchymally derived lineages of fetal kidney. Although Lgl1 expression is stimulated by glucocorticoids in kidney cells, cortisol (10(-7) M) actually suppresses ureteric bud branching of fetal kidneys from HoxB7/GFP mice in explant culture. However, early branching morphogenesis in the lung and kidney is stimulated by retinoic acid, and we identified putative retinoic acid response elements in the Lgl1 promoter. All-trans-retinoic acid (10(-6) M) stimulated Lgl1 promoter activity and endogenous Lgl1 mRNA expression in vitro. Branching of cultured fetal kidney explants was increased in the presence of all-trans retinoic acid (10(-6) M). Heterozygous Lgl1 knockout mice were crossed to HoxB7/GFP mice to visualize the extent of ureteric bud branching at fetal stages. At embryonic (E) days E12.5-E13.0, mutant Lgl1(+/-) embryos showed a 20% reduction in ureteric bud branching compared with wild-type littermates. We propose a model in which retinoic acid stimulates branching morphogenesis by activating Lgl1 early in development. The prominent effects of glucocorticoids on Lgl1 expression in late lung development suggest a second role for LGL1 in alveolar maturation.

Canonical WNT signaling during kidney development.

The canonical WNT signaling pathway plays a crucial role in patterning of the embryo during development, but little is known about the specific developmental events which are under WNT control. To understand more about how the WNT pathway orchestrates mammalian organogenesis, we studied the canonical beta-catenin-mediated WNT signaling pathway in kidneys of mice bearing a beta-catenin-responsive TCF/betaGal reporter transgene. In metanephric kidney, intense canonical WNT signaling was evident in epithelia of the branching ureteric bud and in nephrogenic mesenchyme during its transition into renal tubules. WNT signaling activity is rapidly downregulated in maturing nephrons and becomes undetectable in postnatal kidney. Sites of TCF/betaGal activity are in proximity to the known sites of renal WNT2b and WNT4 expression, and these WNTs stimulate TCF reporter activity in kidney cell lines derived from ureteric bud and metanephric mesenchyme lineages. When fetal kidney explants from HoxB7/GFP mice were exposed to the canonical WNT signaling pathway inhibitor, Dickkopf-1, arborization of the ureteric bud was significantly reduced. We conclude that restricted zones of intense canonical WNT signaling drive branching nephrogenesis in fetal kidney.

A common variant of the PAX2 gene is associated with reduced newborn kidney size.

Congenital nephron number ranges widely in the human population. Suboptimal nephron number may be associated with increased risk for essential hypertension and susceptibility to renal injury, but the factors that set nephron number during kidney development are unknown. In renal-coloboma syndrome, renal hypoplasia and reduced nephron number are due to heterozygous mutations of the PAX2 gene. This study tested for an association between a common haplotype of the PAX2 gene and subtle renal hypoplasia in normal newborns. A PAX2 haplotype was identified to occur in 18.5% of the newborn cohort, which was significantly associated with a 10% reduction in newborn kidney volume adjusted for body surface area. This haplotype was also associated with reduced allele-specific PAX2 mRNA level in a human renal cell carcinoma cell line. Subtle renal hypoplasia in normal newborns may be partially due to a common variant of the PAX2 gene that reduces mRNA expression during kidney development.

Renal hypoplasia: lessons from Pax2.

The functions of Pax2 during renal development are many. It organizes caudal descent of the nephric duct, emergence of the ureteric bud, branching morphogenesis, and sustained arborization of the collecting system. In this review, we use lessons from the study of Pax2 as organizing principles to focus on the developmental processes which, if disrupted, might lead to renal hypoplasia in humans. We consider the problem of renal hypoplasia as a continuum, ranging from renal agenesis to subtle congenital nephron deficits. Early failure in the first two developmental stages (e.g. homozygous inactivation of Pax2) should preclude formation of metanephric kidneys and cause bilateral renal agenesis, incompatible with life. Interference with the later stages affects the extent of branching morphogenesis (e.g. heterozygous Pax2 mutations). Although the resulting nephron deficits are compatible with life, they may be moderately severe and account for up to 40% of the children in dialysis and transplant units around the world. Finally, the effect of Pax2 on apoptosis in the branching ureteric bud seems to imply a quantitative process which is finely tuned. Modest changes in this program could account for subtle nephron deficits in "normal" humans and increased risk of hypertension or susceptibility to acquired renal disease later in life.