Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
To describe patterns of rapid influenza test ordering, diagnosis of influenza, and antiviral prescribing by the treating physician for children and adults presenting to emergency departments (EDs) with fever and acute respiratory symptoms in Winston-Salem, NC over two influenza seasons.
The authors prospectively enrolled patients presenting to the ED with fever and acute respiratory symptoms for two influenza seasons: H1N1 pandemic of September 2009 through mid-May 2010, and November 2010 through April 2011. Enrolled patients had nose or and throat swabs obtained and tested for influenza by viral culture, and polymerase chain reaction (PCR) testing. Demographic information and medical history were obtained by patient or guardian report. Testing, treatment, and discharge diagnosis from the ED visit, as well as medical history and insurance status, were ascertained from chart review.
Among 2,293 eligible patients approached, 1,657 (72%) were enrolled, of whom 38% were younger than 18 years, 47% were 18 to 49 years, and 15% were 50 years of age and older. Overall, 14% had culture- or PCR-confirmed influenza. The odds of 1) rapid influenza test ordering, 2) a physician diagnosis of influenza, and 3) prescribing antiviral treatment during the ED visit were four-fold higher among patients with than without culture- or PCR-confirmed influenza. The odds of rapid influenza test ordering were three-fold lower in 2009/2010 than 2010/2011, whereas the odds of physician diagnosis of influenza and antiviral prescriptions were two-fold and 3.5-fold higher, respectively.
In 2009/2010 as compared to 2010/2011, the odds of rapid influenza test ordering were lower, whereas the odds of influenza-specific discharge diagnoses and antiviral prescriptions were higher among patients presenting to the ED with culture/PCR-confirmed influenza. These results demonstrated a gap between clinical practice and recommendations for the diagnosis and treatment of influenza from the Centers for Disease Control and Prevention.
To evaluate the relationship between maternal preeclampsia resulting in premature delivery and adiposity in the offspring during adolescence.
The 172 study participants were 14 years old and had very low birth weight. We compared height, weight, body mass index (BMI), percent fat, waist circumference, and triceps and subscapular skin fold thicknesses between those born prematurely secondary to preeclampsia (n = 51; 22 male) and those born prematurely after nor-motensive pregnancies (n = 121; 55 male). Multiple linear regression analysis was used to adjust for potential con-founders (maternal BMI, antenatal steroid exposure, and race) and to evaluate potential explanatory variables (fetal, infancy, and childhood weight gain, and caloric intake, level of fitness, and physical activity at 14 years).
When adjusted for potential prenatal confounders (antenatal steroid exposure and race), adolescent male offspring of preeclamptic pregnancies had higher BMI (4.0 kg/m2 [1.5, 6.6]) (mean difference [95% CI]), waist circumference (11.8 cm [3.8, 19.7]), triceps (4.6 mm [0.6, 8.6]) and subscapular skinfold thicknesses (6.2 mm [1.5, 10.9]), and percent body fat (4.1% [−0.1, 8.3]). Adjusting for infancy and childhood weight gain attenuated these group differences. There were no group differences among females.
Male adolescent offspring born prematurely of women with preeclampsia have higher measures of adiposity than those born prematurely of normotensive pregnancies. (J Pediatr 2012; ■:■-■).
To characterize the health care burden of influenza from 2004 through 2009, years when influenza vaccine recommendations were expanded to all children aged ≥6 months.
Population-based surveillance for laboratory-confirmed influenza was performed among children aged <5 years presenting with fever and/or acute respiratory illness to inpatient and outpatient settings during 5 influenza seasons in 3 US counties. Enrolled children had nasal/throat swabs tested for influenza by reverse transcriptase-polymerase chain reaction and their medical records reviewed. Rates of influenza hospitalizations per 1000 population and proportions of outpatients (emergency department and clinic) with influenza were computed.
