Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Abstract

ObjectivesGenome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years.MethodsTwo genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.ResultsIn addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout.ConclusionsOur findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

“…Cross-phenotype associations involving the metabolite uric acid and gout, an inflammatory arthritis driven by excess levels of uric acid (Bodofsky et al, 2020), are illustrative of iCPAGdb’s usefulness. GWAS studies have been conducted on risk of gout (Chen et al, 2018; Lai et al, 2012; Lee et al, 2019; Li et al, 2015; Matsuo et al, 2016; Nakayama et al, 2017; Nakayama et al, 2020; Sulem et al, 2011) as well as uric acid or urate levels (Boocock et al, 2020; Dehghan et al, 2008; Doring et al, 2008; Kamatani et al, 2010; Kottgen et al, 2013; Li et al, 2007; Tin et al, 2019; Tin et al, 2011). Notably, of 31 GWAS loci for gout and 123 GWAS loci for serum uric acid levels at p<5×10 −8 , 13 loci overlap, including 9 loci identified only by LD proxy (nearly 6000-fold enrichment; p=5.9×10 −43 ).…”

Risk of gout among Taiwanese adults with ALDH-2 rs671 polymorphism according to BMI and alcohol intake

“…The A allele of the rs671 has been linked to reduced susceptibility to gout [ 22 ]. ALDH2 rs671 also demonstrated the strongest GWA significance for alcohol drinking [ 21 ]. It was found to be related to alcohol drinking habits and alcohol flushing responses in Asians [ 25 , 37 ].…”

“…Alcohol could influence the risk of gout through its effect on uric acid [ 18 – 20 ]. ALDH2 rs671 attained genome-wide significance as a genetic locus for alcohol drinking [ 21 ].…”

Modulation of Urate Transport by Drugs

“…Hyperuricemia results from an imbalance between the production and excretion of urate, and can be classified as (i) renal underexcretion type (RUE) where FE is ≤5.5% and urinary urate excretion (UUE) is ≤25%; (ii) renal overload (ROL) type when FE ≥5.5% and UUE is ≥25%; (iii) combined type when FE is ≤5.5% and UUE is ≥25%; and (iv) normal type when FE ≥ 5.5 and UUE is ≤25%. Gout, one of the most frequent diseases caused by hyperuricemia, can also be categorized accordingly [ 9 ]. Overproduction of urate is one of the main underlying causes of hyperuricemia, while dietary factors such as consumption of protein-rich food may also contribute to the elevation of SU [ 10 ].…”