Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer

The steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) gene plays a crucial role in androgen metabolism pathway in human prostate. It encodes SRD5A2 enzyme, which catalyses testosterone to dihydrotestosterone (DHT). DHT is the main active structure binding with androgen receptor (AR). After the activation of AR, it further regulates a series of target genes in androgen metabolism pathway. However, no clear consensus has been reached on the association between the SRD5A2 V89L, A49T and TA repeat polymorphisms and prostate cancer (PCa) risk. Thus, we performed a meta-analysis of 31 association studies with 14,726 PCa cases and 15,802 controls. We found no association between PCa and 89L compared with 89V allele [odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.98-1.06, P(heterogeneity) = 0.44]. The 49T allele showed a significantly elevated effect on the high stage (Stages III-IV) of PCa risk both under the dominant genetic model (OR = 2.13, 95% CI 1.44-3.15, P(heterogeneity) = 0.65) and in the contrast T versus A allele (OR = 2.06, 95% CI 1.41-3.02, P(heterogeneity) = 0.69). There was a significantly decreased association between PCa and long TA repeat as compared versus short TA repeat (OR = 0.86, 95% CI 0.74-1.00, P(heterogeneity) = 0.79). No significant between-study heterogeneity was found in all subjects under four genetic models (dominant model, recessive model, allele comparison and homozygosity comparison) for these three polymorphisms, respectively, so the fixed effects model was used to pool the result. Our result indicated that carriers of 49T might improve the risk of PCa in higher stages (Stages III-IV), carriers of long TA repeat might decrease the risk of PCa and 89L may not be an important risk factor for PCa. However, due to the limited sample sizes, this meta-analysis did not achieve sufficiently conclusive results. Still more well-designed studies should be performed to clarify the role of these three polymorphisms in the development of PCa.     

Her2 genotype and breast cancer progression in Korean women

The amplification and overexpression of Her2 proto-oncogene have been found to be associated with the development and progression of human breast cancer. A polymorphic valine allele at codon 655 of the Her2 gene (Her2(V655)) was suggested by some authors to be a susceptible genetic factor for the development of breast cancer. The Her2 polymorphism at codon 655 was investigated in 304 Korean women including 177 patients with breast cancer. The association between Her2 genotype and Her2 protein overexpression was also examined in breast cancers by immunohistochemistry. Her2(V655) was not associated with a significant breast cancer risk (odds ratio (OR), 1.792; 95% confidence interval (CI), 0.459-6.991). The frequency of homozygous or heterozygous valine allele increased in stage 2 patients (OR, 1.67; 95% CI, 0.67-4.19), and patients in stages 3 and 4 (OR, 3.36; 95% CI, 0.85-13.42) compared to patients in stage 0. However, an association between the presence of the valine allele and the overexpression of Her2 protein could not be demonstrated. These results suggest that Her2 polymorphism at codon 655 is not associated with the development of breast cancer in Korean women. However, there is a possibility that the valine allele at codon 655 might be related to increased risk of breast cancer progression.     

CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.

PURPOSE: The study's purpose was to understand the molecular basis for different clinical phenotypes of the 5T variant, a tract of 5 thymidines in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which disrupts processing of CFTR mRNA and reduces synthesis from the corresponding CFTR alleles. METHOD: We analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, Delta F508. Almost all Delta F508 mutation alleles occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. RESULTS: Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which we had clinical information, 17.6% of females (6/34) and 66.7% of males (10/15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42% or 5/12) and more than 80% (5/6) in males is 12TG-5T-470V. We also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. CONCLUSION: Overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype.     

Identification of a human member of the Ly-49 multigene family

Three classes of multigene family-encoded receptors enable NK cells to discriminate between polymorphic MHC class I molecules: Ly-49 homodimers, CD94/NKG2 heterodimers and the killer cell inhibitory receptors (KIR). Of these, CD94/NKG2 has been characterized in both rodents and humans. In contrast, Ly-49 family members have hitherto been found only in rodents, and KIR molecules only in the human. In this report, we describe a human cDNA, termed Ly-49L, that constitutes the first human member of the Ly-49 multigene family. Compared with rodent Ly-49 molecules, the Ly-49L sequence contains a premature stop codon and predicts a truncated protein that lacks the distal part of a C-terminal lectin domain. Evidence is presented that the premature stop codon results from incomplete excision of the intron between the first two lectin domain exons. Splice variants predicting a full-size Ly-49L protein were not detected. As demonstrated by Northern blot analysis, Ly-49L was transcribed by IL-2-activated NK cells, but not by freshly isolated B or T cells. PCR screening of a 22-clone yeast artificial chromosome contig localized the LY49L locus to the human NK gene complex on chromosome 12p12-p13. Southern blot analysis of genomic DNA showed a simple pattern with a full-length Ly-49L probe at low stringency hybridization conditions, suggesting that Ly-49L may be the only human member of the Ly-49 multigene family.     