The study population comprised 2970, 2698, and 2920 children from inpatient, emergency department, and clinic settings, respectively. The single-season influenza hospitalization rates were 0.4 to 1.0 per 1000 children aged <5 years and highest for infants <6 months. The proportion of outpatient children with influenza ranged from 10% to 25% annually. Among children hospitalized with influenza, 58% had physician-ordered influenza testing, 35% had discharge diagnoses of influenza, and 2% received antiviral medication. Among outpatients with influenza, 7% were tested for influenza, 7% were diagnosed with influenza, and <1% had antiviral treatment. Throughout the 5 study seasons, <45% of influenza-negative children ≥6 months were fully vaccinated against influenza.
Despite expanded vaccination recommendations, many children are insufficiently vaccinated, and substantial influenza burden remains. Antiviral use was low. Future studies need to evaluate trends in use of vaccine and antiviral agents and their impact on disease burden and identify strategies to prevent influenza in young infants.
influenza; epidemiology; influenza vaccine; hospitalization; ambulatory care
The cause of historically higher rates of invasive pneumococcal disease among blacks than whites has remained unknown. We tested the hypothesis that sickle cell trait or hemoglobin C trait is an independent risk factor for invasive pneumococcal disease.
Eligible children were born in Tennessee (1996–2003), had a newborn screen, enrolled in TennCare aged <1 year, and resided in a Tennessee county with laboratory-confirmed, pneumococcal surveillance. Race/ethnicity was ascertained from birth certificates. Children were followed through 2005 until loss of enrollment, pneumococcal disease episode, 5th birthday or death. We calculated incidence rates by race/ethnicity and hemoglobin type before and after pneumococcal conjugate vaccine (PCV7) introduction. Poisson regression analyses compared IPD rates among blacks with sickle cell trait or hemoglobin C trait to whites and blacks with normal hemoglobin, controlling for age, gender, time (pre-PCV7, transition year or post-PCV7) and high-risk conditions (i.e. heart disease).
Over 10 years, 415 invasive pneumococcal disease episodes occurred during 451,594 observed child-years. Before PCV7 introduction, disease rates/100,000 child-years were 2941 for blacks with sickle cell disease, 258 for blacks with sickle cell trait or hemoglobin C trait and 188, 172, and 125 for blacks, whites, and Hispanics with normal hemoglobin. Post-PCV7, rates declined for all groups. Blacks with sickle cell trait or hemoglobin C trait had 77% (95% CI 22%–155%) and 42% (95% CI 1%–100%) higher rates than whites and blacks with normal hemoglobin.
Black children with sickle cell trait or hemoglobin C trait have an increased risk of invasive pneumococcal disease.
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation.
HFE; familial aggregation; transferrin saturation; serum ferritin concentration
Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.
Background & Aims
The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload.
A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload.
The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload.
Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals.
Twenty-nine ATP1A3 mutation–positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinson's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale.
NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%).
ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.
A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.
The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.
In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.
The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.
Dystonia; RDP; DYT-12; Rapid-onset dystonia-parkinsonism
We estimated the potential impact of parental Tdap immunization before delivery, at delivery and at the 2-week newborn visit on U.S. infant pertussis hospitalizations. We used published data for pertussis hospitalization rates among U.S. infants aged 0–4 months, the Tdap vaccine efficacy in adults, and the proportion of infants with pertussis <6 months of age in which either parent was the source (16%–40% from mothers and 16%–20% from fathers). Immunizing parents before pregnancy or ≥2 weeks prior to delivery should reduce pertussis hospitalizations among infants 0–4 months by 2694–9314 if both parents are vaccinated, and by 1347–6909 if only mothers are vaccinated. Greater reductions in pertussis hospitalizations would be achieved if parents are immunized ≥2 weeks prior to delivery than after delivery or the 2-week newborn visit. Although immunizing parents prior to pregnancy or delivery is best, immunizing parents in the postpartum period should provide protection to that newborn and to infants of subsequent pregnancies.
