Format

Send to

Choose Destination
Ann Rheum Dis. 2017 May;76(5):869-877. doi: 10.1136/annrheumdis-2016-209632. Epub 2016 Nov 29.

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

Author information

1
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
2
Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
3
Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
4
Department of Dermatology, National Defense Medical College, Tokorozawa, Saitama, Japan.
5
Department of Biochemisty, University of Otago, Dunedin, New Zealand.
6
Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
7
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
8
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
9
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
10
Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan.
11
Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
12
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
13
Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
14
Division of Transcriptomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
15
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
16
Ryougoku East Gate Clinic, Tokyo, Japan.
17
Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan.
18
Program in Radiological and Medical Laboratory Sciences, Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
19
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
20
First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Institute of Inherited Metabolic Disorders, Prague, Czech Republic.
21
Institute of Rheumatology, Prague, Czech Republic.
22
Department of Medicine, University of Otago, Christchurch, New Zealand.
23
Department of Medicine, University of Auckland, Grafton, Auckland, New Zealand.
24
Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
25
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
26
Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
27
Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan.
28
Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
29
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
30
Midorigaoka Hospital, Takatsuki, Osaka, Japan.
31
Kyoto Industrial Health Association, Kyoto, Japan.
32
Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

Abstract

OBJECTIVE:

A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.

METHODS:

Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.

RESULTS:

In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8).

CONCLUSIONS:

Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

KEYWORDS:

Arthritis; Gene Polymorphism; Gout

PMID:
27899376
PMCID:
PMC5530361
DOI:
10.1136/annrheumdis-2016-209632
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center