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia

The chromosome 21q22.11 cytokine receptor cluster contains four genes that encode subunits of the receptors for the cytokines interleukin-10 and interferon-alpha, -beta and -gamma that may have a role in malaria pathogenesis. A total of 15 polymorphic markers located within these genes were initially genotyped in 190 controls and 190 severe malaria cases from The Gambia. Two interferon-alpha receptor-1 (IFNAR1) gene SNPs (17470 and L168 V) showed evidence for an association with severe malaria phenotypes and were typed in a larger series of samples comprising 538 severe malaria cases, 338 mild malaria cases and 562 controls. Both the 17470-G/G and L168V-G/G genotypes were associated with protection against severe malaria, in general, and cerebral malaria, in particular (P=0.004 and 0.003, respectively). IFNAR1 diplotypes were then constructed for these two markers using the PHASE software package. The (17470-G L168V-G/17470-G L168V-G) diplotype was found to be associated with a reduced risk of cerebral malaria and the (17470-C L168V-C/17470-G L168V-G) diplotype with an increased risk of cerebral malaria (overall 3 x 2 chi(2)=12.8, d.f.=2, P=0.002 and 3 x 2 chi(2)=15.2, d.f.=2, P=0.0005, respectively). These data suggest a role for the type I interferon pathway in resistance to cerebral malaria.     

Estrogen receptor codon 594 and HER2 codon 655 polymorphisms and breast cancer risk

The estrogen receptor (ER) and the human epithelial growth factor receptor 2 (HER2) genes have been implicated in the development and prognosis of breast cancer. Several genetic polymorphic sites in these genes have been identified and associated with the risk of breast cancer. We have investigated the association between the estrogen receptor codon 594 (ACA to ACG) and HER2 codon 655 (ATC to GTC) polymorphisms and breast cancer risk. Genomic DNA from breast cancer patients and control subjects was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). When allelic frequencies of the ER codon 594 and HER2 codon 655 gene were compared, no significant differences were observed between the patient and control groups. (P = 0.063, OR = 1.55, 95% CI = 0.25-9.41 and P = 0.949, OR = 1.01, 95% CI = 0.55-1.88, respectively). In conclusion, our results support the view that both the ER codon 594 and HER2 codon 655 polymorphisms are not associated with increased risk of breast cancer.     

Association of TGF-beta1 codon 25 (G915C) polymorphism with hepatitis C virus infection

Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infection (HCV), the production of abnormal cytokine levels appears to contribute to the progression of the disease, viral persistence, and affects response to therapy. Cytokine genes are polymorphic at specific sites, and certain polymorphisms located within coding/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of the present study was to identify potential markers of cytokines genes associated with the susceptibility to HCV infection. The cohort was composed of 128 individuals infected by HCV and 94 healthy controls. Genotyping was carried out by PCR-SSP. The distributions of the following polymorphisms were compared in these groups: TNF-alpha (-308G/A [rs1800629]), TGF-beta1 (codon 10 T/C [rs1982073], codon 25 G/C [rs1800471]), IL-10 (-1082 A/G [rs 1800896]; -819T/C [rs1800871]; -592A/C [rs 1800872]), IL-6 (-174G/C [rs1800795]), and IFN-gamma (+874T/A [rs2430561]). This study demonstrated a statistically significant difference in the frequency of TGF-beta1 codon 25 polymorphism between healthy subjects and those infected with HCV. No associations were observed between polymorphisms of TNF-alpha, IFN-gamma, IL-10, TGF-beta1 codon 10, and IL-6 and HCV infection. These findings suggest that TGF-beta1 codon 25 polymorphism could be a host genetic factor associated with susceptibility to HCV infection.     

