Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

Abstract

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0×10 -8 ) and 4 suggestive loci (P<1.0×10 -6 ) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28×10 -9 ), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel 5 gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus. IntroductionWith approximately 33,000 related deaths every year, pancreatic cancer is the fourth leading cause of cancer deaths in Japan, after lung, colorectal, and stomach cancers 1 . The incidence and mortality rates of pancreatic cancer have increased steadily over the past decades, while those of other gastrointestinal cancers have shown a decreasing trend 1 . Despite the increasing burden levied by pancreatic cancer, few modifiable risk factors other than smoking and type 2 diabetes mellitus (T2D) have been identified, and the 5-year survival rates remain the worst (<10%) among major malignancies.Genome-wide association studies (GWASs) have increasingly revealed the role of inherited genetic variations in pancreatic cancer susceptibility. Since the first GWAS, conducted by the PanScan consortium, identified common variants in the gene coding for the ABO blood group system in 2009, 2 at least 23 genome-wide significant susceptibility loci have been linked to pancreatic cancer risk 3 . However, fewer loci have been identified for pancreatic cancer than for other common cancers, including breast and colorectal cancers 4,5 . Furthermore, the identified risk variants explained approximately 13% of the total heritability on the basis of GWAS-identified SNPs in a population of European ancestry 6 . These observations suggest that additional risk loci can be identified by increasing the sample size,

Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort

“…This hypothesis is supported by a previous genome‐wide association study (GWAS) in Japanese individuals, which identified three pancreatic cancer susceptibility loci that were not observed to be associated with risk in prior GWAS studies of individuals of European ancestry . A recent GWAS meta‐analysis of three Japanese studies further found a genetic risk marker in GP2 that is also distinct to this population . In addition, non‐O blood alleles, which are associated with pancreatic cancer, appear to be more prevalent in Japanese individuals compared to Europeans …”

“…[34][35][36] A recent GWAS meta-analysis of three Japanese studies further found a genetic risk marker in GP2 that is also distinct to this population. 37 In addition, non-O blood alleles, which are associated with pancreatic cancer, 38 appear to be more prevalent in Japanese individuals compared to Europeans. 39…”

Glycoprotein 2 as a gut gate keeper for mucosal equilibrium between inflammation and immunity

“…These findings are particularly noteworthy as they unveil an Asian-specific GP2 gene variant that was previously overlooked in Western populations. Additionally, considering that GP2 variants are associated with a range of diseases and conditions beyond pancreatic cancer, including body mass index (BMI) (rs12597579) [116], type 1 [117] and 2 diabetes (rs117267808) [118], acute myeloid leukemia [119], and sleep quality [120], this study revealed the pleiotropic effects of GP2 variants, suggesting their potential roles in metabolic traits such as type 2 diabetes [63,118]. In fact, in a comprehensive GWAS involving Japanese subjects, the top 3 16p12.3 locus SNPs, including rs78193826, showed significant associations with type 2 diabetes, glycated hemoglobin (HbA1c), and blood glucose levels [121].…”

“…However, whether these mutations are pathogenic has rarely been studied. It was not until 2020 that a groundbreaking study based on a meta-analysis of three genome-wide association study (GWAS) datasets comprising 2039 pancreatic cancer patients and 32,592 controls from Japan confirmed the relatively pivotal role of GP2 gene variants in pancreatic cancer [63]. This study analyzed a total of 7,914,378 SNPs across the whole genome and revealed three genome-wide significant loci associated with pancreatic cancer risk in this population: 13q12.2, 13q22.1, and the previously unreported 16p12.3 locus.…”

“…In fact, in a comprehensive GWAS involving Japanese subjects, the top 3 16p12.3 locus SNPs, including rs78193826, showed significant associations with type 2 diabetes, glycated hemoglobin (HbA1c), and blood glucose levels [121]. Moreover, Mendelian randomization (MR) analysis hinted at intriguing associations between HbA1c levels and pancreatic cancer risk, suggesting the presence of shared genetic susceptibility [63].…”