Polymorphisms of the human platelet alloantigens HPA-1, HPA-2, HPA-3, and HPA-4 in ischemic stroke

Polymorphism in human platelet antigen (HPA)-1 and HPA-3 (GPIIb/IIIa), HPA-2 (GPIb/IX), HPA-4 (GPIIIa), and HPA-5 (GPIa/IIa) was investigated in 329 stroke patients and 444 matched control subjects. HPA genotyping was done by PCR-SSP method. Lower HPA-1a (P < 0.001) and higher HPA-1b (P < 0.001) allele frequencies were seen in patients than control subjects, and homozygosity for HPA-1b (P < 0.001) alleles was more prevalent in stroke cases than in controls. The allele and genotype distributions of the other HPA polymorphic variants were similar between cases and controls. Select HPA combined genotypes comprising the 2121 (Pc = 0.008) and 2221 (Pc = 0.018) genotypes, which were positively associated, and the 1111 (Pc < 0.001), which was negatively associated with stroke, thereby conferred a disease susceptibility and protective nature to these genotype combinations. Multivariate analysis confirmed the negative association of the 1111 (P < 0.001) and the positive association of the 2121 (P = 0.017) combined genotypes with stroke, after adjustment for a number of covariates. This is the first evidence demonstrating differential association of the common 4 HPA gene variants and specific HPA genotype combinations with stroke.     

Gene frequencies of the HPA-1 to HPA-8w platelet antigen alleles in Taiwanese,Indonesian, and Thai

Human platelet antigen (HPA) systems consist of more than eight biallelic antigen polymorphisms in which a base pair substitution leads to change in an amino acid of a glycoprotein expressed on the platelet. HPA typing is essential in the diagnosis and treatment for a variety of diseases. We developed a polymerase chain reaction (PCR)-based method to detect HPA-1 through HPA-8w. In this method, the amplified PCR products were used to recognize the polymorphism after restriction enzyme digestions. Among 295 Taiwanese, 107 Indonesian, and 137 Thai subjects studied, HPA-1a, 2a, 4a, 5a, 6a, 7aw, and 8aw genes were present in every sample tested. HPA-1b, 2b, 4b, 5b, and 6b were rarely found among subjects. Only monomorphic HPA-7aw and 8aw alleles were noted in the samples. HPA-3a and 3b alleles showed frequencies of 0.595/0.405, 0.504/0.496, and 0.507/0.493 in Taiwanese, Indonesian, and Thai subjects, respectively. Our report is the first PCR-based method to detect most of the HPA antigen variants in Taiwanese, Indonesian, and Thai. The genomic typing results were also confirmed by direct sequencing for uncertain and some representative cases. The prevalence rates of HPA-1, 2, 3, 4, and 5 in this study were also consistent with other previous reports using different methods.     

The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel

On chromosome 6q22.3, a cluster of single-nucleotide polymorphisms located in intron 5 of the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) gene were shown to confer susceptibility to type 2 diabetes in multiple ethnic groups. The diabetogenic role of CDKAL1 variants is suggested to consist in lower insulin secretion probably due to the insufficient inhibition of the CDK5 activity. In this study, we assessed the association of several SNPs of CDKAL1 with T2D in 772 Russian affected patients and 773 normoglycemic controls using a Taqman-based allelic discrimination assay. We showed association of the minor allele C of rs10946398 (Odds Ratio (OR) = 1.21, 95% CI = 1.04–1.4, P = 0.016), allele C of rs7754840 (OR = 1.18, 95% CI = 1.01–1.37, P = 0.038), and allele G of rs7756992 (OR = 1.21, 95% CI = 1.04–1.42, P = 0.017) with higher diabetes risk thereby replicating the predisposing role of CDKAL1 in etiology of T2D. These alleles contribute to three haplotypes (CCA, CGG, and CCG) related to higher diabetes risk (OR = 1.48, 2.12, and 1.95). Combinations of these haplotypes between each other form the group of high-risk haplogenotypes whose carriers had decreased HOMA-β compared to other CDKAL1 variants in both diabetic (38.6 ± 19.3 vs. 48.2 ± 21.2, P _adjusted = 0.019–0.044) and non-diabetic (91.8 ± 42.1 vs. 108 ± 47.2, P _adjusted = 0.0054–0.01) patients. The carriage of the risk haplogenotypes of CDKAL1 was associated with reduced response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. These data suggest that CDKAL1 is involved in the pathogenesis of T2D through impaired beta-cell function.     

