Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population

Tanikawa, Chizu; Kamatani, Yoichiro; Terao, Chikashi; Usami, Masayuki; Takahashi, Atsushi; Momozawa, Yukihide; Suzuki, Kichiya; Ogishima, Soichi; Shimizu, Atsushi; Satoh, Mamoru; Matsuo, Keitaro; Mikami, Haruo; Naito, Mariko; Wakai, Kenji; Yamaji, Taiki; Sawada, Norie; Iwasaki, Motoki; Tsugane, Shoichiro; Kohri, Kenjiro; Yu, Alan; Yasui, Takahiro; Murakami, Yoshinori; Kubo, Michiaki; Matsuda, Koichi

doi:10.1681/asn.2018090942

Cited by 33 publications

(51 citation statements)

References 66 publications

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“…1). DNA samples from 8,026 uterine leiomyoma patients and 52,824 controls that were genotyped in a previous analysis 25 were used in stage 2. A Manhattan plot of the meta-analysis (Stage1 and 2) is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

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Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10 −25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma. Uterine leiomyoma is one of the most common gynaecologic benign tumours. Its estimated lifetime risk is 30-50% in Japan 1 and 70-80% in European populations 2,3. Although leiomyoma is a benign neoplasm, patients exhibit many types of symptoms, such as vaginal bleeding, pelvic pain, or infertility 4. Over 600,000 hysterectomies were performed per year in the USA due to leiomyomas, and 9.4 billion dollars for annual medical expenses were needed in the USA 5. Therefore, leiomyomas are gaining much attention in health economics. Leiomyoma growth is stimulated by sex steroids, such as oestrogen and progesterone, and several aetiological factors, such as age, early age at menarche, obesity, and parity, are linked to an increased leiomyoma risk 2,6-11. In

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Section: Resultsmentioning

confidence: 99%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

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“…Given the number of non-synonymous mutation in the genes encoding for transporter proteins, it is very likely that pathogenic mutations can be present independently in more than one gene thus requiring a thorough experimental, genetic, and physiological investigation before supporting a non-canonical inheritance pattern. Interestingly, some of the genes associated with Mendelian diseases are also the site of relatively rare variants that confer increased susceptibility to common forms of renal diseases (nephrolithiasis, chronic kidney disease) [120][121][122].…”

Section: Digenic Inheritancementioning

confidence: 99%

Inherited Renal Tubulopathies—Challenges and Controversies

Iancu

Ashton

2020

Genes

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Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies.

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“…The reported etiology of urolithiasis is multifactorial involving environmental and genetic risk factors with heritability of 50% [5]. Only a few Genome Wide Association Studies (GWAS) are available regarding urolithiasis (predominantly from European and Japanese cohorts) that identified common genetic variants in various genetic loci regulating calcium and phosphate metabolism, urinary transporters and macromolecules among others, as urolithiasis associated risk factors [6,7]. The "common disease-common variant" paradigm stresses the small but significant risk contributed by common genetic variations in the development of complex genetic disorders like urolithiasis [8].…”

Section: Introductionmentioning

confidence: 99%

Osteopontin promoter polymorphisms and risk of urolithiasis: a candidate gene association and meta-analysis study

et al. 2020

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Background: Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population. Methods: A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis. Results: Three SPP1 promoter polymorphisms, rs2853744:G > T, rs11730582:T > C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744: G > T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed. Conclusions: In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G > T polymorphism after metaanalysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease.

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Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population

Cited by 33 publications

References 66 publications

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Inherited Renal Tubulopathies—Challenges and Controversies

Osteopontin promoter polymorphisms and risk of urolithiasis: a candidate gene association and meta-analysis study

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