Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels

Tin, Adrienne; Li, Yong; Brody, Jennifer A.; Nutile, Teresa; Chu, Audrey Y.; Huffman, Jennifer E.; Yang, Qiong; Chen, Ming-Huei; Robinson‐Cohen, Cassianne; Macé, Aurélien; Liu, Jun; Demirkan, Ayşe; Sorice, Rossella; Sedaghat, Sanaz; Swen, Melody; Yu, Bing; Ghasemi, Sahar; Teumer, Alexander; Vollenweider, Péter; Ciullo, Marina; Li, Meng; Uitterlinden, André G.; Kraaij, Robert; Amin, Najaf; Rooij, Jeroen van; Kutalik, Zoltán; Dehghan, Abbas; McKnight, Barbara; Duijn, Cornelia M. van; Morrison, Alanna C.; Psaty, Bruce M.; Boerwinkle, Eric; Fox, Caroline S.; Woodward, Owen M.; Köttgen, Anna

doi:10.1038/s41467-018-06620-4

Cited by 51 publications

(47 citation statements)

References 68 publications

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“…Recently, large scale WES using 19,517 participants (15,821 European Ancestry and 3,696 African Ancestry) identified that novel variants of SLC22A12 and SLC2A9 49 . It is obvious that variants of lowering UA is different by ethnic group in the same genes.…”

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

Cha

Gee²,

Cachau

et al. 2018

Preprint

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Running head:The genetic predisposition of hypouricemia Word count: Abstract 215; text 3,805 AbstractDifferentiating between inherited renal hypouricemia and transient hypouricemia is challenging. Here, we aimed to describe the genetic predisposition of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis in primary screening. WES was performed for the discovery of diagnostic markers in discovery cohorts (N=31). Two known genetic markers SLC22A12 c.774G>A (p.Trp258*) and SLC22A12 c.269G>A (p.Arg90His) were identified, We genotyped for the 2 SLC22A12 SNPs among screened 50 hypouricemia subjects for the replication cohorts; 47 carried known SLC22A12 markers; three unexplained hypouricemic cases were analyzed by using WES. We used 46 healthy internal controls for the variant discovery. Four novel variants of SLC22A12, c.408C>A (p.Asn136Lys), c.674C>A (p.Thr225Lys), c.851G>A (p.Arg284Gln), and c.1285G>A (p.Glu429Lys), and one novel variant of SLC2A9, c. 376A>G (p.Met155Val), were identified. After filtering out known genes (SLC22A12 and SLC2A9), the p.Arg78His variant in ASB12 was overlapped in two unexplained conditions. This is the first attempt to investigate the effectiveness of integrating exome sequencing and genotype into the clinical care for hypouricemia and determine the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two SNPs (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of patients with hypouricemia. Early identification and intervention of hypouricemia is feasible using genetic screening to prevent acute kidney injury, especially for soldiers and athletics. Keywords: SLC22A12, SLC2A9, hypouricemia, screening testto the East Asian populations. Prevalence of hypouricemia is reported as 0.53% in Korea 13 which is similar to data from the west part of Japan. Japanese data reported a geometric difference in its prevalence (0.579% of West Japanese and 0.191% of East Japanese) 14 .Differentiating between inherited and transient hypouricemia is challenging because a low level of UA reflects malnutrition status 15 . Moreover, a genetic utility for the diagnosis has not been conducted so far.In this study, we investigated the genetic features of subjects with extremely low levels of UA using wholeexome sequencing (WES). Many exome-based studies have been able to detect the loss-of-function variants, missense variants and other types of variants due to changes in the triplet codon on particular genetic loci, especially in diseases with high heritability and low prevalence [16][17][18] . After the discovery of targeted SNPs, genetic diagnostic feasibility will be assessed in the different cohorts. MATERIALS AND METHODS Study participantsThis study was approved by the institutional review board of the Kangbuk Samsung Hospital (IRB# KBSMC 2016-12-016). We screened the subjects in the Korean genome and epidemiology study (KoGES) -KoGES health examinee study (Urban Cohort) and KoGES twin and family study. Out ...

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Section: Discussionmentioning

confidence: 99%

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

Cha

Gee²,

Cachau

et al. 2018

Preprint

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“…In some autoinflammatory diseases, the disease mechanism even appeared to be monogenic due to rare causal variants detected in a single gene 23. For serum urate-associated loci and gout, it has also been shown that rare variants contribute to disease pathogenesis 24 25. However, statistical confirmation of rare variants requires high-quality in-depth sequencing and large sample sizes, which is not the case for most GWAS performed to date in gout patients 26–28.…”

Section: Introductionmentioning

confidence: 99%

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Klück

Deuren

Cavalli³

et al. 2020

Annals of the Rheumatic Diseases

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ObjectiveGout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.MethodsVariant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.ResultsWe identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.ConclusionHere, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

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“…As for the rare variants, both single locus and aggregation analysis confirmed increased risk for hypouricemia although they had no significant protection against HUA. These results imply that rare variants have greater impact on urate transportation and may serve as potential targets for urate transporter blocker, which is substantiated by the recent whole‐exome sequencing association studies (Tin et al, ).…”

Section: Discussionmentioning

confidence: 63%

Amplicon targeted resequencing for SLC2A9 and SLC22A12 identified novel mutations in hypouricemia subjects

Zhou

Wang

Zhou

et al. 2019

Molec Gen & Gen Med

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Background To identify potential causative mutations in SLC2A9 and SLC22A12 that lead to hypouricemia or hyperuricemia (HUA). Methods Targeted resequencing of whole exon regions of SLC2A9 and SLC22A12 was performed in three cohorts of 31 hypouricemia, 288 HUA and 280 normal controls. Results A total of 84 high‐quality variants were identified in these three cohorts. Eighteen variants were nonsynonymous or in splicing region, and then included in the following association analysis. For common variants, no significant effects on hypouricemia or HUA were identified. For rare variants, six single nucleotide variations (SNVs) p.T21I and p.G13D in SLC2A9 , p.W50fs, p.Q382L, p.V547L and p.E458K in SLC22A12, occurred in totally six hypouricemia subjects and were absent in HUA and normal controls. Allelic and genotypic frequency distributions of the six SNVs differed significantly between the hypouricemia and normal controls even after multiple testing correction, and p.G13D in SLC2A9 and p.V547L in SLC22A12 were newly reported. All these mutations had no significant effects on HUA susceptibility, while the gene‐based analyses substantiated the significant results on hypouricemia. Conclusion Our study first presents a comprehensive mutation spectrum of hypouricemia in a large Chinese cohort.

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Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels

Cited by 51 publications

References 68 publications

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Amplicon targeted resequencing for SLC2A9 and SLC22A12 identified novel mutations in hypouricemia subjects

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