Antibiotic resistance of Escherichia coli urinary tract infections at a North Carolina community hospital: Comparison of rural and urban community type

ObjectiveWe aimed to identify differences in urinary E. coli resistance rates based on community type of patient residence (rural and urban).MethodsThis cross-sectional study examined antibiotic resistance of E. coli isolates from 12,604 urine specimens at a North Carolina hospital between 2016 and 2018. Using multivariable logistic regression modeling, we investigated the association between resistance and community type, adjusting for patient age, gender, season, and setting of infection onset. Analyses were performed using SAS Version 9.3 (SAS Institute, Cary, NC) at alpha = 0.05.ResultsPrevalence of resistance was highest for ampicillin (42.2%), ampicillin-sulbactam (24.7%), ciprofloxacin (21.8%), trimethoprim-sulfamethoxazole (SXT) (21.6%), and levofloxacin (21.4%). Rural compared to urban community type was significantly associated with resistance of E. coli urinary isolates to ciprofloxacin (adjusted odds ratio [aOR] = 1.29, 95% confidence interval [CI] = 1.16-1.43, P < .0001), levofloxacin (aOR = 1.28, 95% CI = 1.15-1.42, P < .0001), SXT (aOR = 1.15, 95% CI = 1.04-1.27, P = .01), and nitrofurantoin (aOR = 1.57, 95% CI = 1.13-2.17, P = .01).ConclusionsRural community type may influence urinary E. coli resistance to fluoroquinolones, SXT, and nitrofurantoin, indicating the need for antimicrobial stewardship interventions in medically underserved populations.     

Polymorphism of platelet glycoprotein IIb and risk of thrombosis and restenosis after coronary stent placement

Both glycoprotein (GP) IIb and IIIa of platelet fibrinogen receptor are polymorphic proteins. Unlike GPIIIa, there is little information about the clinical significance of the GPIIb polymorphism. We designed this prospective study to assess whether patients with the human platelet antigen (HPA)-3 polymorphism of GPIIb are more susceptible to developing thrombosis and restenosis after coronary stent placement. We included 2,178 consecutive patients with coronary artery disease who underwent intracoronary stent implantation, 789 (36.2%) with HPA-3a/a, 1,023 (47.0%) with HPA-3a/b, and 366 (16.8%) with HPA-3b/b genotype. The incidence of stent thrombosis was 1.7% in HPA-3a/a, 1.7% in HPA-3a/b, and 1.6% in HPA-3b/b patients (p = 0.999). The incidence of stent restenosis was 37.3% in HPA-3a/a, 36.2% in HPA-3a/b, and 34.6% in HPA-3b/b patients (p = 0.724). Event-free survival 1 year after stent placement was 76.1% for HPA-3a/a, 76.5% for HPA-3a/b, and 76.4% for HPA-3b/b patients (p = 0.968). We conclude that the HPA-3 polymorphism of platelet GPIIb is not associated with an increase in the risk of thrombosis and restenosis over 1 year after coronary stent placement. These data indicate that unlike the HPA-1 polymorphism of GPIIIa, the HPA-3 polymorphism of GPIIb may not serve as a useful genetic marker for the risk assessment of patients treated with intracoronary stenting.     

Education is the strongest socio‐economic predictor of smoking in pregnancy

Aims

To investigate socio‐economic disparities in smoking in pregnancy (SIP) by the mother's education, occupational class and current economic conditions.

Design

Cross‐sectional analysis with linked survey and register data.

Setting

South‐western Finland.

Participants

A total of 2667 pregnant women [70% of the original sample (n = 3808)] from FinnBrain, a prospective pregnancy cohort study.

Measurements

The outcome was smoking during the first pregnancy trimester, measured from the Finnish Medical Birth Register. Education and occupational class were linked from population registers. Income support recipiency and subjective economic wellbeing were questionnaire‐based measures of current economic conditions. These were adjusted for age, partnership status, residential area type, parental separation, parity, childhood socio‐economic background, childhood adversities (the Trauma and Distressing Events During Childhood scale) and antenatal stress (Edinburgh Postnatal Depression Scale). Logistic regressions and attributable fractions (AF) were estimated.

