Lower Frequency of PNPLA3 Polymorphism in West African Populations and Divergent Associations With Hepatocellular Carcinoma

Background and Aims: The germline variant patatin-like phospholipase domain-containing protein 3 (PNPLA3)-rs738409 (I148M) is associated with a higher risk of hepatocellular carcinoma (HCC) in European and East Asian populations, but its association with HCC in Africans has not been investigated. We examined the association between PNPLA3-rs738409 and HCC risk in Ghanaian and Nigerian populations, compared to a U.S. population. Methods: We enrolled 363 patients with HCC and 2807 cancer-free control patients from Ghana, Nigeria, and the U.S. Germline genetic sequencing was performed, and data on PNPLA3-rs738409 were extracted for analysis. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals separately for each population. Results: There was a significantly lower frequency of the PNPLA3-rs738409 risk allele [G] in the Ghanaian and Nigerian populations compared to the U.S. population. PNPLA3-rs738409 was associated with increased HCC risk in the U.S. population (OR = 3.40, P < .001), but not in the combined Ghanaian and Nigerian population (OR = 1.32, P = .30). Conclusion: This study highlights the potential ancestral and global geographic differences in the genetic risk factors of HCC. It shows the population-specific variability in the association between PNPLA3-rs738409 and HCC risk, showing no significant association in Ghanaian and Nigerian populations, in contrast to the U.S. population. These findings emphasize the need for the inclusion of diverse populations, especially minority groups, in genetic studies for accurate and equitable assessment of heritable cancer risk.