Variants In Asian Populations Research Articles

Contribution of infectious diseases to the selection of ADH1B and ALDH2 gene variants in Asian populations.

The gene variants ADH1B*2 (Arg48His, rs1229984) and ALDH2*2 (Glu504Lys, rs671) are common in East Asian populations but rare in other populations. We propose that selective pressures from pathogen exposure and dietary changes during the neolithic transition favored these variants. Thus, their current association with differences in alcohol sensitivity likely results from phenotypic plasticity rather than direct natural selection. Samples sourced from the Allele Frequency Database (ALFRED) were utilized to compute the average frequency of ADH1B*2 and ALDH2*2 across 88 and 61 countries, respectively. Following computation of the average national allele frequencies, we tested the significance of their correlations with ecological variables. Subsequently, we subjected them to Principal Component Analysis (PCA) and Elastic Net regularization. For comprehensive evaluation, we collected individual-level phenotypic associations, compiling a Phenome-Wide Association Study (PheWAS) spanning multiple ethnicities. Following multiple testing correction, ADH1B*2 displayed significant correlations with Neolithic transition timing (r = 0.405, p.adj = 2.013e-03, n = 57) and historical trypanosome burden (r = -0.418, p.adj = 0.013, n = 57). The first two components of PCA explained 47.7% of the total variability across countries, with the top three contributors being the historical indices of population density and trypanosome and leprosy burdens. Historical burdens of the Mycobacteria tuberculosis and leprosy were the sole predictive variables with positive coefficients that survived Elastic Net regularization. Our analyses suggest that Mycobacteria may have played a role in the joint selection of ADH1B*2 and ALDH2*2, expanding the "toxic aldehyde hypothesis" to include Mycobacterium leprae. Additionally, our hypothesis, linked to dietary shifts from rice domestication, emphasizes nutritional deficiencies as a key element in the selective pressure exerted by Mycobacteria. This offers a plausible explanation for the high frequency of ADH1B*2 and ALDH2*2 in Asian populations.

The power of representation: Statistical analysis of diversity in US Alzheimer's disease genetics data.

Alzheimer's disease (AD) is a complex disease influenced by genetics and environment. More than 75 susceptibility loci have been linked to late-onset AD, but most of these loci were discovered in genome-wide association studies (GWAS) exclusive to non-Hispanic White individuals. There are wide disparities in AD risk across racially stratified groups, and while these disparities are not due to genetic differences, underrepresentation in genetic research can further exacerbate and contribute to their persistence. We investigated the racial/ethnic representation of participants in United States (US)-based AD genetics and the statistical implications of current representation. We compared racial/ethnic data of participants from array and sequencing studies in US AD genetics databases, including National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and NIAGADS Data Sharing Service (dssNIAGADS), to AD and related dementia (ADRD) prevalence and mortality. We then simulated the statistical power of these datasets to identify risk variants from non-White populations. There is insufficient statistical power (probability <80%) to detect single nucleotide polymorphisms (SNPs) with low to moderate effect sizes (odds ratio [OR]<1.5) using array data from Black and Hispanic participants; studies of Asian participants are not powered to detect variants OR <= 2. Using available and projected sequencing data from Black and Hispanic participants, risk variants with OR = 1.2 are detectable at high allele frequencies. Sample sizes remain insufficiently powered to detect these variants in Asian populations. AD genetics datasets are largely representative of USADRDburden. However,there is a wide discrepancy between proportional representation and statistically meaningful representation.Most variation identified in GWAS of non-Hispanic White individuals have low to moderate effects. Comparable risk variants in non-White populations are not detectable given current sample sizes, which could lead to disparities in future studies and drug development. We urge AD genetics researchers and institutions to continue investing in recruiting diverse participants and use community-based participatory research practices.

Bilirubin metabolism and UDP-glucuronosyltransferase 1A1 variants in Asians: Pathogenic implications and therapeutic response.