Findings

Mother's education was the strongest socio‐economic predictor of SIP. Compared with university education, adjusted odds ratios (aORs) of SIP were: 2.2 [95% confidence interval (CI) = 1.2–3.9; P = 0.011] for tertiary vocational education, 4.4 (95% CI = 2.1–9.0; P < 0.001) for combined general and vocational secondary education, 2.9 (95% CI = 1.4–6.1; P = 0.006) for general secondary education, 9.5 (95% CI 5.0–18.2; P < 0.001) for vocational secondary education and 14.4 (95% CI = 6.3–33.0; P < 0.001) for compulsory schooling. The total AF of education was 0.5. Adjusted for the other variables, occupational class and subjective economic wellbeing did not predict SIP. Income support recipiency was associated positively with SIP (aOR = 1.8; 95% CI = 1.1–3.1; P = 0.022). Antenatal stress predicted SIP (aOR = 2.0; 95% CI = 1.4–2.8; P < 0.001), but did not attenuate its socio‐economic disparities.

Conclusions

In Finland, socio‐economic disparities in smoking in pregnancy are attributable primarily to differences in the mother's educational level (low versus high) and orientation (vocational versus general).     

Gene frequencies of human platelet alloantigens in Bahraini Arabs

Human platelet antigens (HPA) are implicated in the pathophysiology of certain hematological disorders, and as varied distribution of HPA-1 alleles and genotypes were reported fordifferent countries and ethnic populations, we determined the distribution of HPA-1, -2, -3, -4, and -5 alleles, genotypes and haplotypes for 194 healthy Bahraini subjects by polymerase chain reaction with sequence specific primers. The distribution of the HPA polymorphisms was in Hardy-Weinberg equilibrium. Allele frequencies of 0.76 and 0.24 (HPA-1a and -1b), 0.77 and 0.23 (HPA-2a and -2b), 0.57 and 0.43 (HPA-3a and -3b), 0.93 and 0.07 (HPA-4a and -4b), and 0.86 and 0.13 (HPA-5a and -5b) were seen. With the exception of HPA-3a/a (30.4%), the frequencies of homozygous HPA-1a/a (56.8%), 2a/a (60.1%), 4a/a (87.2%), and 5a/a (75.7%) were higher than those of heterozygous (a/b) or homozygous (b/b) variants. Our results provide basic information for further studies of the HPA system polymorphism, which in turn will be instrumental in understanding and treating immune-mediated platelet disorders.     

DNA sequencing-based typing of HPA-1 to HPA-17w systems

Although several DNA-based human platelet antigens (HPA) typing techniques, such as PCR-SSP and PCR-SSO, have been established, the typing errors and the lack of interlaboratory reproducibility are still the issues of concerns. In the present study, polymerase chain reaction primers were designed for identification of all the phenotypically different HPA-1 to HPA-17w types by sequencing-based typing (SBT) method using genomic DNA samples. No discrepancies were observed between PCR-SSP typing and SBT typing in typing a panel of HPA-typed platelet donors that included all common HPA types and the rare HPA-1b, 2b, 3b, and 6bw homozygous donors.     

Association between self-reported masking behavior and SARS-CoV-2 infection wanes from Pre-Delta to Omicron-predominant periods — North Carolina COVID-19 Community Research Partnership (NC-CCRP)

BackgroundWearing a face mask is a primary public health method to reduce SARS-CoV-2 transmission.MethodsWe performed a nested case-control analysis within the North Carolina COVID-19 Community Research Partnership (NC-CCRP) of adults who completed daily surveillance surveys, April 2020 - February 2022. We assessed the association between self-reported mask wearing behavior during nonhousehold interactions and COVID-19 infection during 3 pandemic periods using conditional logistic regression models of risk of infection that were adjusted for demographics, vaccination status, and recent known exposure to COVID-19.ResultsAmong 3,901 cases and 27,813 date-matched controls, there was a significant interaction between mask use and time period (P < .001). Prior to July 2021, the odds of a reported infection were 66% higher (aOR = 1.66, 95% CI = 1.43-1.91) among participants reporting ≥1 day not wearing a mask compared to those who reported no days (1,592 cases, 11,717 controls). During the Delta-predominant period, the results were similar (aOR = 1.53, 95% CI = 1.23-1.89; 659 cases, 4,649 controls). This association was attenuated during the Omicron-predominant period, where odds of an infection was 16% higher (aOR = 1.16, 95% CI = 1.03-1.32; 1,563 cases, 10,960 controls).ConclusionsWhile the effect of not wearing a mask remains significant, during the Omicron-predominant period we observed a decrease in the association between self-reported mask wearing and risk of SARS-CoV-2 infection.     

