Format

Send to

Choose Destination
Diabetologia. 2017 Jan;60(1):107-115. Epub 2016 Oct 15.

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals.

Author information

1
Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
2
Department of Surgery, University of Hong Kong, Hong Kong, People's Republic of China.
3
State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, People's Republic of China.
4
Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, People's Republic of China.
5
Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, People's Republic of China.
6
School of Public Health, Room 505, Faculty of Medicine Building, William M.W. Mong Block, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China.
7
Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China.
8
Department of Psychiatry, University of Hong Kong, Hong Kong, People's Republic of China.
9
Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
10
School of Public Health, Room 505, Faculty of Medicine Building, William M.W. Mong Block, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China. hrmrlth@hku.hk.
11
Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China. hrmrlth@hku.hk.
12
Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China. hftse@hkucc.hku.hk.
13
Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong, Hong Kong, People's Republic of China. hftse@hkucc.hku.hk.
14
Department of Psychiatry, University of Hong Kong, Hong Kong, People's Republic of China. pcsham@hku.hk.
15
Centre for Genomic Sciences, Centre for Genomic Sciences, University of Hong Kong, 6/F, HKJC Building for Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China. pcsham@hku.hk.
16
State Key Laboratory in Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, People's Republic of China. pcsham@hku.hk.
17
Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China. ksllam@hku.hk.
18
State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, People's Republic of China. ksllam@hku.hk.
19
Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, People's Republic of China. ksllam@hku.hk.

Abstract

AIMS/HYPOTHESIS:

Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population.

METHODS:

An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed.

RESULTS:

In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (p discovery < 6.45 × 10-7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (p meta-analysis [p meta] = 3.74 × 10-15) in the combined analysis.

CONCLUSIONS/INTERPRETATION:

We identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings suggest PAX4 is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.

KEYWORDS:

Asian-specific; Exome-chip association analysis; PAX4; Type 2 diabetes

PMID:
27744525
DOI:
10.1007/s00125-016-4132-z
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center