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ABSTRACT
Background: Nutrigenetics explains how the genetic makeup of people affects their ability to metabolise specific nutrients, with the primary goal of enhancing health through a personalised diet. This study identifies genetic variants that may impact nutrient metabolism in families affected by orofacial clefts (OFCs).
Methods: A total of 130 case-parent trios were recruited from the National Cleft Care Centre (NCCC) at KATH. DNA was extracted from saliva and cheek swab samples. DNA quantification and other quality control checks, and whole genome sequencing (WGS) were carried out on 390 individuals. Variants from WGS data were called and filtered using the GATK workflow. In silico modelling using HOPE and PyRx molecular docking was carried out to ascertain how the implicated variants may affect the ability of these affected families to metabolise specific nutrients.
Results: Out of 50 genes studied, we observed 26 variants in 18 genes that could affect the metabolism of specific nutrients in families with OFCs. These include MTHFR (c.1535A>G; p.Tyr512Cys, c.1753G>A; p.Asp585Asn, c.1264G>A; p.Gly422Arg), MGAM (c.3538G>T; p.Gly1180Cys, c.4942T>G; p.Trp1648Gly, c.5060C>T; p.Thr1687Met, c.2188G>T; p.Ala730Ser) ABAT (c.1349G>A; p.Arg450Gln), CPT1B (c.997C>T; p.Arg33Trp), CYP2E1(c.1370A>T; p.His457Leu), CYP1A2 (c.217G>A; p.Gly73Arqurang), DMGDH (c.2261T>C; p.Phe754Ser, c.1478C>T; p.Pro493Leu), ACOX1 (c.497A>G; p.Asn166Ser), ACOX3 (c.460G>T; p.Gly154Ter), LCT (c.1658C>T; p.Thr553Ile c.5399G>A; p.Trp1800Ter), FUT6 (c.964C>T;p.Arg322Trp), APOE (c.487C>T; p.Arg163Cys), LDLR (c.1291G>A; p.Ala431Thr), PGM1 (c.572C>T; p.Ser191Leu), LPL (c.1169C>T; p.Ser390Phe), LIPC (c.1226A>C; p.Asp409Ala), G6PC2 (c.474G>A; p.Trp158Ter), and GLUD1 (c.445+350A>T). These genes play a role in the metabolism of nutrients such as vitamins (CYP1A2), homocysteine and folate (MTHFR), carbohydrate/glucose (MGAM), lipid (ACOX3), ethanol and retinoid acid (CYP2E1). In silico modelling with HOPE and molecular docking with PyRx predicted that most variants affected protein structure and function.
Conclusion: There are genetic variants that could influence how nutrients are used or metabolised in families affected by OFCs. This observation should inform personalised nutrition for the affected families.