Platelet receptor gain-of-function single nucleotide polymorphisms in carotid and vertebral stenosis patients

The role of platelet receptor gain-of-function single nucleotide polymorphisms (SNP) in cardiovascular disease is controversial. We hypothesised that certain SNPs may accelerate the development of carotid artery stenosis. The intronic PAR-1 receptor intervening sequence-14 A/T (IVSn-14 A/T) polymorphism and three additional platelet receptor polymorphisms, i.e. GPIa (807C/T), GPIbα (5T/C) and HPA-1a/HPA-1b (Pl (A1/A2)) of GPIIIa were studied. The interaction of SNPs with conventional risk factors including male gender, hypertension, high cholesterol, diabetes, advanced age and smoking were investigated. The hypothesis was tested in 114 well-characterised patients with symptomatic carotid or vertebral stenosis from the British CAVATAS population and compared the results with 97 unrelated controls. The allele frequency of the platelet gain-of-function SNP was not significantly different in the CAVATAS population as compared to controls (PAR-1A/T (P = 0.13), GPIa C/T (P = 0.25), GPIIIa HPA-1a/HPA-1b (PlA1/A2) (P = 0.66) and GPIb T/C (P = 0.20)). In the subgroup of smokers, however, the prothrombotic GPIbα C mutated allele was found in a significantly higher frequency in the patient as compared to the control group (P = 0.04). Contrary to the primary hypothesis, the PAR-1A/T SNP as well as the other SNPs tested were not over- or underrepresented in the CAVATAS population. However, a significantly increased prevalence of GPIb-α (5C/T) was found in the subgroup of smokers and may represent an important cofactor in this patient group of our hypothesis-generating study.     

A novel isoform of platelet glycoprotein Ibα is prevalent in African Americans

The heavy chain of platelet glycoprotein Ib (GPIb) contains two prevalent sequence polymorphisms. The first, Thr/Met¹⁴⁵ is responsible for the human platelet alloantigen system, human platelet antigen (HPA)-2. The second is a tandem repeat polymorphism that consists of four variants, A, B, C, and D. Previous linkage studies in Caucasian and Eastern Asian populations have demonstrated that HPA-2a (Thr¹⁴⁵) is associated with variants C and D, while HPA-2b (Met¹⁴⁵) is associated with variants A and B. We have determined HPA-2 and variable number of tandem repeats (VNTR) genotypes in three different North American ethnic groups. The gene frequency of HPA-2b in the North American Indians was intermediate between African Americans and Caucasians, and similar to the frequency previously reported in Japanese. Furthermore, the VNTR-A allele, which previously has been reported only in Eastern Asian populations, was present in two of 101 North American Indian individuals. These data are consistent with the hypothesis that the first Native Americans migrated to North America from Eastern Asia. Analysis of HPA-2 and VNTR haplotypes demonstrated an unexpected linkage pattern in the African American population. A rare GPIbα isoform, HPA-2b/VNTR-C, was present in 2.2% of African American haplotypes. Furthermore, a novel GPIbα isoform, HPA-2a/VNTR-B, was present in 6.5% of African American haplotypes. These data suggest a more complex evolutionary pattern of GPIbα isoforms than previously proposed. Am. J. Hematol. 60:77–79, 1999. © 1999 Wiley-Liss, Inc.     

