School of Molecular & Cell Biology (Journal Articles)

Permanent URI for this collectionhttps://hdl.handle.net/10539/38040

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Subject: search.filters.subject.SDG-3: Good health and well-being

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    Genetic risk score for adult body mass index associations with childhood and adolescent weight gain in an African population
    (BioMed Central, 2018-08) Munthali, Richard J.; Sahibdeen, Venesa; Kagura, Juliana; Hendry, Liesl M.; Norris, Shane A.; Ong, Ken K.; Lombard, Zané; Day, Felix R.
    Background: Ninety-seven independent single nucleotide polymorphisms (SNPs) are robustly associated with adult body mass index (BMI kg/m2) in Caucasian populations. The relevance of such variants in African populations at different stages of the life course (such as childhood) is unclear. We tested whether a genetic risk score composed of the aforementioned SNPs was associated with BMI from infancy to early adulthood. We further tested whether this genetic effect was mediated by conditional weight gain at different growth periods. We used data from the Birth to Twenty Plus Cohort (Bt20+), for 971 urban South African black children from birth to 18 years. DNA was collected at 13 years old and was genotyped using the Metabochip (Illumina) array. The weighted genetic risk score (wGRS) for BMI was constructed based on 71 of the 97 previously reported SNPs. Results: The cross-sectional association between the wGRS and BMI strengthened with age from 5 to 18 years. The significant associations were observed from 11 to 18 years, and peak effect sizes were observed at 13 and 14 years of age. Results from the linear mixed effects models showed significant interactions between the wGRS and age on longitudinal BMI but no such interactions were observed in sex and the wGRS. A higher wGRS was associated with an increased relative risk of belonging to the early onset obese longitudinal BMI trajectory (relative risk = 1.88; 95%CI 1.28 to 2.76) compared to belonging to a normal longitudinal BMI trajectory. Adolescent conditional relative weight gain had a suggestive mediation effect of 56% on the association between wGRS and obesity risk at 18 years. Conclusions: The results suggest that genetic susceptibility to higher adult BMI can be tracked from childhood in this African population. This supports the notion that prevention of adult obesity should begin early in life. The genetic risk score combined with other non-genetic risk factors, such as BMI trajectory membership in our case, has the potential to be used to screen for early identification of individuals at increased risk of obesity and other related NCD risk factors in order to reduce the adverse health risk outcomes later.
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    Knock-down of LRP/LR promotes apoptosis in early and late stage colorectal carcinoma cells via caspase activation
    (BioMed Central, 2018-05) Vania, Leila; Rebelo, Thalia M.; Ferreira, Eloise; Weiss, Stefan F. T.
    Background: Cancer remains one of the leading causes of death around the world, where incidence and mortality rates are at a constant increase. Tumourigenic cells are characteristically seen to over-express the 37 kDa/67 kDa laminin receptor (LRP/LR) compared to their normal cell counterparts. This receptor has numerous roles in tumourigenesis including metastasis, angiogenic enhancement, telomerase activation, cell viability and apoptotic evasion. This study aimed to expose the role of LRP/LR on the cellular viability of early (SW-480) and late (DLD-1) stage colorectal cancer cells. Methods: siRNA were used to down-regulate the expression of LRP/LR in SW-480 and DLD-1 cells which was assessed using western blotting. Subsequently, cell survival was evaluated using the MTT cell survival assay and confocal microscopy. Thereafter, Annexin V-FITC/PI staining and caspase activity assays were used to investigate the mechanism underlying the cell death observed upon LRP/LR knockdown. The data was analysed using Student’s ttest with a confidence interval of 95%, with p-values of less than 0.05 seen as significant. Results: Here we reveal that siRNA-mediated knock-down of LRP led to notable decreases in cell viability through increased levels of apoptosis, apparent by compromised membrane integrity and significantly high caspase-3 activity. Down-regulated LRP resulted in a significant increase in caspase-8 and -9 activity in both cell lines. Conclusions: These findings show that the receptor is critically implicated in apoptosis and that LRP/LR downregulation induces apoptosis in early and late stage colorectal cancer cells through both apoptotic pathways. Thus, this study suggests that siRNA-mediated knock-down of LRP could be a possible therapeutic strategy for the treatment of early and late stage colorectal carcinoma.
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    Insights into the genetics of blood pressure in black South African individuals: the Birth to Twenty cohort
    (BMC, 2018) Hendry, Liesl M.; Sahibdeen, Venesa; Choudhury, Ananyo; Norris, Shane A.; Ramsay, Michèle; Lombard, Zané
    Background: Cardiovascular diseases (CVDs) are the leading cause of non-communicable disease deaths globally, with hypertension being a major risk factor contributing to CVDs. Blood pressure is a heritable trait, with relatively few genetic studies having been performed in Africans. This study aimed to identify genetic variants associated with variance in systolic (SBP) and diastolic (DBP) blood pressure in black South Africans. Methods: Genotyping was performed using the Metabochip in a subset of participants (mixed sex; median age 17.9) and their adult female caregivers (median age 41.0) from the Birth to Twenty cohort (n = 1947). Data were analysed as a merged dataset (all participants and caregivers together) in GEMMA (v0.94.1) using univariate linear mixed models, incorporating a centered relatedness matrix to account for the relatedness between individuals and with adjustments for age, sex, BMI and principal components of the genotype information. Results: Association analysis identified regions of interest in the NOS1AP (DBP: rs112468105 - p = 7.18 × 10−5 and SBP: rs4657181 - p = 4.04 × 10−5), MYRF (SBP: rs11230796 - p = 2.16 × 10−7, rs400075 - p = 2.88 × 10−7) and POC1B (SBP: rs770373 - p = 7.05 × 10−5, rs770374 - p = 9.05 × 10−5) genes and some intergenic regions (DACH1|LOC440145 (DBP: rs17240498 - p = 4.91 × 10−6 and SBP: rs17240498 - p = 2.10 × 10−5) and INTS10|LPL (SBP: rs55830938 - p = 1.30 × 10−5, rs73599609 - p = 5.78 × 10−5, rs73667448 - p = 6.86×10−5)). Conclusions: The study provided further insight into the contribution of genetic variants to blood pressure in black South Africans. Future functional and replication studies in larger samples are required to confirm the role of the identified loci in blood pressure regulation and whether or not these variants are African-specific.