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1.  Variant in the 3′ Region of the IκBα Gene Associated With Insulin Resistance in Hispanic Americans: The IRAS Family Study 
Obesity (Silver Spring, Md.)  2009;18(3):555-562.
The IKKβ/NF-κB pathway is known to play an important role in inflammatory response and has also recently been implicated in the process of insulin resistance. We hypothesized that one or more variants in the IκBα gene (NFKBIA) or surrounding untranslated regions would be associated with insulin sensitivity (SI) in Hispanic-American families. We tested for association between 25 single-nucleotide polymorphisms (SNPs) in and near NFKBIA and SI in 981 individuals in 90 Hispanic-American families from the Insulin Resistance Atherosclerosis (IRAS) Family Study. SNP rs1951276 in the 3′ flanking region of NFKBIA was associated with SI in the San Antonio (SA) sample after adjusting for age, gender, and admixture (uncorrected P = 1.69 × 10−5; conservative Bonferroni correction P = 3.38 × 10−4). Subjects with at least one A allele for NFKBIA rs1951276 had ~29% lower SI compared to individuals homozygous for the G allele in the SA sample. Although not statistically significant, the effect was in the same direction in the San Luis Valley (SLV) sample alone (P = 0.348) and was significant in the combined SA and SLV samples (P = 5.37 × 10−4; presence of A allele associated with ~20% lower SI). In SA, when adjusted for subcutaneous adipose tissue area (SAT, cm2), the association was modestly attenuated (P = 1.25 × 10−3), but the association remained highly significant after adjustment for visceral adipose tissue area (VAT, cm2; P = 4.41 × 10−6). These results provide corroborating evidence that the NF-κB/IKKβ pathway may mediate obesity-induced insulin resistance in humans.
doi:10.1038/oby.2009.303
PMCID: PMC3992855  PMID: 19798070
2.  Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis 
Nature genetics  2013;45(6):613-620.
We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.
doi:10.1038/ng.2609
PMCID: PMC3677861  PMID: 23583980
3.  Impact of Glycemic Control on Heart Rate Variability in Youth with Type 1 Diabetes: The SEARCH CVD Study 
Diabetes Technology & Therapeutics  2013;15(12):977-983.
Abstract
Aim: This study explored the role of glycemic control on cardiac autonomic function, measured by heart rate variability (HRV), in youth with type 1 diabetes.
Patients and Methods: A retrospective cohort of 345 youth with type 1 diabetes (mean age, 18.5 years; duration, 10 years) participating in the SEARCH for Diabetes in Youth study were enrolled in the ancillary SEARCH Cardiovascular Disease (CVD) study. Anthropometric, metabolic, and HRV parameters were collected at the current research visit. Glycemic control over time was assessed by the mean glycated hemoglobin (A1c) levels collected over the past 6 years. Multiple linear regression analysis assessed the association between A1c over time and HRV parameters, independent of demographic and CVD risk factors. Participants were categorized into four glycemic control categories based on their mean A1c over time: Group 1, optimal (mean A1c, ≤7.4%); Group 2 (mean A1c, 7.5–8.4%); Group 3 (mean A1c, 8.5–9.4%), and Group 4, poor (mean A1c, ≥9.5%), and a linear trend was explored across these categories.
Results: For every 1% increase in the average A1c over 6 years there was a 5% decrease in the SD of the normal RR interval (SDNN) (P=0.02) and 7% decrease in the root mean square successive difference of the RR interval (RMSSD) (P=0.02), independent of demographic and traditional CVD risk factors. A dose–response relationship between worsening glucose control categories and measures of overall reduced HRV was found.
Conclusions: Chronic hyperglycemia is the main determinant of early cardiac autonomic dysfunction, manifested as reduced overall HRV and parasympathetic loss, among youth with type 1 diabetes.
doi:10.1089/dia.2013.0147
PMCID: PMC3868395  PMID: 24010960
4.  Insulin Sensitivity and Insulin Clearance are Heritable and Have Strong Genetic Correlation in Mexican Americans 
Obesity (Silver Spring, Md.)  2014;22(4):1157-1164.
Objective
We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).
Design and Methods
GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3925 individuals) using variance components.
Results
Across studies, age and gender-adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23–0.48 and of MCRI from 0.35–0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P<0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P<0.0001); and −0.16 to −0.36 for AIRg and MCRI (P <0.0001−0.06).
