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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

ABSTRACT: OBJECTIVE:The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS:We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS:This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10- 8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS:This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

SUBMITTER: Kawamura Y

PROVIDER: S-EPMC6788923 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

Kawamura Yusuke Y Nakaoka Hirofumi H Nakayama Akiyoshi A Okada Yukinori Y Yamamoto Ken K Higashino Toshihide T Sakiyama Masayuki M Shimizu Toru T Ooyama Hiroshi H Ooyama Keiko K Nagase Mitsuo M Hidaka Yuji Y Shirahama Yuko Y Hosomichi Kazuyoshi K Nishida Yuichiro Y Shimoshikiryo Ippei I Hishida Asahi A Katsuura-Kamano Sakurako S Shimizu Seiko S Kawaguchi Makoto M Uemura Hirokazu H Ibusuki Rie R Hara Megumi M Naito Mariko M Takao Mikiya M Nakajima Mayuko M Iwasawa Satoko S Nakashima Hiroshi H Ohnaka Keizo K Nakamura Takahiro T Stiburkova Blanka B Merriman Tony R TR Nakatochi Masahiro M Ichihara Sahoko S Yokota Mitsuhiro M Takada Tappei T Saitoh Tatsuya T Kamatani Yoichiro Y Takahashi Atsushi A Arisawa Kokichi K Takezaki Toshiro T Tanaka Keitaro K Wakai Kenji K Kubo Michiaki M Hosoya Tatsuo T Ichida Kimiyoshi K Inoue Ituro I Shinomiya Nariyoshi N Matsuo Hirotaka H Matsuo Hirotaka H

Annals of the rheumatic diseases 20190708 10

<h4>Objective</h4>The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.<h4>Methods</h4>We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS ( ...[more]

PMID: 31289104

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Project description:BackgroundHyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout.MethodsGenome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis.FindingsThree loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study).InterpretationWe identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

Project description:Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7-10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10(-8) in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10(-9), OR = 1.29, CI = 1.18-1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10(-8), OR = 1.20, Cl = 1.13-1.29, and rs6757804; P = 4.05×10(-8), OR = 1.20, Cl = 1.13-1.29). Using an adjusted Bonferoni significance threshold of 4.51×10(-7) we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10(-7), OR = 1.20, Cl = 1.12-1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10(-7), OR = 1.19, Cl = 1.11-1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.

Project description:Understanding how genomes encode complex cellular and organismal behaviors is an outstanding challenge of modern genetics. Unlike classical screening methods, analysis of the genetic variation that occurs naturally in wild populations can enable rapid, genome-scale trait mapping with a medium-throughput experimental design. Here we describe the results of the first genome-wide association analysis (GWAS) of a microbial eukaryote, using wild isolates of the filamentous fungus Neurospora crassa. We transcriptionally profiled each of 112 individuals collected in Louisiana and used RNA-seq data to genotype each strain at thousands of genetic loci genome-wide. We used these genotypes in a mapping analysis of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion. GWAS identified one gene, NCU04379 (cse-1, encoding a homolog of neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly lowered germling communication and fusion, and two genes encoding predicted binding partners of CSE-1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more novel determinants of germling communication, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. These results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power of population-genetic analyses for the rapid identification of genes contributing to complex traits in microbial species. 112 mycelial mRNA profiles of 16 hour wild type (WT) Neurospora crassa strains were generated by deep sequencing, using Illumina GAIIx.

Project description:BACKGROUND: This study aimed to identify patient-reported outcomes and clinician-assessed characteristics of the first metatarsophalangeal joint (1MTPJ) in people with gout and with asymptomatic hyperuricaemia by comparing them to normouricaemic controls. METHODS: Twenty four people with gout (without current symptoms of acute arthritis), 29 with asymptomatic hyperuricaemia and 34 age- and sex-matched controls participated in this cross-sectional observational study. Patient-reported outcomes included 1MTPJ pain, foot pain and disability, body pain, lower limb function, activity limitation and overall wellbeing. Clinician-assessed characteristics of the 1MTPJ included range of motion (ROM), plantar- and dorsi-flexion force, foot posture, temperature and hallux valgus severity. RESULTS: Compared to controls, participants with gout reported greater 1MTPJ pain (p?=?0.014), greater foot pain and disability (p?<?0.001), increased odds of having disabling foot pain (odds ratio (OR) 13.4, p?<?0.001), decreased lower limb function for daily living (p?=?0.002) and recreational (p?<?0.001) activities, increased activity limitation (p?=?0.002), reduced overall wellbeing (p?=?0.034), reduced ROM (p?<?0.001), reduced plantarflexion force (p?=?0.012), increased 1MTPJ plantar (p?=?0.004), dorsal (p?=?0.003) and medial (p?=?0.004) temperature and had increased odds of having more severe hallux valgus (OR 0.3 p?=?0.041). Compared to controls, participants with asymptomatic hyperuricaemia had increased odds of having disabling foot pain (OR 4.2, p?=?0.013), increased activity limitation (p?=?0.033), decreased lower limb function for daily living (p?=?0.026) and recreational (p?=?0.010) activities, increased 1MTPJ plantarflexion force (p?=?0.004) and a more pronated foot type (p?=?0.036). CONCLUSIONS: People with gout demonstrate 1MTPJ-specific changes indicative of subclinical inflammation, even in the absence of acute arthritis. People with asymptomatic hyperuricaemia, who exhibit no features or symptoms of gout, also report high levels of foot- and lower limb-related pain and disability.

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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

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