Association of IL-18 gene polymorphism (?137C) with arthritis manifestations in SLE: combined effect with IFN gamma gene polymorphism (+874A)

We analyzed the association between single nucleotide polymorphisms in IL-12 and IL-18 genes in disease susceptibility and severity of SLE in Thais. A weak association was observed between A allele of the IL-12 gene at the 3′ untranslated region in SLE patients with proteinuria (OR = 1.89, 95% CI = 1.05–3.40, P = 0.02, Pc = 0.06). In addition, we found a significant association between C allele of IL-18 (−137) with arthritis (OR = 6.88, 95% CI = 1.54–42.93, P = 0.003, Pc = 0.009). The presence of one C allele (C/C+C/G) was associated with significant OR of 8.72 (95% CI = 1.83–56.71, P = 0.001, Pc = 0.003). Interestingly, we found the combined effect between the G/C genotype of IL-18 (−137) and the A/A genotype of IFNG (+874) gene causing susceptibility of arthritis in SLE patients (OR = 13.22, 95% CI = 1.56–291.66, P = 0.004).     

Association Between Knee Pain,Impaired Function,and Development of Depressive Symptoms

Objectives

To examine the association between knee pain and function and depressive symptoms in older Japanese adults.

Design

Community‐based prospective cohort study.

Setting

Kurabuchi Town, Gumma Prefecture, Japan.

Participants

Individuals aged 65 and older (N = 573; n = 260 men, n = 313 women) without depressive symptoms participated in baseline examinations in 2005 and 2006; 95.6% participated in follow‐up interviews (2007–08).

Measurements

Degree of knee pain and functional impairment was assessed at baseline using a self‐administered questionnaire in Japanese based on an English version of the Western Ontario and McMaster Universities Osteoarthritis Index. The Geriatric Depression Scale was used to identify depressive symptoms in face‐to‐face home‐visit interviews conducted 2 years later, and the association between knee pain and functional impairment and depressive symptoms was assessed using logistic regression.

Results

During the 2‐year follow‐up, 11.9% of participants developed depressive symptoms, and pain and functional impairment were found to be associated with development of these symptoms. Pain at night while in bed (adjusted odds ratio (aOR) = 2.6, 95% confidence interval (CI) = 1.4–4.9) and difficulty putting on socks (aOR = 3.7, 95% CI: 1.8–7.5), getting into and out of a car (aOR = 3.4, 95% CI = 1.8–6.5), and taking off socks (aOR = 3.1, 95% CI = 1.5–6.5) were found to be most strongly associated with development of depressive symptoms.

Conclusion

Examining elderly people's responses to questions about pain at night and difficulties performing daily activities may be an efficient way of identifying those at high risk of developing depressive symptoms.     

Mean platelet counts are relatively decreased with malaria but relatively increased with endemic Burkitt Lymphoma in Uganda,Tanzania, and Kenya

Platelet counts are decreased in Plasmodium falciparum malaria, which is aetiologically linked with endemic Burkitt lymphoma (eBL). However, the pattern of platelet counts in eBL cases is unknown. We studied platelet counts in 582 eBL cases and 2 248 controls enrolled in a case-control study in Uganda, Tanzania and Kenya (2010–2016). Mean platelet counts in controls or eBL cases with or without malaria-infection in controls versus eBLcases were compared using Student’s t-test. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using multiple logistic regression, controlling for age, sex, haemoglobin and white blood cell counts. Platelets were decreased with malaria infection in the controls [263 vs. 339 × 10⁹ platelets/l, P < 0·0001; adjusted OR (aOR) = 3·42, 95% CI: 2·79–4·18] and eBL cases (314 vs. 367 × 10⁹ platelets/l, P-value = 0·002; aOR = 2·36, 95% CI: 1·49–3·73). Unexpectedly, platelets were elevated in eBL cases versus  controls in overall analyses (mean: 353 vs. 307 × 10⁹ platelets/l, P < 0·0001; aOR = 1·41; 95% CI: 1·12–1·77), and when restricted to malaria-positive (mean 314 vs. 263 × 10⁹ platelets/l, P < 0·0001; OR = 2·26; 95% CI: 1·56–3·27) or malaria-negative (mean 367 vs. 339 × 10⁹ platelets/l, P < 0·001; OR = 1·46; 95% CI: 1·17–1·83) subjects. Platelets were decreased with malaria infection in controls and eBL cases but elevated with eBL.     

