rs11949767 (MXD3-LMAN2): Serum Uric Acid Locus

Key takeaways

• A genome-wide association study in over 121,000 Japanese individuals identified the MXD3-LMAN2 region as a novel locus for serum uric acid levels
• The locus is linked to cell metabolism, proliferation, and oxidative stress pathways, not the urate transporter genes more commonly studied in gout
• GTEx eQTL data show the alternative allele at rs11949767 is associated with reduced MXD3 expression across at least eight tissues, including multiple brain regions, thyroid, heart, and colon
• Evidence is based on a single Japanese-population GWAS and should be considered preliminary pending independent replication
• No specific lifestyle or drug response data are currently on file for this variant

What the research says A genome-wide meta-analysis of serum uric acid (SUA - a metabolic byproduct whose elevated levels can lead to gout, a form of inflammatory arthritis) in 121,745 Japanese subjects identified the MXD3-LMAN2 region (MXD3 is Max Dimerization Protein 3, a transcription factor involved in cell growth regulation; LMAN2 is Lectin, Mannose Binding 2, a protein involved in the cellular secretory pathway) as one of eight novel genomic loci influencing SUA, with sentinel SNP rs11952102 reaching genome-wide significance (P less than 5 x 10^-8) PMID 32099061. The region is grouped with loci related to cell metabolism, cell proliferation, and oxidative stress, distinguishing it from the well-known urate transporter genes such as ABCG2 and SLC2A9 identified at other loci PMID 32099061. GTEx eQTL (expression quantitative trait loci - genetic variants that influence how much of a gene's RNA is produced in a given tissue) data show the alternative allele at rs11949767 is associated with reduced MXD3 expression across multiple tissues, with the strongest effects in the brain cerebellum and cerebral cortex GTEx Portal.

Reported associations

• Serum uric acid levels: The locus (sentinel SNP rs11952102) was identified as genome-wide significant in 121,745 Japanese subjects as part of a meta-analysis yielding 36 total SUA-associated loci; no separate effect size for rs11949767 as distinct from rs11952102 was reported in the available study text PMID 32099061
• MXD3 gene expression (tissue eQTL): The alternative allele at rs11949767 is associated with reduced MXD3 expression in brain cerebellum, cerebral cortex, cerebellar hemisphere, thyroid, heart atrial appendage, tibial nerve, sigmoid colon, and esophagus muscularis GTEx Portal

Evidence quality The serum uric acid association was established in a meta-analysis across three Japanese cohorts (J-MICC Study, KING Study, and BioBank Japan) totaling 121,745 participants, achieving genome-wide significance (P less than 5 x 10^-8) with a low LD score regression intercept of 1.043, indicating minimal inflation from population stratification PMID 32099061. A trans-ethnic meta-analysis combining the Japanese data with the Global Urate Genetics Consortium identified 15 additional novel SUA loci, though whether the MXD3-LMAN2 locus was independently confirmed in that broader analysis is not specified in the available study text PMID 32099061. No beta coefficient or odds ratio for rs11949767 specifically is reported in the provided material; the sentinel SNP reported for this locus is rs11952102. Independent replication in non-Japanese populations has not been described in the available evidence, and the finding should be treated as preliminary.

Tissue-specific expression effects

• MXD3: The alternative allele is associated with reduced expression across brain cerebellum (strongest tissue effect), cerebral cortex, cerebellar hemisphere, thyroid, heart atrial appendage, tibial nerve, sigmoid colon, and esophagus muscularis; these are eQTL associations indicating a potential regulatory mechanism rather than a direct disease outcome GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.