痛風防治曙光 日發現易發病遺傳基因 2015-02-0914:00 〔本報訊〕近年來痛風發病年齡有下降的趨勢，日本最新研究發現5種類型的易誘發痛風發作遺傳基因，可望未來助於預防及治療痛風。 《日本新聞網》報導，日本國立遺傳學研究所和防衛醫科大學、久留米大學組成的聯合研究小組指出，患者血中尿酸濃度過高，引起尿酸鈉鹽結晶沉積於關節、軟骨、滑囊液、肌腱、軟組織或甚至內臟器官，但引起尿酸過高有多種原因，研究小組發現的5種類型的痛風遺傳基因，可望在痛風預防及治療上起重要作用。 相傳痛風在古代稱「帝王病」，痛風一般好發於40至60歲的男性及停經後的女性，因女性荷爾蒙可促進尿酸排泄，停經後荷爾蒙改變造成尿酸值上升。痛風患者常有體重過重問題及大魚大肉的生活習慣，只要被痛風纏上，不僅走路有困難，就連患部被風吹都會不舒服，有如關節骨頭被啃食般疼痛。
New Genetic Clues to Gout Susceptibility Two susceptibility loci are novel to gout, according to a new study. by Wayne Kuznar Five gout susceptibility loci have been identified from genome-wide association studies (GWAS), potentially opening the door to genetic testing to select appropriate therapy for gout, according to Japanese researchers. Two of these have been identified as novel gout loci. Prior GWASs of gout were conducted in cases with self-reported gout. In the Japanese study, a GWAS was performed in clinically defined gout cases only, followed by an investigation of the relationship between genetic variation and clinical types of gout. The investigators performed a GWAS of 945 clinically defined gout cases from outpatient gout clinics in Japan and 1,213 male controls with normal serum uric acid (≤7.0 mg/dL) according to findings reported in Annals of the Rheumatic Diseases. A total of 123 single nucleotide polymorphisms (SNPs) passed the significance threshold in the GWAS stage and were used for subsequent analyses. From these, 16 SNPs were selected for genotyping a replication study performed in 1,048 cases and 1,334 controls. SNPs in three loci showed evidence of associations at the genome-wide significance level:
rs2728125 of ABCG2 (odds ratio [OR] 2.05)
rs3775948 of SLC2A9 (OR 1.64)
rs2188380 of MYL2-CUX2 (OR 1.78)
The ABCG2 and SLC2A9 genes are urate transporter genes for urate excretion and renal urate absorption, respectively, and have previously been described as genetic loci associated with high serum uric acid levels by GWASs. MYL2-CUX2 is a gene associated with cholesterol and diabetes mellitus. These three SNPs were successfully replicated in the replication study: rs2728125 (OR 2.03), rs3775948 (OR 1.57) and rs2188380 (OR 1.73). Two additional SNPs showed significant associations:
rs1260326 of GCKR (p=2.8 x 10−6; OR 1.32)
rs4073582 of CNIH-2 (p=1.6 x 10−4; OR 1.55).
"The present study revealed for the first time that three loci (GCKR, MYL2-CUX2 and CNIH-2) were associated with gout at the genome-wide significance level. In particular, MYL2-CUX2 and CNIH-2 are novel loci for gout," the authors wrote.
They previously found that risk alleles of rs72552713 and rs2231142 of ABCG2 reside on different haplotypes, indicating independent risks of gout. Further investigation of the cumulative effect of risk alleles of the five significant loci found that individuals with five or more risk alleles had an increased risk for gout compared with individuals with four of fewer risk alleles. "The more risk alleles in an individual, the higher the risk of gout," the researchers noted. A subtype analysis of gout revealed that associations of two non-synonymous SNPs of ABCG2 (rs72552713 and rs2231142) were stronger for the renal overload (ROL) subtype of gout (OR 4.35 and 3.37, respectively) than for the renal under excretion (RUE) subtype (OR 1.28 and 1.88, respectively). SLC2A9 plays an important role in renal urate reabsorption and is a causative gene for renal hypouricemia type 2. The association of rs3775948 of SLC2A9 was stronger for the RUE subtype (OR 1.94) than for the ROL subtype (OR 1.38). MLY2 mutation is associated with cardiomyopathy and metabolism of high-density lipoprotein cholesterol, while CUX2 regulates cell cycle progression, plays an important role in neural development, and is associated with type 1 diabetes. "Thus, rs2188380 of MYL2-CUX2 showed an association with gout because MYL2 and CUX2 might influence such metabolic pathways," according to the authors. Most gout-related genes are also associated with serum uric acid, the researchers note. While this study's goal was to identify novel gout risk loci, using clinically defined gout and controls with normal uric acid levels, future investigation with different study designs are needed to identify gout loci associated with crystal deposition and inflammation. The lack of such data in the current study was an important limitation. The authors added that "genetic testing for gout may well be introduced into future companion diagnostics. For example, patients with risk alleles for ROL-type gout would be given urate synthesis inhibitors such as allopurinol and febuxostat, while patients with risk alleles for RUE-type gout would be administered uricosuric agents including benzbromarone and lesinurad, a selective uric acid reabsorption inhibitor that has just finished its phase III study." The study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, the Ministry of Health, Labour and Welfare of Japan, the Ministry of Defense of Japan, the Japan Society for the Promotion of Science, the Kawano Masanori Memorial Foundation for Promotion of Pediatrics and the Gout Research Foundation of Japan. The BioBank Japan Project and J-MICC Study were supported by MEXT of Japan. Three of the authors report having a patent pending based on the work reported in this study.
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