Background
DolPHIN-2 (NCT 03249181) randomised mothers initiating ART in late pregnancy to efavirenz (EFV)- or dolutegravir (DTG) based regimens. We previously reported no significant differences between arms in weight change post-delivery to 48w postpartum (PP), but observed heterogeneity with numerically greater weight gain in women from South Africa. Here, we undertook a genome-wide association study (GWAS) to identify genetic variants associated with weight change from delivery to 48w PP.
Methods
159 participants were genotyped using the Illumina Infinium™ H3Africa Consortium Array v2 (2.27million variants) and after quality control of the genotyped data, 129 mothers (62 EFV, 67 DTG) were included with 1.8 million variants analysed to identify genes related to weight change, with adjustments for age and the first four principal components. Weights were recorded using standardised procedures at enrolment, <14 days of delivery and at 6, 12, 24 and 48 weeks PP. Weight change was calculated as a percentage from delivery to 48w PP.
Results
Analysis identified 21 loci which reached the suggestive genome-wide threshold (p < 1 x 10−5). The top three associated loci were EMB (p, 2.4 x10-7), LINC02710 (p, 4.0 x10-7), and AL365440.2 (p, 6.3 x10-7). One of the statistically significant loci associated with weight gain was related to the HK1 gene (p, 9.7 x10-6; 95% CI 0.24-0.60; β 0.42) which encodes hexokinases that are involved in the first step of glucose metabolism pathways and could offer a possible explanation for weight changes.
Conclusions
These findings suggest that there are genetic variants which may be associated with changes in postpartum weight in women receiving DTG- or EFZ-based treatments. Further work is underway to undertake genotype imputation across the whole human genome which will allow us to identify potential causal variants associated with DTG- or EFZ-induced postpartum weight change. Data stratification by treatment group will also be carried out to see if any genes are specifically related to DTG- or EFZ-based treatment.
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