Sexual risk characteristics, social vulnerability, and anal cancer screening uptake among men living with HIV in the deep south.

ABSTRACTWithout standard guidelines, there is a critical need to examine anal cancer screening uptake in the South which has the highest HIV incidence in the U.S. We identified factors associated with screening among men living with HIV (MLHIV) at a large academic HIV outpatient clinic in Alabama. Relationships between sociodemographic, clinical, sexual risk characteristics and screening were examined using T-tests, Fisher's exact, Chi-square, and logistic regression analyses. Unadjusted and adjusted odds ratios (AOR) were computed to estimate the odds of screening. Among 1,114 men, 52% had received annual anal cytology (pap) screening. Men who were screened were more likely to have multiple sexual partners compared to men who were not screened (22.8% vs. 14.8%, p = 0.002). Among men with one partner, the youngest were almost five times more likely to be screened compared to middle-aged men (AOR = 4.93, 95% CI: 2.34-10.39). Heterosexual men had lower odds and men who reported unprotected anal sex had higher odds of screening. Our findings suggest a racial disparity, with older black MLHIV being the least likely to be screened. In the South, MLHIV who are older, black, heterosexual, or live in high social vulnerability counties may be less likely to receive annual anal cancer screening.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup'ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis.

BACKGROUND: Obesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. OBJECTIVES: The aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. METHODS: In total, 571 Yup'ik Alaska Native adults (18-87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). RESULTS: In this Yup'ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. CONCLUSIONS: Intake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup'ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.

HLA-DQB1*06 and Select Neighboring HLA Variants Predict Chlamydia Reinfection Risk.

Associations of HLA class II alleles with genital chlamydial infection outcomes have been reported, especially HLA DQB1*06. However, the potential role of DQB1*06 in influencing reinfection risk has still not been established. The purpose of this study was to determine whether the association of DQB1*06 with chlamydia reinfection was impacted by any other nearby HLA class II variants that were also associated with reinfection. We used next-generation sequencing to map HLA class II variants spanning the HLA-DQ and -DR loci. DQB1*06 as well as DQB1*04 were confirmed as significant predictors of chlamydia reinfection, when controlling for age and percent African ancestry. SKAT analysis revealed one region each in DRB1, DRB5, DQA2, and three intergenic regions that had variants associated with reinfection. Further analyses of these variants revealed that rs112651494 within DRB5 and an intergenic SNP rs617058 in DRB1:DQA1 were significantly associated with reinfection, but this did not impact the significance of the association of DQB1*06 or DQB1*04 with reinfection.

HSV-infection-related herpetic anogenital ulcer disease among PLWH in southeastern US: electronic medical record based analysis.

ObjectivesThe southeastern US is a domestic epicentre for incident HIV with high prevalence of herpes simplex virus (HSV) coinfection. We estimated the incidence rates (IR) of symptomatic herpetic anogenital ulcer disease (HAUD) and assessed its associations with demographic and clinical characteristics, specifically with immunological markers using median, nadir and trajectory CD4 counts. METHODS: Electronic medical records (EMR) of over 7000 people living with HIV (PLWH) attending one of the leading HIV clinics in the southeastern US between 2006 and 2018 were reviewed and analysed. IR of HSV-related HAUD were estimated per 10 000 person years. Joinpoint regressions were performed to examine temporal changes in the trends of IR. All IR and trends were stratified by gender and race. Six CD4 trajectory groups were constructed using the group-based trajectory modelling. Multivariable logistic models were conducted to assess the associations of CD4 counts (nadir, median CD4 and newly defined CD4 trajectory), separately with HAUD. RESULTS: Of the 4484 PLWH eligible individuals (3429 men, 1031 women and 24 transgender), we observed 425 patients with HSV-related HAUD. The mean log10viral load was higher in HAUD than HAUD-free groups, whereas the median nadir CD4 count (cells/uL) was higher in the non-cases than the case groups (p<0.05). HAUD were more frequent in women than men. Median CD4 (<200 cell/uL) was associated with HAUD (OR=2.1), but there were no significant associations with nadir CD4. Significant associations with declining and sustained low CD4 counts trajectory patterns were observed with HAUD. CONCLUSIONS: There were significant differences between men and women with incident HAUD among PLWH. EMR-based studies can provide innovative trajectory models that can potentially be helpful in guiding screening and clinical care of HAUD among high-risk PLWH.

Habitual Intake of Marine-Derived n-3 PUFAs is Inversely Associated with a Cardiometabolic Inflammatory Profile in Yup'ik Alaska Native People.

