Associations between APOL1 genetic variants and blood pressure in African American mothers and children from a U.S. pregnancy cohort: Modification by air pollution exposures.

INTRODUCTION: Carriage of high-risk APOL1 genetic variants is associated with increased risks for kidney diseases in people of African descent. Less is known about the variants' associations with blood pressure or potential moderators. METHODS: We investigated these associations in a pregnancy cohort of 556 women and 493 children identified as African American. Participants with two APOL1 risk alleles were defined as having the high-risk genotype. Blood pressure in both populations was measured at the child's 4-6 years visit. We fit multivariate linear and Poisson regressions and further adjusted for population stratification to estimate the APOL1-blood pressure associations. We also examined the associations modified by air pollution exposures (particulate matter ≤2.5 µ m in aerodynamic diameter [PM2.5] and nitrogen dioxide) and explored other moderators such as health conditions and behaviors. RESULTS: Neither APOL1 risk alleles nor risk genotypes had a main effect on blood pressure in mothers or children. However, each 2-µg/m3 increase of four-year average PM2.5 was associated with a 16.3 (95%CI: 5.7, 26.9) mmHg higher diastolic blood pressure in mothers with the APOL1 high-risk genotype, while the estimated effect was much smaller in mothers with the low-risk genotype (i.e., 2.9 [95%CI: -3.1, 8.8] mmHg; Pinteraction = 0.01). Additionally, the associations of APOL1 risk alleles and the high-risk genotype with high blood pressure (i.e., SBP and/or DBP ≥ 90th percentile) were stronger in girls vs. boys (Pinteraction = 0.02 and 0.005, respectively). CONCLUSION: This study sheds light on the distribution of high blood pressure by APOL1 genetic variants and informs regulatory policy to protect vulnerable population subgroups.

Fetal-Not Maternal-APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry.

Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. At University of Tennessee Health Science Center (UTHSC), we studied 93 pregnancies in black women with preeclampsia and 793 pregnancies without preeclampsia. We measured serum markers of preeclampsia soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Fetal APOL1 high-risk (HR) genotype was associated with preeclampsia, with odds ratios at EMC and UTHSC of 1.84 (95% CI 1.11, 2.93) and 1.92 (95% CI 1.05, 3.49), respectively. Maternal APOL1 HR genotype was not associated with preeclampsia. Mothers with the fetal APOL1 HR genotype had more cerebral or visual disturbances (63% versus 37%, p = 0.04). In addition, fetal APOL1 HR genotype was associated with a higher sFLT-1/PlGF ratio at birth (p = 0.04). Fetal APOL1 high-risk genotype increases the risk for preeclampsia, likely by adversely affecting placental function. Further research is needed to assess whether APOL1 genetic testing can predict preeclampsia and improve pregnancy outcomes.

Joint Associations of Maternal-Fetal APOL1 Genotypes and Maternal Country of Origin With Preeclampsia Risk.

RATIONALE & OBJECTIVES: Preeclampsia, which disproportionately affects Black women, is a leading cause of preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Apolipoprotein L1 (APOL1) kidney risk alleles, common among Black individuals, contribute substantially to CKD disparities. Given the strong link between preeclampsia and CKD, we investigated whether maternal and fetal APOL1 risk alleles can jointly influence preeclampsia risk, and explored potential modifiers of the association between APOL1 and preeclampsia. STUDY DESIGN: Nested case-control study. SETTING & PARTICIPANTS: 426 Black mother-infant pairs (275 African Americans and 151 Haitians) from the Boston Birth Cohort. EXPOSURE: Maternal and fetal APOL1 risk alleles. OUTCOMES: Preeclampsia. ANALYTICAL APPROACH: Logistic regression models with adjustment for demographic characteristics were applied to analyze associations between fetal and maternal APOL1 risk alleles and risk of preeclampsia and to investigate the effects of modification by maternal country of origin. RESULTS: Fetal APOL1 risk alleles tended to be associated with an increased risk of preeclampsia, which was not statistically significant in the total genotyped population. However, this association was modified by maternal country of origin (P<0.05 for interaction tests): fetal APOL1 risk alleles were significantly associated with an increased risk of preeclampsia among African Americans under recessive (odds ratio [OR], 3.6 [95% CI, 1.3-9.7]; P=0.01) and additive (OR, 1.7 [95% CI, 1.1-2.6]; P=0.01) genetic models but not in Haitian Americans. Also, maternal-fetal genotype discordance at the APOL1 locus was associated with a 2.6-fold higher risk of preeclampsia (P<0.001) in African Americans. LIMITATIONS: Limited sample size in stratified analyses; self-reported maternal country of origin; pre-pregnancy estimated glomerular filtration rate (eGFR) and proteinuria data in mothers were not collected; unmeasured confounding social and/or environmental factors; no replication study. CONCLUSIONS: This study supports the hypothesis that fetal APOL1 kidney risk alleles are associated with increased risk for preeclampsia in a recessive mode of inheritance in African Americans and suggests that maternal-fetal genotype discordance is also associated with this risk. These conclusions underscore the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia.