Bordetella pertussis; parental immunization; Tdap; cocooning
The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF.
genetics; mutation; transferrin saturation
This analysis describes the association of health and functional status with private and public religious practice among ethnically diverse (African American, Native American, white) rural older adults with diabetes.
Data were collected using a population-based, cross-sectional, stratified, random sample survey of 701 community-dwelling elders with diabetes in two rural North Carolina counties. Outcome measures were private religious practice, church attendance, religious support provided, and religious support received. Correlates included religiosity, health and functional status, and personal characteristics. Statistical significance was assessed using multiple linear regression and logistic regression models.
These rural elders had high levels of religious belief, and private and public religious practice. Religiosity was associated with private and public religious practice. Health and functional status were not associated with private religious practice, but they were associated with public religious practice, such that those with limited functional status participated less in public religious practice. Ethnicity was associated with private religious practice: African Americans had higher levels of private religious practice than Native Americans or whites, while Native Americans had higher levels than whites.
Variation in private religious practice among rural older adults is related to personal characteristics and religiosity, while public religious practice is related to physical health, functional status and religiosity. Declining health may affect the social integration of rural older adults by limiting their ability to participate in a dominant social institution.
rural aging; minority aging; chronic disease; diabetes; religious participation; religiosity; social integration
We estimated the potential impact of administering the first dose of rotavirus vaccine at 6 weeks (42 days of life) instead of 2 months of age, which is permissible for all U.S. vaccines recommended at 2 months of age, on rotavirus hospitalization rates. We used published data for hospitalization rates, vaccine coverage, and vaccine efficacy after one dose and assumed a two-week delay in seroconversion after vaccine administration in the United States. Administering the first dose of rotavirus vaccine at 6 weeks instead of 8 weeks of age should have prevented 1110, 1660, and 2210 rotavirus hospitalizations among U.S. infants <3 months of age in 2006 when the vaccine was first introduced. This estimated benefit represents a 2%-4% reduction in rotavirus hospitalizations among children <5 years of age.
rotavirus vaccine; infants; rotavirus; hospitalizations; prevention; epidemiology
To assess the validity of parental report for seasonal and monovalent H1N1 influenza vaccinations among children 6 months-<18 years who were recommended to receive both vaccines in 2009–2010.
Children with fever or respiratory symptoms were prospectively enrolled in both emergency departments in Forsyth County, North Carolina and the only pediatric hospital in the region. Enrollment occurred from September 1, 2009 through April 12, 2010, during the H1N1 influenza pandemic. A parental questionnaire was administered by trained interviewers to ascertain the status of seasonal and monovalent H1N1 influenza vaccines. Parental report was compared to that documented in the medical record and/or the North Carolina immunization registry.
Among 297 enrolled children 6 months -<18 years of age, 174 (59%) were 6 months-4 years, 67 (23%) were 5–8 years and 56 (19%) were 9-<18 years. Parents reported that 140 (47%) children had received ≥1 dose of 2009–2010 influenza vaccine-- 128 (43%) for seasonal vaccine and 63 (21%) for H1N1 vaccine. Confirmed vaccination data indicated that 156 (53%) children had received ≥1 dose of any 2009–2010 vaccine—120 (40%) for seasonal vaccine and 53 (18%) for H1N1 vaccine.
Parental report of any seasonal influenza vaccination was 92% sensitive and 86% specific and had a kappa of 0.76. Parental report for any H1N1 influenza vaccination was 88% sensitive and 92% specific with a kappa of 0.71.
Parental report of 2009–2010 seasonal and monovalent H1N1 influenza vaccinations was sensitive and specific and had reasonable agreement with the medical record and/or immunization registry.
During the 2009–2010 H1N1 pandemic when seasonal and monovalent H1N1 vaccines were recommended for all children, we found that parental report for both influenza vaccines among children aged 6 months-<18 years had reasonable sensitivity, specificity and validity as compared to the medical record and/or immunization registry.
influenza vaccine; parental report; child; validity; accuracy; seasonal influenza vaccine; monovalent H1N1 influenza vaccine
The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤12 µg/L (cases) and controls (SF >100 µg/L in men, SF >50 µg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7×10−6) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4×10−5); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0×10−5). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.