BACKGROUND: The relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health. OBJECTIVES: The aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation. METHODS: A total of 569 Yup'ik Alaska Native adults (18-87 years old) were enrolled in this cross-sectional study between December 2016 and November 2019. The RBC nitrogen isotope ratio (NIR; 15N/14N) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intakes. Outcomes included 38 pro- and anti-inflammatory cytokines and 8 measures of glucose homeostasis associated with type 2 diabetes risks. These outcomes were evaluated for their associations with direct measurements of EPA, DHA, and arachidonic acid in RBCs. ANALYSIS: Linear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose-related variables. RESULTS: The DHA concentration in RBC membranes was inversely associated with IL-6 (ß = -0.0066; P < 0.001); EPA was inversely associated with TNFα (ß = -0.4925; P < 0.001); and the NIR was inversely associated with Monocyte chemoattractant protein-1 (MCP-1) (ß = -0.8345; P < 0.001) and IL-10 (ß = -1.2868; P < 0.001). CONCLUSIONS: Habitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup'ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.

Impact of atrial fibrillation on the outcomes of transcatheter mitral valve repair using MitraClip: a systematic review and meta-analysis.

Atrial fibrillation (AF) is a common arrhythmia in patients with mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR). In this systematic review, we aimed to investigate the outcomes of TMVR using MitraClip in AF patients. We performed a systematic search using PubMed, SCOPUS, EMBASE, and Google Scholar, from inception to May 10, 2020, for studies that reported outcomes following MitraClip, in patients with AF versus without AF. Seven studies with a total of 7678 patients met the inclusion criteria. The risk of 1-year all-cause mortality following TMVR was higher in AF patients (RR 1.40, 95% CI 1.27-1.54, p ≤ 0.001). Similarly, the risk of heart failure hospitalization was higher in patients with AF (RR 1.17, 95% CI 1.06-1.30, p = 0.002) and the risk of bleeding was elevated in AF patients (RR 1.29, 95% CI 1.15-1.45, p ≤ 0.001). The risk of procedural failure, in-hospital mortality, cardiovascular mortality, and stroke was not significantly different between the two groups. The higher risk of all-cause mortality, HF hospitalization, and risk of bleeding in AF patients undergoing MitraClip warrants attention.

Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension.

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

CD4 Trajectory Models and Onset of Non-AIDS-Defining Anal Genital Warts, Precancer, and Cancer in People Living With HIV Infection-1.

BACKGROUND: It is unclear how the characteristics of CD4 counts predict non-AIDS-defining human papillomavirus-related anogenital warts (AGWs) and anal high-grade squamous intraepithelial lesions/cancer (HSIL) in people living with HIV infection-1 (PLWH). We compared the associations between 3 CD4 counts measures and these disease outcomes in the study. METHODS: Retrospective sociobehavioral and clinical data from electronic health records of 4803 PLWH from 2006 to 2018 were included. Three different measurements of CD4 counts-(a) nadir, (b) median, and (c) trajectory-were estimated. Six CD4 trajectory groups were constructed using the group-based trajectory modeling from all patients older than 18 years with ≥3 clinical visits. Univariate and multivariable logistic regression models were used to assess the associations with AGW and HSIL, separately. RESULTS: A total of 408 AGW, 102 anal HSIL (43 HSIL, 59 cancer), 4 penile cancer, and 15 vaginal cancer cases were observed. Median CD4 (<200 cell/µL) was associated with AGW (odds ratio [OR], 2.2 [95% confidence interval {CI}, 1.6-3.0]), and anal HSIL (OR, 2.7 [95% CI, 1.5-5.0]; each, P < 0.001). Low nadir CD4 (<200 cell/µL) was associated with AGW (OR, 1.8 [95% CI, 1.3-2.6]) and anal HSIL (OR, 2.4 [95% CI, 1.2-4.7]; each, P ≤ 0.001). Different patterns (declining and sustained low CD4 counts) of CD4 trajectories showed the strongest associations with onset of both AGW (OR, 1.8-3.1) and HSIL (OR, 2.7-6.7). CONCLUSIONS: People living with HIV infection-1 with the same median CD4 could have very different CD4 trajectories, implying different dynamics of immune status. CD4 trajectory could be a better predictor of incident AGW and HSIL among PLWH.

Comorbidities associated with HPV infection among people living with HIV-1 in the southeastern US: a retrospective clinical cohort study.

