RESUMEN

BACKGROUND: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. OBJECTIVE: To identify genetic factors underlying glycemic traits in an adolescent H/L population. METHODS: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. RESULTS: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency = 0.10) that was associated with FI (ß = -0.299, SE = 0.054, p = 2.72×10-8 ) and was only slightly attenuated after adjusting for body mass index z-scores (ß = -0.252, SE = 0.047, p = 1.03×10-7 ). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. CONCLUSION: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease aetiology.

Asunto(s)

Estudio de Asociación del Genoma Completo , Insulina , Adolescente , Glucemia , Chile , Ayuno , Frecuencia de los Genes , Humanos , Insulina/sangre , Estudios Longitudinales , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética

RESUMEN

OBJECTIVE: Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry. METHODS: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis. RESULTS: In the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. CONCLUSIONS: PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.

Asunto(s)

Alanina Transaminasa/genética , Aspartato Aminotransferasas/genética , Lipasa/genética , Proteínas de la Membrana/genética , Americanos Mexicanos/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Modelos Lineales , Hígado/enzimología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/etnología , Polimorfismo de Nucleótido Simple , gamma-Glutamiltransferasa/genética

RESUMEN

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Asunto(s)

Ejercicio Físico , Sitios Genéticos/genética , Lípidos/sangre , Lípidos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Población Negra/genética , Brasil , Proteínas de Unión al Calcio/genética , Colesterol/sangre , HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Hispánicos o Latinos/genética , Humanos , Proteínas con Homeodominio LIM/genética , Metabolismo de los Lípidos/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Proteínas Musculares/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Triglicéridos/sangre , Triglicéridos/genética , Población Blanca/genética , Adulto Joven

RESUMEN

Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG = 3.67 × 10-10, LODTG = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r2 = 1.0) rs189547099 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) and chr4:157997598 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10-08). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LODLDL = 4.30, PLDL = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10-05, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, PLDL = 4.44 × 10-17, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.

Asunto(s)

Aterosclerosis/patología , Variación Genética , Lípidos/sangre , Americanos Mexicanos/genética , Adulto , Apolipoproteína A-V/genética , Aterosclerosis/genética , Proteínas Portadoras/genética , Femenino , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Humanos , Resistencia a la Insulina/genética , Lipoproteínas HDL/sangre , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Triglicéridos/sangre , Secuenciación del Exoma

RESUMEN

OBJECTIVE: This study aimed to explore the genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity. METHODS: A genome-wide association study of 7,757,139 single-nucleotide polymorphisms (SNPs) in 983 Mexican Americans (nmale = 403; nfemale = 580) from the Insulin Resistance Atherosclerosis Family Study was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue, visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography. RESULTS: The strongest signal identified was SNP rs2185405 (minor allele frequencies [MAF] = 40%; PVAT = 1.98 × 10-8 ) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF = 19%) was associated with VAT in males (Pmale = 2.39×10-8 ; Pfemale = 2.5 × 10-3 ). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6 cm2 increased VAT compared with noncarriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF = 14%; Pint = 3.07 × 10-8 ) in PAPPA2 and rs10923724 (MAF = 38%; Pint = 2.89 × 10-8 ) upstream of TBX15 were strongly associated with the interaction effect for VSR. CONCLUSIONS: Six loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.

Asunto(s)

Tejido Adiposo/metabolismo , Adiposidad/genética , Estudio de Asociación del Genoma Completo/métodos , Obesidad/metabolismo , Índice de Masa Corporal , Femenino , Genotipo , Humanos , Masculino , Americanos Mexicanos , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo

RESUMEN

OBJECTIVE: To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. STUDY DESIGN: There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. RESULTS: The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7-07). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9-07). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. CONCLUSIONS: In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies.

Asunto(s)

Hispánicos o Latinos/genética , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple

RESUMEN

Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.