To determine whether maternal vaccination during pregnancy was associated with a reduced risk of laboratory-confirmed influenza hospitalizations in infants <6 months old.
Active population-based, laboratory-confirmed influenza surveillance was conducted in children hospitalized with fever and/or respiratory symptoms in 3 U.S. counties from November-April during the 2002–2009 influenza seasons. The exposure, influenza vaccination during pregnancy, and the outcome, positive/negative influenza testing among their hospitalized infants, were compared using logistic regression analyses.
Among 1510 hospitalized infants <6 months old, 151 (10%) had laboratory-confirmed influenza and 294 (19%) mothers reported receiving influenza vaccine during pregnancy. Eighteen (12%) mothers of influenza-positive infants and 276 (20%) mothers of influenza-negative infants were vaccinated (unadjusted OR= 0.53, 95%CI 0.32–0.88 and adjusted OR=0.52, 95%0.30–0.91).
Infants of vaccinated mothers were 45%–48% less likely to have influenza hospitalizations than infants of unvaccinated mothers. Our results support the current influenza vaccination recommendation for pregnant women.
infants; influenza hospitalization; influenza vaccine; maternal vaccination; vaccine effectiveness
Several genetic variants associated with platelet count and mean platelet volume
(MPV) were recently reported in people of European ancestry. In this
meta-analysis of 7 genome-wide association studies (GWAS) enrolling African
Americans, our aim was to identify novel genetic variants associated with
platelet count and MPV. For all cohorts, GWAS analysis was performed using
additive models after adjusting for age, sex, and population stratification. For
both platelet phenotypes, meta-analyses were conducted using inverse-variance
weighted fixed-effect models. Platelet aggregation assays in whole blood were
performed in the participants of the GeneSTAR cohort. Genetic variants in ten
independent regions were associated with platelet count
(N = 16,388) with p<5×10−8 of
which 5 have not been associated with platelet count in previous GWAS. The novel
genetic variants associated with platelet count were in the following regions
(the most significant SNP, closest gene, and p-value): 6p22 (rs12526480,
LRRC16A, p = 9.1×10−9), 7q11
(rs13236689, CD36, p = 2.8×10−9),
10q21 (rs7896518, JMJD1C,
p = 2.3×10−12), 11q13 (rs477895,
BAD, p = 4.9×10−8), and 20q13
(rs151361, SLMO2, p = 9.4×10−9).
Three of these loci (10q21, 11q13, and 20q13) were replicated in European
Americans (N = 14,909) and one (11q13) in Hispanic
Americans (N = 3,462). For MPV
(N = 4,531), genetic variants in 3 regions were significant
at p<5×10−8, two of which were also associated with
platelet count. Previously reported regions that were also significant in this
study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22,
17q11, and 19p13 for MPV. The most significant SNP in 1 region was also
associated with ADP-induced maximal platelet aggregation in whole blood (12q24).
Thus through a meta-analysis of GWAS enrolling African Americans, we have
identified 5 novel regions associated with platelet count of which 3 were
replicated in other ethnic groups. In addition, we also found one region
associated with platelet aggregation that may play a potential role in
The majority of the variation in platelet count and mean platelet volume between
individuals is heritable. We performed genome-wide association studies in more
than 16,000 African American participants from seven population-based cohorts to
identify genetic variants that correlate with variation in platelet count and
mean platelet volume. We observed statistically significant evidence
(p-value<5×10−8) that 10 genomic regions were
associated with platelet count and 3 were associated with mean platelet volume.