Conclusions
These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.
doi:10.1002/oby.20639
PMCID: PMC3968231  PMID: 24124113
insulin sensitivity; insulin clearance; heritability; genetic correlation; environmental correlation
5.  Reduced Heart Rate Variability Is Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes 
Diabetes Care  2013;36(8):2351-2358.
OBJECTIVE
Reduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors.
RESEARCH DESIGN AND METHODS
The SEARCH Cardiovascular Disease (SEARCH CVD) study explored the cross-sectional relationships between HRV and several measures of AS in youth with (n = 344) and without (n = 171) type 1 diabetes. The SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure HRV using SD of normal R-R interval (SDNN), as well as AS, using pulse wave velocity in the carotid to femoral segment (PWV-trunk) and augmentation index adjusted to a heart rate of 75 bpm (AIx75). Brachial distensibility (BrachD), another index of AS, was measured with a DynaPulse instrument (Pulse Metric, San Diego, CA). Multiple linear regression analyses explored the associations between HRV and each of the three AS measures, after adjusting for demographic characteristics and traditional CVD risk factors (blood pressure, lipids, obesity, microalbuminuria, and smoking) separately, for youth with and without type 1 diabetes.
RESULTS
Among youth with type 1 diabetes, lower SDNN was associated with peripheral AS (lower BrachD, P = 0.01; r2 = 0.30) and central AS (higher PVW-trunk, P < 0.0001; r2 = 0.37; and higher AIx75, P = 0.007; r2 = 0.08). These associations were attenuated with adjustment for CVD risk factors, but remained statistically significant for BrachD and PWV-trunk. While a similar association between HRV and BrachD was present in control youth, lower HRV was not associated with increased central AS or with AIx75.
CONCLUSIONS
Longitudinal studies are needed to understand the pathways responsible for these associations.
doi:10.2337/dc12-0923
PMCID: PMC3714513  PMID: 23435158
6.  Exploring Differences in Adiposity in Two US Hispanic Populations of Mexican Origin Using Social, Behavioral, Physiologic and Genetic Markers: The IRAS Family Study 
Ethnicity & disease  2012;22(1):65-71.
Objective
The census classification of Hispanic origin is used in epidemiological studies to group individuals, even though there is geographical, cultural, and genetic diversity within Hispanic Americans of purportedly similar backgrounds. We observed differences in our measures of adiposity between our two Mexican American populations, and examined whether these differences were attributed to social, behavioral, physiologic or genetic differences between the two populations.
Research Design and Methods
In the IRAS Family Study, we examined 478 Hispanics from San Antonio, Texas and 447 Hispanics from the San Luis Valley, Colorado. Associations with body mass index (BMI), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) using social, behavioral, physiologic and genetic variables were examined.
Results
Hispanics of Mexican origin in our clinic population in San Antonio had significantly higher mean BMI (31.09 vs 28.35 kg/m2), VAT (126.3 vs 105.5 cm2), and SAT (391.6 vs 336.9 cm2), than Hispanics of Mexican origin in the San Luis Valley. The amount of variation in adiposity explained by clinic population was 4.5% for BMI, 2.8% for VAT, and 2.7% for SAT. After adjustment, clinic population was no longer associated with VAT and SAT, but remained associated with BMI, although the amount of variation explained by population was substantially less (1.0% for BMI).
Conclusion
Adiposity differences within this population of Mexican origin can be largely explained by social, behavioral, physiologic and genetic differences. (Ethn Dis. 2012;22(1):65–71)
PMCID: PMC4020784  PMID: 22774311
Hispanics; Adiposity; Admixture; Environmental Differences; Social Factors; Behavior; Genetics
7.  Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia 
Psychiatric genetics  2012;22(1):10.1097/YPG.0b013e32834c0c33.
Objective
The chromosomal region, 15q13-q14, including the α7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7.
Methods
Family-based and case–control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia.
Results
Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians.
Conclusion
Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism. Psychiatr Genet 22:1–14 © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
doi:10.1097/YPG.0b013e32834c0c33
PMCID: PMC3878876  PMID: 21970977
association; CHRNA7; chromosome 15; copy number variation; nicotinic receptor; schizophrenia
8.  Reduced Heart Rate Variability Among Youth With Type 1 Diabetes 
Diabetes Care  2012;36(1):157-162.
OBJECTIVE
This study compared heart rate variability (HRV) parameters in youth with and without type 1 diabetes and explored potential contributors of altered HRV.