Asunto(s)

Apolipoproteína A-I/sangre , Diabetes Mellitus/sangre , Insulina/sangre , Lipasa/sangre , Obesidad/sangre , Absorciometría de Fotón , Adiposidad/genética , Adiposidad/fisiología , Adulto , Estudios Transversales , Diabetes Mellitus/enzimología , Diabetes Mellitus/patología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/genética , Resistencia a la Insulina/genética , Lipasa/genética , Lípidos/sangre , Hígado/enzimología , Masculino , Americanos Mexicanos/genética , Obesidad/fisiopatología

RESUMEN

CONTEXT AND OBJECTIVE: We examined whether a prevalent caveolin-1 gene (CAV1) variant, previously related to insulin resistance, is associated with metabolic syndrome (MetS). PATIENTS AND METHODS: We included subjects genotyped for the CAV1 variant rs926198 from two cohorts: 735 Caucasians from the HyperPATH multicenter study, and 810 Hispanic participants from the HTN-IR cohort. RESULTS: Minor allele carriers from HyperPATH cohort (57% of subjects) had higher Framingham risk scores, higher odds of diabetes (10.7% vs 5.7%, p=0.016), insulin resistance (44.3% vs 35.1%, p=0.022), low HDL (49.3% vs 39.6%, p=0.018) and MetS (33% vs 20.5%, p<0.001) but similar BMI. Consistently, minor allele carriers exhibited higher odds of MetS, even when adjusted for confounders and relatedness (OR 2.83 (1.73-4.63), p<0.001). The association with MetS was replicated in the Hispanic cohort HTN-IR (OR 1.61, [1.06-2.44], p=0.025). Exploratory analyses suggest that MetS risk is modified by a CAV1 variant-BMI status interaction, whereby the minor allele carrier status strongly predicted MetS (OR 3.86 [2.05-7.27], p<0.001) and diabetes (OR 2.27 [1.07-4.78], p=0.03) in non-obese, but not in obese subjects. In addition, we observed a familial aggregation for MetS diagnosis in minor allele carriers. CONCLUSION: The prevalent CAV1 gene variant rs926198 is associated with MetS in separate Caucasian and Hispanic cohorts. These findings appear to be driven by an interaction between the genetic marker and obesity status, suggesting that the CAV1 variant may improve risk profiling in non-obese subjects. Additional studies are needed to confirm the clinical implications of our results.

Asunto(s)

Caveolina 1/genética , Hispánicos o Latinos/genética , Síndrome Metabólico/genética , Población Blanca/genética , Adulto , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Asunto(s)

Glucemia/genética , Diabetes Mellitus Tipo 2/metabolismo , Variación Genética , Homeostasis/fisiología , Glucemia/metabolismo , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/etnología , Regulación de la Expresión Génica/fisiología , Genoma , Estudio de Asociación del Genoma Completo , Genotipo , Hispánicos o Latinos , Homeostasis/genética , Humanos

RESUMEN

The Puerto Rico population may be modeled as an admixed population with contributions from three continents: Sub-Saharan Africa, Ancient America, and Europe. Extending the study of the genetics of inflammatory bowel disease (IBD) to an admixed population such as Puerto Rico has the potential to shed light on IBD genes identified in studies of European populations, find new genes contributing to IBD susceptibility, and provide basic information on IBD for the care of US patients of Puerto Rican and Latino descent. In order to study the association between immune-related genes and Crohn's disease (CD) and ulcerative colitis (UC) in Puerto Rico, we genotyped 1159 Puerto Rican cases, controls, and family members with the ImmunoChip. We also genotyped 832 subjects from the Human Genome Diversity Panel to provide data for estimation of global and local continental ancestry. Association of SNPs was tested by logistic regression corrected for global continental descent and family structure. We observed the association between Crohn's disease and NOD2 (rs17313265, 0.28 in CD, 0.19 in controls, OR 1.5, p = 9×10-6) and IL23R (rs11209026, 0.026 in CD, 0.0.071 in controls, OR 0.4, p = 3.8×10-4). The haplotype structure of both regions resembled that reported for European populations and "local" continental ancestry of the IL23R gene was almost entirely of European descent. We also observed suggestive evidence for the association of the BAZ1A promoter SNP with CD (rs1200332, 0.45 in CD, 0.35 in controls, OR 1.5, p = 2×10-6). Our estimate of continental ancestry surrounding this SNP suggested an origin in Ancient America for this putative susceptibility region. Our observations underscored the great difference between global continental ancestry and local continental ancestry at the level of the individual gene, particularly for immune-related loci.