BACKGROUND: The southeastern US is an epicenter for incident HIV in the US with high prevalence of human papillomavirus (HPV) co-infections. However, epidemiologies of HPV-associated clinical conditions (CC) among people living with HIV-1 infection (PLWH) are not fully known. METHODS: Electronic medical records (EMR) of PLWH attending one of the leading HIV clinics in the southeastern US between 2006 and 2018 were reviewed and analyzed. The retrospective study was nested within the University of Alabama at Birmingham HIV clinical cohort, which has electronically collected over 7000 PLWH's clinical and sociobehavioral data since 1999. Incidence rates of HPV-related CC including anogenital warts, penile, anal, cervical, and vaginal/vulvar low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) were estimated per 10,000 person years. Joinpoint regressions were performed to examine temporal changes in the trends of incident CC. All rates and trends were stratified by gender and race. RESULTS: Of the 4484 PLWH included in the study (3429 men, 1031 women, and 24 transgender), we observed 1038 patients with HPV-related CC. The median nadir CD4 count (cells/uL) was higher in the HPV-condition free group than the case groups (P < 0.0001). Anogenital warts, anal LSIL, HSIL, and cancer were more likely to be diagnosed among HIV-infected men than women. White men presented more frequently with anal LSIL and anal and penile cancers than black men (P < 0.03). White women were also more likely to be diagnosed with cervical HSIL (P = 0.023) and cancer (P = 0.037) than black women. CONCLUSIONS: There were significant differences between gender and race with incidence of HPV-related CC among HIV patients. EMR-based studies provide insights on understudied HPV-related anogenital conditions in PLWH; however, large-scale studies in other regions are needed to generalize current findings and draw public health attention to co-infection induced non-AIDS defining comorbidities among PLWH.

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population.

AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model. RESULTS: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10-8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10-7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10-8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations. CONCLUSIONS/INTERPRETATION: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations. DATA AVAILABILITY: The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/ ) under the accession EGAS00001002641.

Cancer-related risk factors and incidence of major cancers by race, gender and region; analysis of the NIH-AARP diet and health study.

BACKGROUND: Racial disparities in the incidence of major cancers may be attributed to differences in the prevalence of established, modifiable risk factors such as obesity, smoking, physical activity and diet. METHODS: Data from a prospective cohort of 566,398 adults aged 50-71 years, 19,677 African-American and 450,623 Whites, was analyzed. Baseline data on cancer-related risk factors such as smoking, alcohol, physical activity and dietary patterns were used to create an individual adherence score. Differences in adherence by race, gender and geographic region were assessed using descriptive statistics, and Cox proportional hazards models were used to determine the association between adherence and cancer incidence. RESULTS: Only 1.5% of study participants were adherent to all five cancer-related risk factor guidelines, with marked race-, gender- and regional differences in adherence overall. Compared with participants who were fully adherent to all five cancer risk factor criteria, those adherent to one or less had a 76% increased risk of any cancer incidence (HR: 1.76, 95% CI: 1.70 - 1.82), 38% increased risk of breast cancer (HR: 1.38, 95% CI: 1.25 - 1.52), and doubled the risk of colorectal cancer (HR: 2.06, 95% CI: 1.84 - 2.29). However, risk of prostate cancer was lower among participants adherent to one or less compared with those who were fully adherent (HR: 0.79, 95% CI: 0.75 - 0.85). The proportion of cancer incident cases attributable to low adherence was higher among African-Americans compared with Whites for all cancers (21% vs. 19%), and highest for colorectal cancer (25%) regardless of race. CONCLUSION: Racial differences in the proportion of cancer incidence attributable to low adherence suggests unique opportunities for targeted cancer prevention strategies that may help eliminate racial disparities in cancer burden among older US adults.

Genetics, Diet, and Season Are Associated with Serum 25-Hydroxycholecalciferol Concentration in a Yup'ik Study Population from Southwestern Alaska.