RESEARCH DESIGN AND METHODS
HRV parameters were measured among 354 youth with type 1 diabetes (mean age 18.8 years, diabetes duration 9.8 years, and mean A1C 8.9%) and 176 youth without diabetes (mean age 19.2 years) participating in the SEARCH CVD study. Multiple linear regression was used to assess the relationship between diabetes status and HRV parameters, adjusting for covariates.
RESULTS
Compared with control subjects, youth with type 1 diabetes had reduced overall HRV (10.09 ms lower SD of NN intervals [SDNN]) and markers of parasympathetic loss (13.5 ms reduced root mean square successive difference of NN intervals [RMSSD] and 5.2 normalized units (n.u.) reduced high frequency [HF] power) with sympathetic override (5.2 n.u. increased low frequency [LF] power), independent of demographic, anthropometric, and traditional cardiovascular risk factors. Older age, female sex, higher LDL cholesterol and triglyceride levels, and presence of microalbuminuria were independently associated with lower HRV but did not account for the observed differences between youth with and without diabetes. Youth with type 1 diabetes and A1C levels ≥7.5% had significantly worse HRV parameters than control subjects; however, in youth with optimal glycemic control (A1C <7.5%), HRV parameters did not differ significantly from control subjects.
CONCLUSIONS
Youth with type 1 diabetes have signs of early cardiac autonomic neuropathy: reduced overall HRV and parasympathetic loss with sympathetic override. The main driver of these subclinical abnormalities appears to be hyperglycemia.
doi:10.2337/dc12-0463
PMCID: PMC3526238  PMID: 22961570
9.  MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities 
The New England journal of medicine  2013;368(23):2192-2200.
BACKGROUND
A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population.
METHODS
We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus.
RESULTS
Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association.
CONCLUSIONS
The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00005121.)
doi:10.1056/NEJMoa1216076
PMCID: PMC3747636  PMID: 23692170
10.  A Common MUC5B Promoter Polymorphism and Pulmonary Fibrosis 
The New England Journal of Medicine  2011;364(16):1503-1512.
BACKGROUND
The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk.
METHODS
Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue.
RESULTS
Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10−15; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10−37). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis.
CONCLUSIONS
A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dys-regulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
doi:10.1056/NEJMoa1013660
PMCID: PMC3379886  PMID: 21506741
11.  Risk of Chronic Beryllium Disease by HLA-DPB1 E69 Genotype and Beryllium Exposure in Nuclear Workers 
Rationale: Beryllium sensitization (BeS) and chronic beryllium disease (CBD) are determined by at least one genetic factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, and by exposure to beryllium. The relationship between exposure and the E69 genotype has not been well characterized.
Objectives: The study goal was to define the relationship between beryllium exposure and E69 for CBD and BeS.
Methods: Workers (n = 386) from a U.S. nuclear weapons facility were enrolled into a case–control study (70 BeS, 61 CBD, and 255 control subjects). HLA-DPB1 genotypes were determined by sequence-specific primer-polymerase chain reaction. Beryllium exposures were reconstructed on the basis of worker interviews and historical exposure measurements.
Measurements and Main Results: Any E69 carriage increased odds for CBD (odds ratio [OR], 7.61; 95% confidence interval [CI], 3.66–15.84) and each unit increase in lifetime weighted average exposure increased the odds for CBD (OR, 2.27; 95% CI, 1.26–4.09). Compared with E69-negative genotypes, a single E69-positive *02 allele increased the odds for BeS (OR, 12.01; 95% CI, 4.28–33.71) and CBD (OR, 3.46; 95% CI, 1.42–8.43). A single non-*02 E69 allele further increased the odds for BeS (OR, 29.54; 95% CI, 10.33–84.53) and CBD (OR, 11.97; 95% CI, 5.12–28.00) and two E69 allele copies conferred the highest odds for BeS (OR, 55.68; 95% CI, 14.80–209.40) and CBD (OR, 22.54; 95% CI, 7.00–72.62).
Conclusions: E69 and beryllium exposure both contribute to the odds of CBD. The increased odds for CBD and BeS due to E69 appear to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes.
doi:10.1164/rccm.201002-0254OC
PMCID: PMC3136994  PMID: 21471109
berylliosis; genetics; case–control studies; occupational exposure; HLA-DP antigens
12.  Genome-wide association study of vitamin D concentrations in Hispanic Americans: The IRAS Family Study 
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
doi:10.1016/j.jsbmb.2010.06.013
PMCID: PMC2949505  PMID: 20600896
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
13.  The α7 Nicotinic Acetylcholine Receptor and The Acute Stress Response: Maternal Genotype Determines Offspring Phenotype 
Physiology & behavior  2010;104(2):321-326.