CD31 mismatching affects marrow transplantation outcome.

Graft-versus-host disease (GVHD) complicating allogeneic bone marrow transplantation (BMT) is often attributed to mismatched minor histocompatibility antigens (mHags), which are poorly defined in humans. CD31 is a candidate human mHag relevant to acute GVHD, but reports disagree about its level of significance, the role of HLA restriction, and the relative importance of different polymorphic codons within the molecule. We therefore examined in greater detail the impact of CD31-matching on BMT outcome in a prospective study from a single institution. Samples of recipient and donor DNA were collected pretransplantation for all patients receiving unmanipulated bone marrow from an HLA-identical sibling over a 45-month period at our institution. CD31 DNA typing of alleles at the 3 polymorphic codons 125 (L or V), 563 (N or S), and 670 (R or G) was performed for 118 patient-donor pairs plus 2 additional pairs who had codon 125 typing only. Donor-recipient CD31 nonidentity was tested for correlation with BMT clinical outcome measures of severe acute GVHD, chronic GVHD, relapse, and survival. Gene frequencies of approximately 0.5 for each allele at all 3 codons were comparable to previous reports. Because complete association was seen for 563N with 670G and for 563S with 670R, nonidentity for those codons was analyzed as a single genetic marker designated codon 563/670. Donor-recipient CD31 nonidentity was a significant risk factor for overall survival, both at codon 563/670 (hazard ratio [hr] = 2.58, P = .005) and at codon 125 (hr = 1.07, P = .036). Similar results held for disease-free survival. Nonidentity at codon 563/670 was also a significant risk factor (odds ratio [OR] = 11.15, P = .011) for severe (grades III, IV) versus no (grade 0) acute GVHD. Nonidentity at codon 125 posed less but still significant risk (OR = 9.30, P = .030). When the comparison group without severe acute GVHD was expanded to include grade I as well as grade 0 patients, the risk from CD31 nonidentity increased for both codon 563/670 (OR = 12.31, P = .010) and codon 125 (OR = 11.24, P = .011). CD31 nonidentity remained a significant independent risk factor for survival and for severe acute GVHD when tested in multivariate analysis with the covariates of adulthood, recipient-donor sex difference, ethnic group, disease, pretransplantation risk category, HLA-A2 type, B44-like types, and GVHD prophylactic regimen. CD31 nonidentity showed a trend but failed to achieve statistical significance as a risk factor for relapse and for chronic GVHD. In conclusion, donor-recipient CD31 nonidentity is a significant risk factor for survival and for severe acute GVHD in HLA-identical sibling BMT. The stronger associations with codon 563/670 suggest that polymorphism may be more important than the linked polymorphism at codon 125.     

Identification of four novel melanocortin 1 receptor (MC1R) gene variants in a Mediterranean population

The melanocortin 1 receptor (MC1R) gene is a major determinant of human pigmentation and specific allelic variants have been associated with red hair and sun sensitive skin types as well as increased skin cancer risk in Caucasian individuals. We screened for allelic variants the entire MC1R coding region of 100 unrelated individuals sampled from an Italian population who has darker pigmentary traits than populations analyzed to date. Twenty MC1R variants were identified, eighteen located at non-synonymous sites and two at synonymous sites. We report four novel MC1R allelic variants: C35Y (g.104G>A), V38M (g.112G>A), L44V (g.130C>G) and I120T (g.359T>C).     