Genetic risk of APOL1 and kidney disease in children and young adults of African ancestry.

PURPOSE OF REVIEW: Understanding the genetic risk of APOL1 in children and young adults is important given the lifetime risk of hypertension and kidney disease among children of African descent. We review recent epidemiologic and biologic findings on the effects of APOL1 and kidney disease. RECENT FINDINGS: APOL1 in children and young adults is associated with hypertension, albuminuria and more rapid decline in kidney function and progression to end-stage kidney disease, especially among those with glomerular causes of kidney disease, and those affected by sickle cell disease or HIV. There are conflicting data on the APOL1 association with cardiovascular disease in children and young adults. APOL1 functions as part of the innate immune system. Podocyte expression of APOL1 likely contributes to the development of kidney disease. In cell culture and model organisms, APOL1 expression disrupts autophagic and ion flux, leads to defects in mitochondrial respiration and induces cell death. SUMMARY: APOL1 explains almost 70% of the excess risk of kidney disease in those of African descent, and is common in children with glomerular disease. An evolving understanding of the pathogenesis of APOL1-mediated kidney damage may aid in personalized medicine approaches to APOL1 attributable kidney disease.

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

BACKGROUND: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. METHODS: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). RESULTS: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). CONCLUSIONS: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.

Neonatal Hypertension.

Neonatal hypertension is uncommon but is becoming increasingly recognized. Normative blood pressure data are limited, as is research regarding the risks, treatment, and long-term outcomes. Therefore, there are no clinical practice guidelines and management is based on clinical judgment and expert opinion. Recognition of neonatal hypertension requires proper blood pressure measurement technique. When hypertension is present there should be a thorough clinical, laboratory, and imaging evaluation to promptly diagnose causes needing medical or surgical management. This review provides a practical overview for the practicing clinician regarding the identification, evaluation, and management of neonatal hypertension.

Type XXVII collagen at the transition of cartilage to bone during skeletogenesis.

COL27A1 is a member of the collagen fibrillar gene family and is expressed in cartilaginous tissues including the anlage of endochondral bone. To begin to understand its role in skeletogenesis, the temporospatial distributions of its RNA message and protein product, type XXVII collagen, were determined in developing human skeletal tissues. Laser capture microdissection and quantitative reverse-transcription polymerase chain reaction demonstrated that gene expression occurred throughout the growth plate and that it was higher in the resting and proliferative zones than in hypertrophic cartilage. Immunohistochemical analyses showed that type XXVII collagen was most evident in hypertrophic cartilage at the primary ossification center and at the growth plate and that it accumulated in the pericellular matrix. Synthesis of type XXVII collagen overlapped partly with that of type X collagen, a marker of chondrocyte hypertrophy, preceded the transition of cartilage to bone, and was associated with cartilage calcification. Immunogold electron microscopy of extracted ECM components from mouse growth plate showed that type XXVII collagen was a component of long non-banded fibrous structures, filamentous networks, and thin banded fibrils. The timing and location of synthesis suggest that type XXVII collagen plays a role during the calcification of cartilage and the transition of cartilage to bone.

Long-term Outcomes of Childhood Onset Nephrotic Syndrome.

There are limited studies on long-term outcomes of childhood onset nephrotic syndrome (NS). A majority of children with NS have steroid-sensitive nephrotic syndrome (SSNS). Steroid-resistant nephrotic syndrome (SRNS) is associated with a high risk of developing end-stage renal disease. Biomarkers and analysis of genetic mutations may provide new information for prognosis in SRNS. Frequently relapsing and steroid-dependent NS is associated with long-term complications, including dyslipidemia, cataracts, osteoporosis and fractures, obesity, impaired growth, and infertility. Long-term complications of SSNS are likely to be under-recognized. There remain many gaps in our knowledge of long-term outcomes of childhood NS, and further study is indicated.