α7 nicotinic acetylcholine receptors (α7nAchRs) modulate immune activation by suppressing production of pro-inflammatory cytokines in peripheral immune cells. α7nAchRs also modulate inhibitory output in the hippocampus, which provides input to key circuits of the HPA axis. Therefore the α7 nicotinic acetylcholine receptor gene (CHRNA7) may be associated with cortisol stress response. Polymorphisms in the CHRNA7 promoter decrease its expression and may dampen the cholinergic response, leading to an increase in inflammation. Increased inflammation may change the intrauterine environment, altering neuroendocrine development in the offspring. Maternal CHRNA7 genotype could affect an offspring’s HPA regulation via reprogramming in utero. Patients with allergic disorders have a differential cortisol response to stress. This study utilized samples collected from a cohort of 198 adolescents in a previous study of atopic disorders, who demonstrated a disturbance in HPA response associated with atopy. Salivary cortisol samples collected from the adolescents after a series of laboratory procedures and DNA samples collected from the adolescents and their parents were used for further analysis. DNA samples were genotyped for allelic variation in the CHRNA7 promoter. Genetic association analyses with the cortisol levels were performed in the adolescents. Maternal genotype influences were investigated for the CHRNA7 gene. We also included maternal and child atopy diagnosis as covariates in determining cortisol levels and tested for association of CHRNA7 to atopy. Polymorphisms in the CHRNA7 promoter were associated with lower cortisol levels after a small laboratory stress. Our findings also show that although the child’s CHRNA7 genotype affects stress response, the maternal genotype has a stronger influence on cortisol release after stress in male offspring. These effects were independent of atopy status.
doi:10.1016/j.physbeh.2010.11.007
PMCID: PMC3094732  PMID: 21073885
Stress; Cortisol; Genetics; Association Study; Adolescents
14.  Association of 25-hydroxyvitamin D with Blood Pressure in Predominantly 25-hydroxyvitamin D Deficient Hispanic and African Americans 
American journal of hypertension  2009;22(8):867-870.
Background
Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25-hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans.
Methods
The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three U.S. recruitment centers (n=1334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure.
Results
An inverse association was found between 25[OH]D and both systolic (β for 10 ng/mL difference= −2.05; p<0.01) and diastolic (β for 10 ng/mL difference= −1.35; p<0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (β for 10 ng/mL difference= −0.94; p=0.14 and β for 10 ng/mL difference = −0.64; p=0.09, respectively).
Conclusions
25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted.
doi:10.1038/ajh.2009.88
PMCID: PMC2865679  PMID: 19444222
Vitamin D; 25-hydroxyvitamin D; blood pressure; hypertension; race; ethnic groups; Hispanic; African American
15.  Genome Wide Association Study and Follow-Up Analysis of Adiposity Traits in Hispanic-Americans: the IRAS Family Study 
Obesity (Silver Spring, Md.)  2009;17(10):1932-1941.
We investigated candidate genomic regions associated with computed tomography (CT)-derived measures of adiposity in Hispanic from the IRAS Family Study. In 1190 Hispanic individuals from 92 families from the San Luis Valley, CO and San Antonio, TX, we measured CT-derived visceral adipose tissue (VAT); subcutaneous adipose tissue (SAT); and visceral: subcutaneous ratio (VSR). A genome-wide association study (GWAS) was completed using the Illumina HumanHap 300 BeadChip (~317K single nucleotide polymorphisms (SNPs)) in 229 individuals from the San Antonio site (Stage 1). Two hundred ninety-seven SNPs with evidence for association with VAT, SAT, or VSR, adjusting for age and sex (p<0.001), were genotyped in the remaining 961 Hispanic samples. The entire Hispanic cohort (n = 1190) was then tested for association, adjusting for age, sex, site of recruitment and admixture estimates (Stage 2). In Stage 3, additional SNPs were genotyped in four genic regions showing evidence of association in Stage 2.
