Association of genetic variants in GABRA3 gene and thyrotoxic hypokalaemic periodic paralysis in Thai population.
BACKGROUND
Genetic predisposition has been suggested to play role in the pathogenesis of thyrotoxic hypokalaemic periodic paralysis (THPP).


OBJECTIVE
In this study, we assessed the differences of single-nucleotide polymorphisms (SNP) allelic frequency between THPP patients and well-characterized controls in order to find the susceptibility genetic variants related to THPP using microarray-based assessments on pooled DNA.


METHODS
Fifty cases of THPP and 50 male hyperthyroid patients without hypokalaemia as controls were recruited. Equal amounts of individual genomic DNA were pooled from each group. Estimated allele frequencies of SNPs were derived by averaging relative allele signal score obtained by Affymetrix GeneChip(R) Mapping 10K Arrays.


RESULTS
Sixty-nine loci that display robust allele frequency differences between THPP and controls were identified. SNP rs750841 (A > T) in intron 3 of the gamma-aminobutyric acid (GABA) receptor alpha3 subunit (GABRA3) gene possessed the most significant difference in allele frequency (27% in THPP case and 5% in controls, P = 0.007). Actual allele frequencies obtained from genotyping in each individual were very similar to the estimated frequency from the pools (28% in THPP and 2% in controls, and P = 0.0002). Nearby DNA sequences of GABRA3 were sequenced and an additional two SNPs were found (A > C at exon 1 and G > T of rs12688128). Allele A of rs750841 and allele G of rs12688128 in intron 3 were predominantly found in THPP with significant genetic relative risk of 19 (P < 0.0002; 95%CI 2.4-151.6).


CONCLUSIONS
Whole-genome scanning on pooled DNA provides an accurate, useful screening tool for elucidating genetic underpinnings of THPP. SNPs at intron 3 of GABRA3 are found to be associated with THPP.
Jongjaroenprasert
Wallaya
W
Endocrine and Metabolism unit, Ramathibodi Hospital, Mahindol University, Bangkok, Thailand. rawjj@mahidol.ac.th
Chanprasertyotin
Suwannee
S
Butadej
Siriwan
S
Nakasatien
Soontaree
S
Charatcharoenwitthaya
Natthinee
N
Himathongkam
Thep
T
Ongphiphadhanakul
Boonsong
B
D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D007008:Hypokalemia; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*; D013785:Thailand; D013958:Thyroid Crisis / Q000235:genetics
C546257:GABRA3 protein, human; D011963:Receptors, GABA-A