Thrombomodulin Gene Mutation and Associated Predisposing Factors in Familial Collapsing Glomerulopathy.

Collapsing glomerulopathy (CG) is a rare glomerular disease and its familial form is even rarer. CG and non-collapsing forms of focal segmental glomerulosclerosis may both be caused by pathogenic variants in the same genes, but there is less information on genetics of the former disease. We hypothesized that different hits (viral infection and genetic variants) may be involved in the development of a familial CG here described. We performed renal and etiological routine evaluation, PVB19 serology, genetic tests including whole-exome analysis and dosage of serum thrombomodulin (THBD) in two siblings with CG, one healthy sister, and their mother. The THBD gene variant p.A43T in homozygosity was identified in the proband and her affected brother, both with CG. The same mutation was identified in their mother in heterozygosity. THBD levels were elevated in the serum of both affected siblings. They also had PVB19 positive serology and the G1 high-risk apolipoprotein L1 (APOL1) alleles in homozygosity. Their healthy sister had no PVB19-positive serology and no THBD nor APOL1 gene variants. In this case of familial CG, THBD, and APOL1 gene variants, and a previous PVB19 infection may be associated with the development of CG in a multihit process. In addition, the p.A43T THBD variant, identified in the affected siblings, has never been previously described in homozygosis, pointing to a likely autosomal recessive CG trait caused by this gene mutation.

APOL1 genotyping via buccal mucosa cell samples to establish risk of kidney disease.

Two alleles (G1 and G2) of the apolipoprotein 1 gene (APOL1) predispose people of African descent to developing or accelerating the course of certain types of kidney disease. Population studies to determine the frequency of the G1 and G2 alleles are important to inform resource allocation by public health authorities. Traditionally, APOL1 genotyping is carried out in blood samples. However, sample collection, transport, and storage is cumbersome. Here we compared APOL1 genotyping in blood and buccal mucosa cell samples obtained from 23 individuals. Alleles G0 (wild), G1, and G2, as well as genotypes G0/G0, G0/G1, G1/G1, G0/G2, G1/G2, and G2/G2 were detected using both blood and buccal mucosa cells with 100% coincidence. Our data indicate that buccal mucosa cell samples may represent a suitable alternative to blood samples for APOL1 genotyping in the field.

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.

APOL1 risk variants and kidney disease: what we know so far / Variantes de risco APOL1 e doença renal: o que sabemos até agora

ABSTRACT There are striking differences in chronic kidney disease between Caucasians and African descendants. It was widely accepted that this occurred due to socioeconomic factors, but recent studies show that apolipoprotein L-1 (APOL1) gene variants are strongly associated with focal segmental glomerulosclerosis, HIV-associated nephropathy, hypertensive nephrosclerosis, and lupus nephritis in the African American population. These variants made their way to South America trough intercontinental slave traffic and conferred an evolutionary advantage to the carries by protecting against forms of trypanosomiasis, but at the expense of an increased risk of kidney disease. The effect of the variants does not seem to be related to their serum concentration, but rather to local action on the podocytes. Risk variants are also important in renal transplantation, since grafts from donors with risk variants present worse survival.

RESUMO Existem importantes diferenças na doença renal crônica entre caucasianos e afrodescendentes. Foi amplamente aceito que isso ocorreu devido a fatores socioeconômicos, mas estudos recentes mostraram que as variantes gênicas da apolipoproteína L-1 (APOL1) estão fortemente associadas à glomeruloesclerose segmentar e focal, nefropatia associada ao HIV, nefroesclerose hipertensiva e nefrite lúpica na população afrodescendente. Essas variantes chegaram à América do Sul através do tráfico intercontinental de escravos, e proporcionaram uma vantagem evolutiva aos portadores, protegendo contra formas de tripanossomíase, mas à custa de um maior risco de doença renal. O efeito das variantes não parece estar relacionado à sua concentração sérica, mas sim à sua ação local sobre os podócitos. Variantes de risco também são importantes no transplante renal, já que enxertos de doadores com variantes de risco apresentam pior sobrevida.