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein–Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0–15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%) or differed by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR = 0·59, 95% CI 0·38–0·91), HLA-B*41 (aOR = 0·36, 95% CI 0·13–1·00), and HLA-B*58 alleles (aOR = 0·59, 95% CI 0·36–0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR = 0·57, 95% CI 0·40–0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR = 2·19, 95% CI 1·42–3·37). Our results suggest that variation in HLA may be associated with eBL risk.     

Triglyceride glucose index and renal function decline in Han Chinese hypertensive patients

Elevated triglyceride glucose (TyG) index is associated with an increased risk of cardiovascular disease. The current study aimed to investigate whether the TyG index was correlated with renal function decline in patients with hypertension. Han Chinese participants with essential hypertension were included. The TyG index was calculated as ln[fasting triglycerides (mg/dL) * fasting glucose (mg/dL)/2]. Renal function decline was defined as >25% decline in estimated glomerular filtration rate (eGFR). The Cox proportional hazard regression model was used to examine the independent effect of the TyG index on renal events. In total, 548 Han Chinese hypertensive participants with a mean age of 62.1 ± 14.3 years were eligible for enrollment. During a mean follow-up period of 4.7 ± 3.1 years, 97 patients suffered from >25% decline in eGFR. When compared to those without eGFR decline, patients with eGFR decline had higher fasting triglyceride levels (P = .056), fasting glucose levels (P = .014), and TyG indexes (P = .014). The Cox proportional hazard regression model revealed that the TyG index (hazard ratio [HR] = 1.490; 95% confidence interval [CI] = 1.016–2.185, P = .041), office systolic blood pressure (HR = 1.013; 95% CI = 1.000–1.026, P = .047), diabetes mellitus (HR = 1.797, 95% CI = 1.026–3.147, P = .040), and baseline eGFR (HR = 1.015; 95% CI = 1.002–1.028, P = .025) were associated with renal events. In conclusions, an elevated TyG index is independently associated with an increased risk of eGFR decline in hypertensive patients.     

Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease

Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover, data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and gender-matched healthy subjects. Significantly higher frequency of 677T allele and homozygous 677T/T genotype were seen in patients vs. control subjects; the distribution of A1298C alleles and genotypes being comparable in the two groups. Specific MTHFR haplotypes comprising 677C/1298A (P < 0.001) and 677T/1298A (P < 0.001) were negatively and positively associated with CAD, respectively. Plasma homocysteine concentration was significantly higher in 677T/T genotype with respect to 677C/C and 677C/T genotypes in patients and controls, but homocysteine levels were generally comparable between both groups. Univariate analysis identified 677T/1298A (P = 0.033) haplotype to be positively associated with CAD, which remained significant by multivariate analysis after adjusting for a number of covariates (P = 0.038). MTHFR C677T, but not A1298C SNPs, is associated with CAD and with elevated homocysteine levels in a Tunisian population. The negative and positive association of the 1298A allele with CAD being indicative of a neutral (absent) effect of the A1298C SNP on disease pathogenesis.     

Substance Use and its Association with Psychiatric Symptoms in Perinatally HIV-infected and HIV-Affected Adolescents

Drug use in combination with psychiatric illness may lead to unsafe sexual risk behavior and increased risk for secondary HIV transmission among adolescents with HIV infection. We compared the prevalence of substance use for perinatally HIV-infected youth to uninfected adolescents living in families affected by HIV infection, and evaluated the association of psychiatric symptoms with risk of substance use. Among 299 adolescents (196 HIV+, 103 HIV−) aged 12–18 years enrolled in IMPAACT P1055, a multisite US cohort study, 14% reported substance use at enrollment (HIV+: 13%, HIV−: 16%). In adjusted logistic regression models, adolescents had significantly higher odds of substance use if they met symptom criteria for ADHD [adjusted odds ratio (aOR) = 2.7, Wald χ² = 5.18, P = 0.02], major depression or dysthymia (aOR = 4.0, Wald χ² = 7.36, P = 0.01), oppositional defiant disorder (aOR = 4.8, Wald χ² = 12.7, P = 0.001), or conduct disorder (aOR = 15.4, Wald χ² = 28.12, P = 0.001). Among HIV-infected youth, those with lower CD4 lymphocyte percentage (CD4% < 25%) had significantly increased risk of substance use (aOR = 2.7, Wald χ² = 4.79, P = 0.03). However, there was no overall association of substance use with HIV infection status, and the association between psychiatric symptoms and substance use did not differ by HIV status. Programs to prevent substance use should target both HIV-infected and uninfected adolescents living in families affected by HIV infection, particularly those with psychiatric symptoms.     