In the Asian general population, at least six single-nucleotide variants (SNVs) in the UDP-glucuronosyltransferase (UGT) 1A1 gene have been identified: -3279T>G, -53A(TA)6 TAA>A(TA)7 TAA, 211G>A, 686C>A, 1091C>T, and 1456T>G. Each of these six SNVs was observed in at least four ethnic groups of the 12 Asian populations studied. In East Asian populations, the descending frequency of these six SNVs was as follows: -3279G>[-53A(TA)7 TAA, 211A]>(686A, 1091T)>1456G. Because of the presence of linkage disequilibrium and the expulsion phenomenon, when the SNVs -3279G, -53A(TA)7 TAA, 211A, and 686A were simultaneously involved, 15 instead of the estimated 81 genotypes were observed. Those carrying 686AA or 1456GG developed Gilbert's syndrome or Crigler-Najjar syndrome type 2. Both -53A(TA)7 TAA/A(TA)7 TAA and 211AA are the main causes of Gilbert's syndrome in East Asian populations. In East Asian populations, the 211AA genotype is the main cause of neonatal hyperbilirubinemia, whereas -53A(TA)7 TAA/A(TA)7 TAA exerts a protective effect on hyperbilirubinemia development in neonates fed with breast milk. Both 211A and -53A(TA)7 TAA are significantly associated with adverse drug reactions induced by irinotecan (one of the most widely used anticancer agents) in Asians. However, at least three common SNVs (-3279G, -53A(TA)7 TAA, and 211A) should be comprehensively analyzed. This study investigated the clinical significance of these six SNVs and demonstrated that examining UGT1A1 variants in Asian populations is considerably challenging.

Penetrance of Parkinson disease LRRK2 G2385R-associated variant in the Chinese population.

Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population. The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009-2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face-to-face PD assessment during 2020-2021. The penetrance of PD was estimated by the Kaplan-Meier method. A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers (p= 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural. The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age-related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.

The Contribution of Deleterious Rare Alleles in ENPP1 and Osteomalacia Causative Genes to Atypical Femoral Fracture.

Atypical femoral fractures (AFFs) are very rare atraumatic or mild trauma fractures in the subtrochanteric region or femoral shaft. Some unique genetic variants in Asian populations might confer susceptibility to AFF, since the incidence of AFFs is higher in Asian populations. Because rare variants have been found to be causative in some diseases and the roles of osteomalacia causative genes have not been reported, we investigated rare variants in genes causing abnormal mineralization. Exome sequencing was performed to detect variants in gene coding and boundary regions, and the frequencies of deleterious rare alleles were compared between Japanese patients with AFF (n = 42) and controls of the 4.7KJPN panel of Tohoku Medical Megabank by whole genome sequencing (n = 4773). The frequency of the deleterious rare allele of ENPP1 was significantly increased in AFF (P = .0012, corrected P [Pc] = .0155, OR 4.73, 95% CI 2.15-10.40). In multigene panel analysis, the frequencies of deleterious rare alleles of candidate genes were increased in AFF (P = .0025, OR 2.72, 95% CI 1.49-4.93). Principal component analysis of bone metabolism markers identified a subgroup of patients with AFF with higher frequencies of deleterious rare alleles in ENPP1 (P = 4.69 × 10-5, Pc = .0006, OR 8.47, 95% CI 3.76-19.09) and the candidate genes (P = 1.08 × 10-5, OR 5.21, 95% CI 2.76-9.86). AFF is associated with genes including ENPP1 that cause abnormal mineralization, suggesting that osteomalacia is an underlying condition predisposing to AFF and that higher incident rates of AFFs in Asian populations might be explained by the genetic risk factors including ENPP1.

Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6β-Hydroxylation.

CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone). The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment. The kinetic parameters of midazolam and testosterone hydroxylation by wild-type CYP3A4 and 29 CYP3A4 variants (K m , k cat , and catalytic efficiency) were determined, and the causes of their kinetic differences were evaluated by three-dimensional structural modeling. Our findings offer insight into the mechanism underlying interindividual differences in CYP3A4-dependent drug metabolism. Moreover, our results provide guidance for improving drug administration protocols by considering the information on CYP3A4 genetic polymorphisms. SIGNIFICANCE STATEMENT: CYP3A4 metabolizes more than 30% of clinically used drugs. Interindividual differences in drug efficacy and adverse-effect rates have been linked to ethnicity-specific differences in CYP3A4 gene variants in Asian populations, including Japanese individuals, indicating the presence of CYP3A4 polymorphisms resulting in the increased expression of loss-of-function variants. This study detected alterations in CYP3A4 activity due to amino acid substitutions by assessing the enzymatic activities of coding variants for two representative CYP3A4 substrates.

&lt;i&gt;CYP2D6&lt;/i&gt; Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase 2 Study

Background: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. There is a high frequency of CYP2D6 decreased-function variant in Asian populations. Therefore, we prospectively evaluated whetherCYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact in the clinical outcome. Methods: In this randomized, open-label, multicenter, phase 2 study, patients who needed first-line tamoxifen therapy were enrolled in Japan. Based on individual CYP2D6 genotype, patients heterozygous (wt/V) or homozygous (V/V) for variant alleles of decreased or no-function were randomly assigned (1:1) to tamoxifen at increased dose (40 mg daily, ID arm) or regular dose (20 mg daily, RD arm), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was progression-free survival (PFS) rate at 6-month. The secondary endpoints included PFS and correlation of (Z)-endoxifen concentration with clinical outcomes. Findings: Between December 2012 and July 2016, 186 patients were enrolled. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6-month were not significantly different between ID and RD arms (67·6% vs. 66·7%). The serum trough concentrations of (Z)-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89·2 nM vs. 51·1 nM; P < 0.0001) and were also higher compared with wt/wt patients (72·0 nM; P = 0·0452). No significant difference in (Z)-endoxifen concentrations was observed between patients with and without progression at 6-month (p = 0·43). Interpretation: In patients with CYP2D6 variant alleles, increasing tamoxifen dosing did not achieve higher PFS rate at 6-month. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen. Clinical Trial Number: This study is registered with UMIN Clinical Trials Registry, number UMI09155. Funding Statement: This study was supported by grants from the Project for Development of Innovative Research on Cancer Therapeutics and from the Tailor-made Medical Treatment Program (BioBank Japan Project) funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the AMED under Grant Number 17ck0106191h0003). Declaration of Interests: YF reports grants from the Japan Agency for Medical Research and Development (AMED). MK reports grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). KT reports grants from AstraZeneca and Daiichi-Sankyo outside the submitted work. CKI, MT, and YT report personal fees from AstraZeneca outside the submitted work. TT and JT report grants and personal fees from Daiichi-Sankyo outside the submitted work. SS reports grants and personal fees from AstraZeneca, and personal fees from Daiichi-Sankyo outside the submitted work. TY and YF report personal fees from AstraZeneca and Daiichi-Sankyo outside the submitted work. NTU reports grants from Daiichi-Sankyo outside the submitted work. YT reports personal fees from Meiji Seika Pharma outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: We obtained written informed consent from each patient before participation. The trial followed the ethical principles of the Declaration of Helsinki and Japanese Ethical Guidelines and Clinical Research. This study protocol and any amendments thereof were approved by an independent Ethics Committee or Institutional Review Board at each institution.

Body mass index modulates the association between CDKAL1 rs10946398 variant and type 2 diabetes among Taiwanese women