Of the regions that were significantly associated, we found 5 novel regions that
were not reported previously in other populations. Three of these 5 regions were
also associated with platelet count in European Americans and Hispanic
Americans. All these regions contain genes that are either known to have or
potentially may have a role in determining platelet count and/or mean platelet
volume. We further found that one of these regions was also associated with
agonist-induced platelet aggregation. Further studies will determine the exact
role played by these genomic regions in platelet biology. The knowledge
generated by this and other studies will not only help us better understand
platelet biology but can also lead us to the discovery of new anti-platelet
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived “null” variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10−8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.
Although recent genome-wide association studies have identified common genetic variants associated with total white blood cell (WBC) and WBC sub-type counts in European and Japanese ancestry populations, whether these or other loci account for differences in WBC count among African Americans is unknown. By examining >16,000 African Americans, we show that, in addition to the previously identified Duffy Antigen Receptor for Chemokines (DARC) locus on chromosome 1, another variant, rs9131, and other nearby variants on human chromosome 4 are associated with total WBC count in African Americans. The variants span the CXCL2 gene, which encodes an inflammatory mediator involved in WBC production and migration. We show that the association is not restricted to African Americans but is also present in independent samples of European Americans, Hispanic Americans, and Japanese. This finding is potentially important because WBC mediate or have altered counts in a variety of acute and chronic disorders.
The goal of this analysis is to evaluate the effectiveness of a promotora program for teaching women in Latino farmworker families about pesticide safety and increasing pesticide safety behaviors. Volunteer promotoras delivered a pesticide safety curriculum (intervention) and nutrition curriculum (control) to farmworker women residing in western North Carolina and Virginia. Pre- and post-intervention interviews assessed differences in delivery of the intervention, recognition of the intervention, pesticide knowledge, pesticide exposures behaviors, and integrated pest management behaviors. Participants in the intervention group reported significantly more receipt of pesticide education and greater recognition of the key messages. However, their knowledge, pesticide exposure behaviors, and integrated pest management behaviors did not change. A more structured program is needed to be sure that the dose of interventions is large enough to overcome educational and cultural characteristics of immigrant communities. Policy changes are needed to address circumstances outside of farmworkers’ control that affect pesticide exposure.
The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10−7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0×10−9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.
The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.
A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.
Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects.
Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.
Haemochromatosis; Hemochromatosis; HFE; Iron overload
Dietary self-management of diabetes is often difficult for older adults to practice, particularly in rural communities. We describe patterns and correlates of dietary fat reduction among older rural adults with diabetes of any type. In-home interviews were conducted with a multiethnic random sample of 701 adults ≥65 with diabetes from two North Carolina counties. The Fat and Fiber Behavior Questionnaire was used to measure dietary behaviors. Separate multiple linear regressions assessed effects of gender, ethnicity, and diabetes education. In general, scores were more favorable for practices that involved modifying food preparation (e.g., avoiding frying) and less favorable for practices that involved changing foods consumed (e.g., substituting fruits and vegetables as desserts or snacks). American Indians and African Americans had less favorable scores than whites, and diabetes education was associated with greater fat restriction for women than men. Older men and ethnic minorities with diabetes should be targeted for dietary change education.
diabetes; African Americans; American Indians; gender differences; diet; self-management
To assess the association of depressive symptoms with diabetes self-management regimens among older adults with type 2 diabetes in a rural, ethnically diverse community.
Data from 696 rural older African Americans, American Indians and whites were used to assess depressive symptoms (modified CES-D) and diabetes self-management (physical activity, blood glucose self-monitoring, self foot checks, following a healthful eating plan, and medication adherence).
In bivariate analyses, high CES-D scores were associated with decreased adherence to a healthful eating plan and physical activity, and increased foot checks; the latter 2 remained significant in multivariate analyses.
Older adults with diabetes and depression are less likely to adhere to self-management, increasing their risk of complications.
depressive symptoms; type 2 diabetes; African Americans; American Indians; diabetes self-management
Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.
To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening.
Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364).
Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.
Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.
Complications; Cross-sectional study; Hemochromatosis; HFE; Iron overload; Prevalence