Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III)

Abstract

Background: Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent. Several candidate gene studies have been performed in various populations, but most have been inconclusive. Given that gallstones consist of up to 80% cholesterol, we hypothesized that common genetic variants associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) would also be associated with gallstone risk.

Methods: To test this hypothesis, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study as part of the Population Architecture using Genomics and Epidemiology (PAGE) study performed tests of association between 49 GWAS-identified lipid trait SNPs and gallstone disease in non-Hispanic whites (446 cases and 1,962 controls), non-Hispanic blacks (179 cases and 1,540 controls), and Mexican Americans (227 cases and 1,478 controls) ascertained for the population-based Third National Health and Nutrition Examination Survey (NHANES III).

Results: At a liberal significance threshold of 0.05, five, four, and four SNP(s) were associated with disease risk in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. No one SNP was associated with gallstone disease risk in all three racial/ethnic groups. The most significant association was observed for ABCG5 rs6756629 in non-Hispanic whites [odds ratio (OR) = 1.89; 95% confidence interval (CI) = 1.44-2.49; p = 0.0001). ABCG5 rs6756629 is in strong linkage disequilibrium with rs11887534 (D19H), a variant previously associated with gallstone disease risk in populations of European-descent.

Conclusions: We replicated a previously associated variant for gallstone disease risk in non-Hispanic whites. Further discovery and fine-mapping efforts in diverse populations are needed to fully describe the genetic architecture of gallstone disease risk in humans.

Figure 1

Associations between HDL-C associated SNPs and gallstone disease by population. Each high-density lipoprotein (HDL)-associated SNP was tested for an association with gallstone disease (yes/no) assuming an additive genetic model adjusted for age, sex, and body mass index [kg/m²]. The odds ratio and 95% confidence intervals are plotted by race-ethnicity using Synthesis-View [26]. SNP locations (genome build 37.5) are given on the y-axis. Each square represents an odds-ratio and each line represents a 95% confidence interval for each population. The larger square represents a significantly associated SNP at p < 0.05. Populations are color-coded as follows: non-Hispanic whites (blue), non-Hispanic blacks (red), and Mexican Americans (green). The grey vertical line represents the 1.0 threshold for odds-ratio values.

Figure 2

Associations between LDL-C associated SNPs and gallstone disease by population. Each low-density lipoprotein (LDL)-associated SNP was tested for an association with gallstone disease (yes/no) assuming an additive genetic model adjusted for age, sex, and body mass index [kg/m²]. The odds ratio and 95% confidence intervals are plotted by race-ethnicity using Synthesis-View [26]. SNP locations (genome build 37.5) are given on the y-axis. Each square represents an odds-ratio and each line represents a 95% confidence interval for each population. The larger square represents a significantly associated SNP at p < 0.05. Populations are color-coded as follows: non-Hispanic whites (blue), non-Hispanic blacks (red), and Mexican Americans (green). The grey vertical line represents the 1.0 threshold for odds-ratio values.

Figure 3

Associations between TG associated SNPs and gallstone disease by population. Each triglyceride (TG)-associated SNP was tested for an association with gallstone disease (yes/no) assuming an additive genetic model adjusted for age, sex, and body mass index [kg/m²]. The odds ratio and 95% confidence intervals are plotted by race-ethnicity using Synthesis-View [26]. SNP locations (genome build 37.5) are given on the y-axis. Each square represents an odds-ratio and each line represents a 95% confidence interval for each population. The larger square represents a significantly associated SNP at p < 0.05. Populations are color-coded as follows: non-Hispanic whites (blue), non-Hispanic blacks (red), and Mexican Americans (green). The grey vertical line represents the 1.0 threshold for odds-ratio values.