APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans

Background

Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term.

Results

Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 × HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies.

Conclusions

Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1645-7) contains supplementary material, which is available to authorized users.     

Association between evolutionary history of angiotensinogen haplotypes and plasma levels

Over the last decade, considerable effort has been invested in studying the associations between angiotensinogen (AGT) variants, AGT plasma levels and high blood pressure. Evidence accumulated to date consistently supports the relationship between the AGT locus and the protein level, while an influence on blood pressure has been difficult to establish; in both instances the predisposing molecular variants are not fully defined. An evolutionary approach, taking into account the phylogenetic relationship between all the polymorphisms at this locus, may improve our understanding of the genetic nature of these quantitative phenotypes. Accordingly we sequenced a 6.8 kb region of the AGT gene in 57 Nigerian individuals (29 with high AGT plasma levels and 28 with low AGT plasma levels). Haplotypes were grouped into seven major haplogroups and their phylogenetic relationship was established. The association between haplogroups and AGT plasma levels was investigated. A significant linear correlation was detected between haplogroup genetic distance and AGT levels, suggesting a nonrandom accumulation of risk-associated mutations during the evolutionary history of the AGT gene.Ryk Ward has died since this article was written     

A parkinsonian syndrome induced in the goldfish by the neurotoxin MPTP.

Parkinson's disease has been modeled in humans, lower primates, and to a lesser extent in some other vertebrates by administration of the potent neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine). The MPTP model has thus drawn considerable attention as a system to search for anti-Parkinson's disease drugs, although the cost and scarcity of primates has limited extensive applications. We now report that a parkinsonian syndrome can be elicited in the common goldfish (Carassius auratus) by a single dose of MPTP. The syndrome is characterized by profound bradykinesia (slow movement), the full extent of which is reached 3 days after MPTP administration. The reduction in movement is paralleled by loss of dopamine and norepinephrine from the forebrain and midbrain and in other brain regions as well. The toxic oxidative product of MPTP, MPP+, is also accumulated predominantly in forebrain and midbrain, and pretreatment with the monoamine oxidase blocker tranylcypromine substantially reduces accumulation of the toxic metabolite. A barely perceptible coarseness in balance adjustment also occurs in treated animals. The MPTP-treated goldfish recover normal movement and normal brain monoamine levels within 10-13 days after administration of the drug. We interpret these and other data to indicate that MPTP can induce a Parkinson's disease-like syndrome in the goldfish that is similar in many aspects to the syndrome induced by MPTP in humans and other primates. This remarkable parallel may permit the goldfish to supplement expensive and scarce primates for the purpose of searching and screening neuroprotective drugs with specific relevance to Parkinson's disease.     

Development of polymorphic microsatellite DNA loci for characterizing Oreochromis shiranus subspecies in Malawi

Six sets of microsatellite primers were developed from Oreochromis shiranus nuclear DNA. These cross‐primed in species of the genera Sarotherodon and Tilapia, and were polymorphic in most of the species. The total number of alleles ranged from 18 to 30 per locus; the mean heterozygosity per population ranged from 0.51 ± 0.12 to 0.82 ± 0.03, which is higher than reported in allozyme studies. Five sets of primers were used to characterize five putative populations of O. shiranus, an indigenous mouth brooding tilapia which has been widely distributed in fish farms and reservoirs in Malawi. Two postulated subspecies of O. shiranus (subspecies shiranus and subspecies chilwae) have been difficult to distinguish morphologically. Lake Chilwa, Lake Chiuta and Bunda Reservoir populations cluster together as O. sh. chilwae, while the Lake Malombe and Bishop Reservoir populations form a second cluster as O. sh. shiranus. The assignment of the Chiuta and Chilwa populations of O. sh. chilwae to a single subspecies is consistent with the fact that the two lakes were a single open lake until about 8000–9000 _bp. There is no connection between them and the Lake Malawi‐Malombe drainage system where the O. sh. shiranus subspecies is found.     