CDKAL1 rs10946398 is a type 2 diabetes (T2D)-associated variant. It is a new body mass index (BMI)-associated variant in Asian populations. We investigated the association between rs10946398 and T2D among 9908 participants aged 30–70 years based on BMI: normal weight; 18.5 ≤ BMI < 24 kg/m2, overweight; 24 ≤ BMI < 27 kg/m2, and obesity; BMI ≥27 kg/m2. The CC genotype conferred a higher risk of T2D than the CA genotype. The odds ratios (ORs) were 1.83; 95% confidence interval (CI) 1.49–2.26 and 1.20; 95% CI 1.02–1.40, respectively. The C allele was the significant risk allele compared with A allele (OR = 1.32; 95% CI 1.19–1.47). For normal, overweight and obese participants with CC genotype, the ORs were respectively 1.69; 95% CI 1.02–2.81, 2.34; 95% CI 1.50–3.66, and 1.58; 95% CI 1.02–2.45 among men and 1.22; 95% CI 0.67–2.22, 2.42; 95% CI 1.30–4.52, and 2.3; 95% CI 1.19–4.50 among women. The C allele ORs were higher in obese and overweight women. In conclusion, the rs10946398 CC/CA genotypes, as well as the C allele increased the risk of T2D. The ORs were higher in women who were overweight and obese than in those with normal weight. Nonetheless, significant results were prominent only among those with CC genotype and C allele.

P154 Complete sequence-based NUDT15 and TPMT variants for predicting thiopurine-induced leukopenia in patients with Crohn's disease

Background: Thiopurine-induced leukopenia is a life-threatening complication in Asians. Other than previously known thiopurine S-methyltransferase (TPMT) mutation, the NUDT15 genetic variant was recently identified to have a strong association with thiopurine-induced leukopenia. We investigated the association of NUDT15, TPMT, metabolites of thiopurines on leukopenia in patients with Crohn's disease (CD). Methods: We investigated the data of 168 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were performed every 1–3 months. We carried out a complete sequencing analysis for evaluating NUDT15 and TPMT variants and measured thiopurine metabolites levels. Results: Of 168 patients, 34 patients (20.2%) had NUDT15 variant alleles. NUDT15 heterozygous variants were found in 28 patients (16.7%) and NUDT15 homozygous variants were found in 6 patients (3.6%). Among the 168 patients, 35 (20.8%) patients experienced leukopenia during first year of thiopurine treatment. NUDT15 variant types were strongly associated with developing leukopenia [10.9% wild type as reference; 48.5% heterozygous variant genotype; 100% homozygous variant genotype, odds ratio (OR) 3.44 (95% CI, 1.21–9.78)]. Table 1. The risk of leukopenia according to NUDT15 and TPMT genotype However, TPMT genotype was not associated with developing leukopenia (OR 0.58, 95% CI 0.07–4.96). Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with average 88.2% (range, 84–94%) reduction from baseline WBC count at 4 weeks. Figure 1. WBC count as a percentage of baseline at 4 weeks after thiopurines treatment. In subgroup of NUDT15 variant type, there was no significant difference of 6-TGN levels between patients with and without leukopenia [298.5 (205–407) vs. 280.8 (174–327) pmol/8×108 RBC, p=0.344]. Table 2. Thiopurine metabolites levels and thiopurine-induced leukopenia in NUDT15 variant genotype subgroup Conclusions: This is the first complete sequence-based analysis for NUDT15 variants in Asian populations. Our findings suggest that NUDT15 genotype should be detected rather than TPMT before initiating thiopurines. Thiopurines treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.

Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite.

Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for the treatment of rheumatoid arthritis and osteoarthritis. The predominant hepatic metabolism of celecoxib to celecoxib carboxylic acid (CCA) is mediated mainly by CYP2C9. We investigated the effects of the major CYP2C9 genetic variants in Asian populations, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in healthy Korean subjects. A single 200-mg oral dose of celecoxib was given to 52 Korean subjects with different CYP2C9 genotypes: CYP2C9EM (n=26; CYP2C9*1/*1), CYP2C9IM (n=24; CYP2C9*1/*3 and *1/*13), and CYP2C9PM (n=2; CYP2C9*3/*3). Celecoxib and CCA concentrations in plasma samples collected up to 48 or 96h after drug intake were determined by HPLC-MS/MS. The mean area under the plasma concentration-time curve (AUC0-∞) of celecoxib was increased 1.63-fold (P<0.001), and the apparent oral clearance (CL/F) of celecoxib was decreased by 39.6% in the CYP2C9IM genotype group compared with that of CYP2C9EM (P<0.001). The overall pharmacokinetic parameters for celecoxib in CYP2C9*1/*13 subjects were similar to those in CYP2C9*1/*3 subjects. Two subjects with CYP2C9PM genotype both showed markedly higher AUC0-∞, prolonged half-life, and lower CL/F for celecoxib than did subjects with CYP2C9EM and IM genotypes. CYP2C9*3 and CYP2C9*13 variant alleles significantly affected the plasma concentration of celecoxib.