Several SNPs were associated in the GWAS (p<1×10−5) and were confirmed to be significantly associated in the entire Hispanic cohort (p<0.01), including: rs7543757 for VAT; rs4754373, and rs11212913 for SAT; and rs4541696, and rs4134351 for VSR. Numerous SNPs were associated with multiple adiposity phenotypes. Targeted analysis of four genes whose SNPs were significant in Stage 2 suggest candidate genes for influencing the distribution (RGS6) and amount of adiposity (NGEF).
Several candidate loci, including RGS6 and NGEF, are associated with CT-derived adipose fat measures in Hispanic Americans in a three-stage genetic association study.
doi:10.1038/oby.2009.143
PMCID: PMC2832211  PMID: 19461586
genetic association; visceral fat; subcutaneous fat; obesity; body mass index
16.  A Likelihood Model That Accounts for Censoring Due to Fetal Loss Can Accurately Test the Effects of Maternal and Fetal Genotype on the Probability of Miscarriage 
Human Heredity  2008;67(1):57-65.
Objective
Heritable maternal and fetal thrombophilia and/or hypofibrinolysis are important causes of miscarriage. Under the constraint that fetal genotype is observed only after a live birth, estimating risk is complicated. Censoring prevents use of published statistical methodology. We propose techniques to determine whether increases in miscarriage are due to the fetal genotype, maternal genotype, or both.
Methods
We propose a study to estimate the risk of miscarriage contributed by an allele, expressed in either dominant or recessive fashion. Using a multinomial likelihood, we derive maximum likelihood estimates of risk for different genotype groups. We describe likelihood ratio tests and a planned hypothesis testing strategy.
Results
Parameter estimation is accurate (bias <0.0011, root mean squared error <0.0780, n = 500). We used simulation to estimate power for studies of three gene mutations: the 4G hypofibrinolytic mutation in the plasminogen activator inhibitor gene (PAI-1), the prothrombin G20210A mutation, and the Factor V Leiden mutation. With 500 families, our methods have approximately 90% power to detect an increase in the miscarriage rate of 0.2, above a background rate of 0.2.
Conclusion
Our statistical method can determine whether increases in miscarriage are due to fetal genotype, maternal genotype, or both despite censoring.
doi:10.1159/000164399
PMCID: PMC2755496  PMID: 18931510
PAI-1; Pregnancy loss; Thrombophilia; Hypofibrinolysis; Genetics
17.  A Likelihood Model That Accounts for Censoring Due to Fetal Loss Can Accurately Test the Effects of Maternal and Fetal Genotype on the Probability of Miscarriage 
Human heredity  2008;67(1):57-65.
Objective
Heritable maternal and fetal thrombophilia and/or hypofibrinolysis are important causes of miscarriage. Under the constraint that fetal genotype is observed only after a live birth, estimating risk is complicated. Censoring prevents use of published statistical methodology. We propose techniques to determine whether increases in miscarriage are due to the fetal genotype, maternal genotype, or both.
Methods
We propose a study to estimate the risk of miscarriage contributed by an allele, expressed in either dominant or recessive fashion. Using a multinomial likelihood, we derive maximum likelihood estimates of risk for different genotype groups. We describe likelihood ratio tests and a planned hypothesis testing strategy.
Results
Parameter estimation is accurate (bias < 0.0011, root mean squared error <0.0780, n = 500). We used simulation to estimate power for studies of three gene mutations: the 4G hypofibrinolytic mutation in the plasminogen activator inhibitor gene (PAI-1), the prothrombin G20210A mutation, and the Factor V Leiden mutation. With 500 families, our methods have approximately 90% power to detect an increase in the miscarriage rate of 0.2, above a background rate of 0.2.
Conclusion
Our statistical method can determine whether increases in miscarriage are due to fetal genotype, maternal genotype, or both despite censoring.
doi:10.1159/000164399
PMCID: PMC2755496  PMID: 18931510
PAI-1; Pregnancy loss; Thrombophilia; Hypofibrinolysis; Genetics
18.  Association of the 5′-upstream regulatory region of the α7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia 
Schizophrenia research  2009;109(1-3):102-112.
Background
The α7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies.
Methods
Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5′-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia.
Results
The rs3087454 SNP, located at position −1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P = 0.0009, African American; P = 0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia.
Conclusions
The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia.
doi:10.1016/j.schres.2008.12.017
PMCID: PMC2748327  PMID: 19181484
Nicotinic receptor; Schizophrenia; Polymorphism; Association; Sensory Processing; Alpha 7 nicotinic receptor; Regulatory region; Promoter

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