Population structure and colour variation of the cichlid fishes Labeotropheus fuelleborni Ahl along a recently formed archipelago of rocky habitat patches in southern Lake Malawi

Extremely fine-scale genetic partitioning has recently been detected among populations of Lake Malawi''s rock-dwelling cichlids through the study of microsatellite loci. Understanding the mechanisms of genetic differentiation that operate in this rapidly speciating group requires further investigation of the geographic patterns of gene flow and the congruence between morphological and genetic divergence. In pursuit of this goal, genetic variation at four microsatellite loci and variation in male breeding coloration were examined in several populations of Labeotropheus fuelleborni from southern Lake Malawi. Significant genetic differentiation exists among populations (overall F_ST = 0.063; p = 0.0002). While migration appears unrestricted within continuous rocky patches, deep waters and sandy bays more than 2 km wide act as strong barriers to gene flow. Dispersal of L. fuelleborni appears to follow a stepping-stone model in which the distribution of habitats often constrains migration to one dimension. It is hypothesized that clinal colour variation in the study area has resulted from the secondary contact of divergent lineages, although reproductive isolation between colour variants is not apparent. Relative to shoreline populations, reduced levels of gene flow among populations inhabiting isolated, deep-water islands provides greater opportunities for drift, adaptation to local conditions, or sexual selection to effect genetic differentiation in this species.     

Growth performance, haematology and serum biochemistry of African catfish (Clarias gariepinus) fingerlings fed graded levels of dietary fumonisin B1

Fingerlings of Clarias gariepinus were used to evaluate the effect of dietary fumonisin B₁ (FB₁), a mycotoxin produced by Fusarium verticillioides, on growth, haematological and serum biochemical parameters. The fingerlings were sorted, weighed and randomly stocked in 16 plastic tanks at the rate of 20 fingerlings per tank. Fusarium-cultured maize grains containing FB₁ were used to formulate three diets containing approximately 5.0, 10.0 and 15.0 mg FB₁/kg, constituting diets 2, 3, and 4 respectively. These three diets, plus diet 1, which contained non-Fusarium cultured maize grains that served as the control, were used in a 6-week feeding trial. The final weight gains by the fingerlings were significantly (P?<?0.05) influenced by FB₁. The final weights of the fingerlings fed diets 2, 3 and 4 ranged from 70.07 to 87.10% of the controls. The haematocrit, erythrocytes, haemoglobin, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and the serum protein constituents (total protein, albumin and globulin) values significantly (P?<?0.05) decreased, while the leucocytes, MCV and MCH increased significantly (P?<?0.05) with increase in the dietary FB₁. The total serum protein values of the fingerlings fed diets 2, 3 and 4 were 34.53, 39.42 and 50.17% lower than the total serum protein values of those fed the control diet. These results indicate that Fusarium-contaminated diets containing about 5.0 mg or more FB₁/kg reduced weight gain and significantly altered haematological parameters and serum protein constituents in the fingerlings. These may have a significant impact on physiological activities and may be vital in immunosuppression in the fingerlings with a strong negative impact on subsequent performance of the fish.     

An Improved Fst Estimator

The fixation index F _st plays a central role in ecological and evolutionary genetic studies. The estimators of Wright (F^st1), Weir and Cockerham (F^st2), and Hudson et al. (F^st3) are widely used to measure genetic differences among different populations, but all have limitations. We propose a minimum variance estimator F^stm using F^st1 and F^st2. We tested F^stm in simulations and applied it to 120 unrelated East African individuals from Ethiopia and 11 subpopulations in HapMap 3 with 464,642 SNPs. Our simulation study showed that F^stm has smaller bias than F^st2 for small sample sizes and smaller bias than F^st1 for large sample sizes. Also, F^stm has smaller variance than F^st2 for small F _st values and smaller variance than F^st1 for large F _st values. We demonstrated that approximately 30 subpopulations and 30 individuals per subpopulation are required in order to accurately estimate F _st.     

Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations

Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a well-powered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3% of these loci transferred (p-values≤0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r ²≥0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8% for associations originally reported as genome-wide significant and 38.0% for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation of these transferable associations.