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men.

The *2 allele of the aldehyde dehydrogenase 2 gene (ALDH2) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. A case-control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. ALDH2 genotypes differed significantly between male controls (*1/*1 versus *1/*2 versus *2/*2=53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (*1/*1 versus *1/*2 versus *2/*2=51.5% versus 37.3% versus 11.2%; P=0.048). No significant difference was found between groups for female patients (P=0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07-3.46]; P=0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women.

Complete sequence-based screening of TPMT variants in the Korean population.

Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs and its activity is largely influenced by polymorphisms of the TPMT gene. To date, more than 35 TPMT variants are known to be associated with reduced enzyme activity, but most studies on the TPMT genotype have included only common nonfunctional variants, such as TPMT*2 and TPMT*3. In this study, we carried out a complete sequencing analysis to screen all TPMT variants in Korean patients. A total of 900 Korean patients were genotyped for TPMT and 30 patients (3.3%) had the known TPMT variant alleles. TPMT*3C was found in 25 patients (2.8%): 24 patients with TPMT*1/*3 and one with TPMT*3/*3. Rare TPMT variants including TPMT*6, TPMT*16, and TPMT*32 were detected in five patients (0.6%) and a novel variant, TPMT*38 (c.514T>C, p.S172P), was identified in two patients. This is the first complete sequence-based screening study evaluating all TPMT variants in Asian populations.

Distribution of CYP2C9*13 allele in the Chinese Han and the long‐range haplotype containing CYP2C9*13 and CYP2C19*2

Cytochrome P450 2C9 (CYP2C9) and CYP2C19, located in tandem on chromosome 10q23-24, are known as genetically polymorphic. CYP2C9*13 is an important CYP2C9 variant in Asian populations, and is correlated with the reduced plasma clearance of some clinically important drugs. In this research, the allele frequency of CYP2C9*13 was determined to be 0.42% (95% CI of 0.17% to 0.86%) in 839 Chinese Han, male subjects. All detected subjects with CYP2C9*13 carry the CYP2C19*2 allele, too. Sequencing results infer the CYP2C9*13 haplotype, which contains eight linked SNPs, originates from the CYP2C9*1B haplotype group. CYP2C9*1B has been reported to be linked with CYP2C19*2. These indicate a long-range haplotype containing the CYP2C9*13 and CYP2C19*2 mutation, which means most CYP2C9*13 carriers will carry the CYP2C19*2 allele and the six SNPs of the CYP2C9*1B haplotype group, and may have more reduced intrinsic clearance of drugs such as phenytoin, tolbutamide and chlorpropamide that are metabolized by both CYP2C9 and CYP2C19.

Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy-Weinberg equilibrium in controls (P<0.01). In all, 7/46 SNPs in 6 genes (ICAM1, IL1A, IL17RC, IL13, LTA and TNF) were associated with severe malaria, with 3/7 SNPs in the TNF/LTA region. Genotype-phenotype correlations between SNPs and clinical parameters revealed that genotypes of rs708567 (IL17RC) correlate with parasitemia (P=0.028, r(2)=0.0086), with GG homozygotes having the lowest parasite burden. Additionally, rs708567 GG homozygotes had a decreased risk of severe malaria (P=0.007, OR=0.78 (95% CI; 0.65-0.93)) and death (P=0.028, OR=0.58 (95% CI; 0.37-0.93)) than those with AA and AG genotypes. In summary, variants in six genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Further replicative studies in independent populations will be necessary to confirm these findings.

Letter to the Editor Case-control investigations of a DRD2 missense variant in Asian populations: more noise, less signal

Letter to the Editor Case-control investigations of a DRD2 missense variant in Asian populations: more noise, less signal

Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.