Dataset Information

Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD.

ABSTRACT:

Background

The clinical significance of rare mutations in LDL metabolism genes on nonalcoholic fatty liver disease (NAFLD) severity is not well understood.

Objective

To examine the significance of mutations in LDL metabolism genes including apolipoprotein B (APOB), proprotein convertase subtilisin kexin 9 (PCSK9) and LDL receptor (LDLR) in patients with NAFLD.

Methods

Patients with biopsy-confirmed NAFLD from the NASH Clinical Research Network studies were stratified into 3 groups of LDL-C (≤50 mg/dL, 130-150 mg/dL, ≥ 190 mg/dL) and then 120 (40 per group) were randomly selected from the strata. We examined the presence of mutations on LDL genes and analyzed its association with selected NAFLD-related features. Multivariable analyses were adjusted for age, race, gender and use of statins.

Results

Among 40 patients with LDL-C ≤ 50 mg/dL, 7 (18%) patients had heterozygous variants in APOB and 2 had heterozygous variants in PCSK9 (5%). We also found heterozygous mutations in 3 (8%) patients with LDL-C ≥ 190 mg/dL; 2 and 1 located in LDLR and APOE genes, respectively. Compared to wild-type controls with LDL-C ≤ 50, APOB carriers displayed higher levels of alanine aminotransferase (85.86 ± 35.14 U/L vs 45.61 ± 20.84 U/L, Adj. P = 0.002) and steatosis >66% (57% vs 24%, Adj. P = 0.050). These associations remained statistically significant after excluding statin users. Other histological features of NAFLD severity were not different between wild-type controls and APOB mutation carriers.

Conclusion

Mutations in the APOB gene are common among NAFLD patients with very low LDL-C and may be associated with increased aminotransferase levels and steatosis severity.

SUBMITTER: Vilar-Gomez E

PROVIDER: S-EPMC8187295 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.