BACKGROUND: Low blood vitamin D concentration is a concern for people living in circumpolar regions, where sunlight is insufficient for vitamin D synthesis in winter months and the consumption of traditional dietary sources of vitamin D is decreasing. OBJECTIVE: The objective was to characterize the effects of diet, genetic variation, and season on serum 25-hydroxycholecalciferol [25(OH)D3] concentrations in Yup'ik Alaska Native people living in rural southwest Alaska. METHODS: This study was a cross-sectional design that assessed the associations of traditional diet (via a biomarker, the RBC δ(15)N value), age, gender, body mass index (BMI), community location, and genotype of select single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2, subfamily R, peptide 1 (CYP2R1), 7-dehydrocholesterol reductase (DHCR7), and vitamin D binding protein (GC) with serum 25(OH)D3 concentrations in 743 Yup'ik male and female participants, aged 14-93 y, recruited between September 2009 and December 2013. RESULTS: Yup'ik participants, on average, had adequate concentrations of serum 25(OH)D3 (31.1 ± 1.0 ng/mL). Variations in diet, BMI, age, gender, season of sample collection, and inland or coastal community geography were all significantly associated with serum 25(OH)D3 concentration. In models not adjusting for other covariates, age, diet, and seasonal effects explained 33.7%, 20.7%, and 9.8%, respectively, of variability in serum 25(OH)D3 concentrations. Of the 8 SNPs interrogated in CYP2R1 and DHCR7, only rs11023374 in CYP2R1 was significantly associated with serum 25(OH)D3, explaining 1.5% of variability. The GC haplotype explained an additional 2.8% of variability. Together, age, diet, gender, season of sample collection, BMI, geography of the community, and genotype at rs11023374 explained 52.5% of the variability in serum 25(OH)D3 concentrations. CONCLUSIONS: Lower consumption of the traditional diet was associated with lower serum concentrations of 25(OH)D3. Younger adults and youth in this community may be at increased risk of adverse outcomes associated with vitamin D insufficiency compared with older members of the community, especially during seasons of low sunlight exposure, because of lower consumption of dietary sources of vitamin D.

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

A family-specific linkage analysis of blood lipid response to fenofibrate in the Genetics of Lipid Lowering Drug and Diet Network.

Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-cholesterol (LDL-C) on chromosome 7 (peak logarithm of odds score = 4.76) in the full sample (n = 821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N = 19), we observed a peak logarithm of odds score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.

OBJECTIVES: Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. METHODS: We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). RESULTS: We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. CONCLUSION: Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.

Admixture mapping of genetic variants for uterine fibroids.

Uterine leiomyoma (UL) are benign neoplasms arising from the smooth muscle cells of the uterus. One of the established risk factors for UL is African American ethnicity. Studies have consistently shown that African Americans have two to three times higher risk compared with that of non-Hispanic Whites. However, there is still no adequate explanation for the higher risk among African Americans. To investigate the genetic contribution to the observed difference between the African American and European American populations, we conducted an admixture scan in 525 eligible African American women participants to the NIEHS uterine fibroid study (NIEHS-UFS). In models with no stratification, we found multiple genomic regions showing significant and suggestive evidence of association, with chromosomal band 2q32.2 at rs256552 showing the highest score (Z-score=7.86, Bonferroni adjusted P-value=5.5 × 10(-12)) consistent with the suggestive evidence reported for this genomic region in the Black Women's Health Study. However, in models stratified by the body mass index (BMI) covariate, chromosome 1q42.2 was the sole genomic region that consistently showed suggestive associations across the BMI categories tested (Z-scores ⩽-3.96, Bonferroni adjusted P-values ⩽0.107). In age-stratified models, a significant association was observed in the older category (age >40) reaching a Z-score of 6.44 (Bonferroni-adjusted P-value=1.64 × 10(-7)) at rs256552. The mean percentage of European ancestry among cases was lower than that among controls in the NIEHS-UFS study. However, our study did not show a significant association between mean percentage of European ancestry and UL.

Packet randomized experiments for eliminating classes of confounders.

BACKGROUND: Although randomization is considered essential for causal inference, it is often not possible to randomize in nutrition and obesity research. To address this, we develop a framework for an experimental design-packet randomized experiments (PREs), which improves causal inferences when randomization on a single treatment variable is not possible. This situation arises when subjects are randomly assigned to a condition (such as a new roommate) which varies in one characteristic of interest (such as weight), but also varies across many others. There has been no general discussion of this experimental design, including its strengths, limitations, and statistical properties. As such, researchers are left to develop and apply PREs on an ad hoc basis, limiting its potential to improve causal inferences among nutrition and obesity researchers. METHODS: We introduce PREs as an intermediary design between randomized controlled trials and observational studies. We review previous research that used the PRE design and describe its application in obesity-related research, including random roommate assignments, heterochronic parabiosis, and the quasi-random assignment of subjects to geographic areas. We then provide a statistical framework to control for potential packet-level confounders not accounted for by randomization. RESULTS: Packet randomized experiments have successfully been used to improve causal estimates of the effect of roommates, altitude, and breastfeeding on weight outcomes. When certain assumptions are met, PREs can asymptotically control for packet-level characteristics. This has the potential to statistically estimate the effect of a single treatment even when randomization to a single treatment did not occur. CONCLUSIONS: Applying PREs to obesity-related research will improve decisions about clinical, public health, and policy actions insofar as it offers researchers new insight into cause and effect relationships among variables.