Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations.A pproximately one half of childhood hearing loss is thought to have a genetic aetiology, the majority of which is non-syndromic and not associated with abnormalities of other organ systems. Estimates from clinical and epidemiological studies suggest that 80-85% of hereditary, non-syndromic, prelingual deafness is autosomal recessive, 15% is autosomal dominant, and a few percent is inherited as an X linked trait or via matrilineal transmission.

P-glycoprotein (PGP) is a polymorphic transporter encoded by the ABCB1 gene that contributes to the access of xenobiotics into the brain. There is no report on associations between genetic polymorphisms in ABCB1 and the clinical effects of fentanyl, although fentanyl may be a substrate of PGP. One hundred and twenty-six (126) unrelated Korean patients under spinal anesthesia with intravenous fentanyl (2.5 microg/kg) were recruited. Clinical effects (bispectral index, respiration rate, and need for oxygen supplementation) were monitored and these were compared between genotypes for three single nucleotide polymorphisms in ABCB1 (1236C>T, 2677G>T/A, and 3435C>T). The allele and genotype frequencies were similar to previous data from Asians; the three major haplotypes, TTT (30%), TGC (24%), and CGC (24%) were expected among nine known haplotypes. During the initial 10 min, there were differences in suppression of respiration rate by fentanyl among the three genotypes (P=0.0933 for 1236C>T; P=0.0941 for 2677G>A/T; P=0.0013 for 3435C>T, repeated-measures analysis of variance), but the differences in bispectral index among genotypes were not observed. Furthermore, patients carrying the linked 3435T and 2677T alleles showed a significant difference in the level of respiratory suppression (P=0.0056); those with genotypes susceptible to fentanyl (1236TT, 2677TT, and 3435TT) showed early (2-3 min) and profound suppression of respiration (65-73% of initial respiration rate) compared with other resistant genotypes (83-85% of initial respiration rate in 1236CC, 2677GG, and 3435CC). Although the need to supply oxygen was not significantly different between genotypes, there was a trend for increased demand by patients carrying both 1236T and 3435T alleles (P=0.0847). In conclusion, our results confirm ABCB1 genotype data for Koreans and suggest that analysis of ABCB1 polymorphisms may have clinical relevance to prevent respiratory suppression by intravenous fentanyl or to anticipate its clinical effects.

Toll-like receptors (TLRs) are innate immune mediators that stimulate nuclear factor kappa B and the inflammatory cytokines. TLR1 is expressed in renal tubular epithelial cells when the kidney is injured, but the role of TLR1 gene in glomerulonephritis has not been clearly elucidated. We aimed to investigate the association of TLR1 polymorphisms with immunoglobulin A nephropathy (IgAN) in children. One hundred and ninety pediatric patients with biopsy-proven IgAN and 283 healthy control subjects were enrolled. Two single nucleotide polymorphisms of TLR1 gene [rs4833095 (missense, Asn248Ser) and rs5743557 (promoter, -414C/T)] were selected and genotyped by direct sequencing. For rs4833095, the C/T genotype in the codominant model (vs. the T/T genotype) [odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.21-3.69, P = 0.009] and the genotype containing C allele (C/T and C/C) in the dominant model (vs. the T/T genotype) (OR = 1.97, 95% CI: 1.16-3.34, P = 0.012) were associated with an increased risk of IgAN. For rs5743557, the T/T genotype in the codominant model (vs. the C/C genotype) (OR = 1.74, 95% CI: 1.02-2.96, P = 0.041) appeared to be associated with IgAN risk. In haplotype analysis, the CT haplotype revealed an association with IgAN (codominant model, OR = 1.38, 95% CI: 1.06-1.80, P = 0.017; dominant model, OR = 1.76, 95% CI: 1.16-2.67, P = 0.008). After Bonferroni correction, the association of the genotypes of rs4833095 and the CT haplotype with IgAN risk remained significant. These findings suggest that TLR1 gene polymorphisms may affect IgAN susceptibility in Korean children.

The haplotype frequencies among the five ethnic groups revealed that haplotype distributions in Koreans were similar to those of the Japanese and Chinese, but were quite different to those of the Africans and Europeans. These LD and haplotype data should be useful in drug development and in understanding genetic associations of CYP1A2 with adverse drug effects. These inter-ethnic differences in frequencies of SNPs and haplotypes may help to explain inconsistencies that have been reported in association studies and could contribute to predict the pharmacokinetics and pharmacodynamics of drugs that are metabolized by CYP1A2.

ABSTRACT. Alopecia areata (AA) is a common disease, which causes hair loss in humans. AA has a genetically complex inheritance. This study investigated the possible correlations between single nucleotide polymorphisms (SNPs) in the promoter regions of the chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) (CXCL1) and chemokine (C-X-C motif) ligand 2 (CXCL2) genes and the development of AA in the Korean population. Two hundred and thirtyfive AA patients and 240 control subjects were recruited. The specific SNPs occurring in the promoter regions of the CXCL1 and CXCL2 genes (rs3117604, -429C/T and rs3806792, -264T/C, respectively) were genotyped. All data obtained was evaluated using the SNPStats, SPSS 18.0, and the Haploview v.4.2 software platforms. The Odd's ratios (OR), 95% confidence intervals (CI), and P values were calculated using multiple logistic regression models. Analyses of the genetic sequences obtained revealed a significant correlation between the two SNPs and the development of AA (rs3117604, P = 0.0009 in co-dominant model 1, P = 0.01 in co-dominant model 2, P = 0.004 in the dominant model, P = 0.005 in the log-additive model, P = 0.012 in allele distribution; rs3806792, P = 0.036 in co-dominant model 2, P = 0.0046 in the logadditive model). The TT and CC haplotypes were also observed to show a significant association with increased risk of AA (TT haplotype, P = 0.0018; CC haplotype, P = 0.0349). Our data suggests that the CXCL1 and CXCL2 genes may be associated with AA susceptibility.