中国人内源性高甘油三酯血症患者载脂蛋白AⅣ基因变异的研究

目的　探讨载脂蛋白 A (apolipoprotein A ,apo A )基因变异是否与中国人内源性高甘油三酯血症有关联 ,为其分子遗传基础提供依据。方法　应用多聚酶链反应 -限制性片段长度多态性及DNA片段序列分析法 ,对成都地区汉族 171名正常人及 10 6例内源性高甘油三酯血症 (hypertri glyc-eridemia,HTG)患者 apo A 基因多态性进行了研究。检测的 apo A 基因位点有 :密码子 9(A→ G突变 ,同义突变 ) ,密码子 34 7(A→T突变 ,错义突变 )、密码子 36 0 (G→T突变 ,错义突变 )及 Msp (内含子 2 C→T突变 )。结果　与正常对照组比较 ,HTG组密码子 9的 G等位基因频率显著升高 (0 .45 3vs0 .36 6 ,P<0 .0 5 ) ,其它位点等位基因频率未见差异 (P>0 .0 5 )。中国人 apo A 基因密码子 9、密码子 34 7和密码子 36 0等位点相应的 G等位基因、T等位基因和 T等位基因频率与欧洲白种人存在明显种族差异 (0 .36 6 vs 0 .0 32 ,P<0 .0 0 1;0 .0 0 0 vs0 .16 0 ,P<0 .0 0 1;0 .0 0 0 vs0 .0 70 ,P<0 .0 0 1)。与日本人比较 ,上述位点的等位基因频率及 Msp 位点 T等位基因频率均差异无显著性 (P>0 .0 5 )。正常男性 apo A 基因密码子 9位点G/G基因型携带者其血清 apo A 水平显著高于 A/A基因型携带者 (P<0 .0 1) ;而 HTG组 Msp 位点     

The TAF5L gene on chromosome 1q42 is associated with type 1 diabetes in Russian affected patients

Type 1 diabetes (T1D) is a multifactorial autoimmune disease, with strong genetic component. Several susceptibility loci contribute to genetic predisposition to T1D. One of these loci have been mapped to chromosome 1q42 in UK and US joined affected family data sets but needs to be replicated in other populations. In this study, we evaluated sixteen microsatellites located on 1q42 for linkage with T1D in 97 Russian affected sibling pairs. A 2.7-cm region of suggestive linkage to T1D between markers D1S1644 and D1S225 was found by multipoint linkage analysis. The peak of linkage was shown for D1S2847 (P = 0.0005). Transmission disequilibrium test showed significant undertransmission of the 156-bp allele of D1S2847 from parents to diabetic children (28 transmissions vs. 68 nontransmissions, P = 0.043) in Russian affected families. A preferential transmission from parents to diabetic offspring was also shown for the T(-25) and T1362 alleles of the C/T(-25) and C/T1362 dimorphisms, both located at the TAF5L gene, which is situated 103 kb from D1S2847. Together with the A/C744 TAF5L SNP, these markers share common T(-25)/A744/T1362 and C(-25)/C744/T1362 haplotypes associated with higher and lower risk of diabetes (Odds Ratio = 2.15 and 0.62, respectively). Our results suggest that the TAF5L gene, encoding TAF5L-like RNA polymerase II p300/CBP associated factor (PCAF)-associated factor, could represent the susceptibility gene for T1D on chromosome 1q42 in Russian affected patients.     

No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned

The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone. A non-synonymous single-nucleotide polymorphism, A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999, we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype [odds ratio (OR) = 1.16, 95% confidence interval (CI) 0.79-1.69] in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men, respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating more than 6000 cases and 6000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.     

Codon usage bias and A+T content variation in human papillomavirus genomes

We analyzed the codon usage bias of eight open reading frames (ORFs) across up to 79 human papillomavirus (HPV) genotypes from three distinct phylogenetic groups. All eight ORFs across HPV genotypes show a strong codon usage bias, amongst degenerately encoded amino acids, toward 18 codons mainly with T at the 3rd position. For all 18 degenerately encoded amino acids, codon preferences amongst human and animal PV ORFs are significantly different from those averaged across mammalian genes. Across the HPV types, the L2 ORFs show the highest codon usage bias (73.2+/-1.6% and the E4 ORFs the lowest (51.1+/-0.5%), reflecting as similar bias in codon 3rd position A+T content (L2: 76.1+/-4.2%; E4: 58.6+/-4.5%). The E4 ORF, uniquely amongst the HPV ORFs, is G+C rich, while the other ORFs are A+T rich. Codon usage bias correlates positively with A+T content at the codon 3rd position in the E2, E6, L1 and L2 ORFs, but negatively in the E4 ORFs. A general conservation of preferred codon usage across human and non-human PV genotypes whether they originate from a same supergroup or not, together with observed difference between the preferred codon usage for HPV ORFs and for genes of the cells they infect, suggests that specific codon usage bias and A+T content variation may somehow increase the replicational fitness of HPVs in mammalian epithelial cells, and have practical implications for gene therapy of HPV infection.     