Tumour necrosis factor alpha (-238 and -308) and beta gene polymorphisms in pulmonary tuberculosis: haplotype analysis with HLA-A, B and DR genes

Setting: A study of tumour necrosis factor α and β (TNFα and β) gene polymorphism and haplotype analysis with HLA in pulmonary tuberculosis.Objective: To determine whether TNFα (-238 and -308) and TNFβ (Nco I polymorphism in intron 2) genes either alone or in combination with human leucocyte antigens (HLA) as haplotypes afford susceptibility or resistance to pulmonary tuberculosis as well as bacteriological relapse of the disease.Design: Tumour necrosis factor α -238, -308 (TNFα -238, -308) and TNFβ (Nco I) gene polymorphisms were carried out in HLA-A,B and DR typed pulmonary tuberculosis patients (n=210) and 120 normal healthy control subjects.Results: No difference in the genotype frequencies of TNFα-238 and -308 and TNFβ was seen between control subjects and pulmonary tuberculosis patients. Of the HLA-TNF haplotypes analysed, the infrequent allele (A) of TNFα238 was in strong linkage disequilibrium with HLA-A1 (P corrected: Pc=0.001), B17 (Pc<0.0001) and DR7 (Pc=0.01) in control subjects and with B17 (Pc<0.0001) in pulmonary tuberculosis. The infrequent allele 2 of TNFα-308 and the infrequent allele 2 of TNFβ were in strong linkage disequilibrium with HLA-B21. An increased haplotype frequency of HLA-B17-TNFα-238/A (P=0.05), B17-TNFα308/2 (P=0.03) and B17-TNFα308/2 (P=0.01) was observed in bacteriological relapse patients than quiescent patients.Conclusion: The present study suggests that TNFα (-238 and -308) and TNFβ gene variants are not associated independently with the susceptibility to pulmonary tuberculosis. However, in combination with the HLA genes/gene products such as HLA-A1, B17, B21 and DR7, the TNFα and β genes as haplotypes are associated with protection against the disease as well as an increased susceptibility to bacteriological relapse.     

Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso‐occlusive crisis

Objectives: Vaso‐occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients. Insofar as polymorphism in human platelet alloantigen (HPA) exhibit a prothrombotic nature, we hypothesized that specific HPA polymorphic variants are associated with VOC. We investigated the distribution of HPA1, HPA2, HPA3, HPA4, and HPA5 alleles genotypes among VOC and non‐VOC control SCA patients. Patients/methods: This was a case–control study. Study subjects comprised SCA patients with (VOC group; n = 127) or without (Steady‐state group; n = 130) VOC events. HPA genotyping was done by PCR‐SSP. Results: Significantly higher frequencies of HPA‐2b, HPA‐3b, and HPA‐5b alleles, and marked enrichment of HPA‐3b/3b, HPA‐5a/5b, and HPA‐5b/5b genotypes, were seen in VOC than in control SCA patients. Taking homozygous wild‐type genotypes as reference, univariate analysis identified HPA‐3a/3b, HPA‐3b/3b, and HPA‐5b/5b to be associated with VOC. Multivariate analysis confirmed the independent association of only HPA‐3a/3b and HPA‐3b/3b genotypes with VOC. HPA‐3 genotypes were significantly correlated with VOC frequency, type, and medication, and requirement for hospitalization. While both HPA 3a/3b (P = 0.002; OR = 2.94; 95% CI = 1.49–5.77) and 3b/3b (P = 0.006; OR = 3.16; 95% CI = 1.40–7.17) genotypes were associated with need for hospitalization, only HPA‐3b/3b was associated with VOC frequency, type (localized vs. generalized), and medication (narcotics vs. NSAIDs). Conclusion: This confirms the association of HPA polymorphisms with SCA VOC, of which HPA‐3 appears to be independent genetic risk factors for SCA VOC.