Paternal bias in parental origin of HRAS mutations in Costello syndrome

Costello syndrome (CS) is a rare congenital condition caused by heterozygous de novo missense mutations affecting the codon for glycine 12 or 13 of the HRAS gene. We have identified 39 CS patients harboring the p.Gly12Ser mutation (NM_005343.2:c.34 G > A), two patients with c.35G > C mutations resulting in p.Gly12Ala substitutions, and one patient carrying the p.Gly13Cys substitution (c.37G > A). We analyzed the region flanking the mutated sites in 42 probands and 59 parents, and used four polymorphic markers to trace the parental origin of the germline mutations: one highly polymorphic hexanucleotide (GGGCCT) repeat region, defining three alleles with different numbers of repeat units (two, three, or four), and three SNPs. One of the SNPs, rs12628 (c.81T > C), was found in strong linkage disequilibrium with the hexanucleotide repeat region. Out of a total of 24 probands with polymorphic markers, 16 informative families were tested and the paternal origin of the germline mutation was found in 14 CS probands; a distribution that is neither consistent with an equal likelihood of mutations arising in either parent (P = 0.0018), nor with exclusive paternal origin.     

Matrix metalloproteinase-3 genotypes influence recovery from hepatitis B virus infection

The reasons for the viral persistence of hepatitis B virus (HBV) infection are unknown, but are probably related to host immune factors. Several matrix metalloproteinases (MMPs) can regulate an inflammatory response. The aim of this study was to assess the effects of the single nucleotide polymorphisms (SNPs) of MMP-3 and -9 genes on the susceptibility to persistent HBV infection. We studied 489 Korean patients with HBV infection (144 inactive carriers, 182 chronic hepatitis, and 163 liver cirrhosis) and 174 healthy individuals who had recovered from HBV infection. MMP-3 gene SNPs were identified at two polymorphic sites (codon 45 [E45K] and codon 96 [D96D]) and MMP-9 gene SNPs at three polymorphic sites (codon 279 [R279Q], codon 607 [G607G], and codon 668 [Q668R]) in study subjects. The frequency of T allele at third position of codon 96 in the MMP-3 gene was higher in HBV persistence patients when analyzed by co-dominant model (age- and sex-adjusted OR=1.242, 95% CI= 1.001-1.540, p=0.049). In conclusion the T allele at the third position of codon 96 in the MMP-3 gene might be associated with persistent HBV infection.     

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer's disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.     

Molecular and serological investigations of the Influenza A(H1N1) 2009 pandemic virus in Turkey

Intense research has been conducted on influenza A(H1N1)pdm09 virus to determine the virulence markers. Limited information on characteristics of pandemic virus has become available in Turkey since the pandemic. In this first report from Turkey, we investigated the molecular markers that have been associated with increased virulence and oseltamivir resistance. We also conducted serological studies in people after infection, vaccination, exposure, and no-exposure controls to determine the level of protection against the pandemic H1N1 influenza virus. Thirteen rRT-PCR positive samples were analyzed for presence of mutations that have been associated with host range, virulence, and antiviral resistance: substitution D222G in the HA, E627K in the PB2, and H275Y in the neuraminidase (NA). In addition, 135 serum samples from vaccinated, recovered, asymptomatic contacts, and control individuals were tested using hemagglutination inhibition (HI) assay. D222G was detected in nasal samples from two severe cases. No specified mutations in the PB2 and NA were identified. Additional substitutions, I216V, V321I, E374K, S203T in HA, V655I in PB2, and I163V in NA, were detected. HI testing from vaccinated individuals, recovered patients, asymptomatic contacts, and control individuals showed that 97.9, 99.7, 88.2, and 44.2 % had HI titers ≥40, respectively. Molecular markers promoting influenza A(H1N1)pdm09 to become a pandemic virus are still under investigation. Serological results confirm that younger, un-exposed individuals are at increased risk of pandemic virus infections. Influenza A(H1N1)pdm09 viruses are still in circulation around the globe. Therefore, these viruses need to be monitored closely for development of new markers including antiviral resistance mutations.     

Sex dependent influence of a functional polymorphism in steroid 5‐α‐reductase type 2 (SRD5A2) on post‐traumatic stress symptoms

A non‐synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5‐α‐reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post‐traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African‐American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post‐traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex‐dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex‐specific way, the severity of post‐traumatic stress symptoms and risk for diagnosis of PTSD. © 2013 Wiley Periodicals, Inc.