Asunto(s)

Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Proteína Adaptadora de Señalización NOD2/genética , Receptores de Interleucina/genética , Adulto , Femenino , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Puerto Rico , Sitios de Carácter Cuantitativo , Factores de Riesgo , Adulto Joven

RESUMEN

OBJECTIVE: The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). METHODS: GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 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 3,925 individuals) using variance components. RESULTS: Across studies, age, and gender-adjusted heritability of insulin sensitivity (SI , M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 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.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Insulina/metabolismo , Tasa de Depuración Metabólica/genética , Americanos Mexicanos/genética , Adulto , Anciano , Estudios de Cohortes , Colorado , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Estudio de Asociación del Genoma Completo , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Estudios Retrospectivos , Texas

RESUMEN

The powerful relation between atherosclerosis and diabetes may have a common genetic basis. However, few genes predisposing to both have been identified. Calpain-10 (CAPN10) was the first gene for type 2 diabetes identified by positional cloning, wherein a combination of haplotypes conferred increased risk of diabetes. We sought to determine whether CAPN10 influences subclinical atherosclerosis. Among nondiabetic subjects from 85 Mexican-American families with a history of coronary artery disease, subclinical atherosclerosis was assessed by common carotid artery intima-media thickness (IMT), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretion was estimated by the oral glucose tolerance test. These phenotypes were tested for association with CAPN10 haplotypes. Haplotype 1112 (of single nucleotide polymorphisms [SNPs] 44, 43, 56, and 63) was associated with increased IMT, while haplotype 1221 was associated with decreased IMT. The 112/121 haplotype combination (of SNPs 43, 56, and 63), originally found to confer increased risk for diabetes, was associated with the largest IMT in our study population. CAPN10 was also associated with both insulin sensitivity and insulin secretion. Covariate analysis suggested that CAPN10 affects IMT independently of these diabetes-related phenotypes. The fact that the diabetes gene CAPN10 also influences the risk for atherosclerosis shows that inherited factors may underlie the frequent co-occurrence of these two conditions.

Asunto(s)

Arteriosclerosis/genética , Calpaína/genética , Adolescente , Adulto , Anciano , Arteriosclerosis/enzimología , Arteriosclerosis/etnología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Enfermedad Coronaria , Diabetes Mellitus Tipo 2/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Resistencia a la Insulina/genética , Masculino , Americanos Mexicanos/genética , Persona de Mediana Edad , Fenotipo , Túnica Íntima/patología

RESUMEN

OBJECTIVES: Medical dictionaries and anthropologic sources define brachycephaly as a cranial index (CI = width divided by length x 100%) greater than 81%. We examine the impact of supine sleeping on CI and compare orthotic treatment with repositioning. STUDY DESIGN: We compared the effect of repositioning versus helmet therapy on CI in 193 infants referred for abnormal head shape. RESULTS: Eighty percent of the infants had a pretreatment CI > 81%. Their initial mean CI at mean age 5.3 months was 89%, and after treatment, their mean CI was 87% (+/-2 SE = 0.9%) at mean age 9.0 months. For 92 infants with an initial CI at or above 90%, their initial mean CI of 96.1% was reduced to a mean of 91.9%. CONCLUSIONS: Post-treatment CI was 86% to 88%, CI in neonates delivered by cesarean section was 80%, and CI in supine-sleeping Asian children was 85% to 91%, versus 78% to 83% for prone-sleeping American children. Repositioning was less effective than cranial orthotic therapy in correcting severe brachycephaly. We recommend varying the head position when putting infants to sleep.

Asunto(s)

Plagiocefalia no Sinostótica/terapia , Cráneo/anomalías , Posición Supina/fisiología , Femenino , Dispositivos de Protección de la Cabeza , Humanos , Lactante , Estudios Longitudinales , Masculino , Plagiocefalia no Sinostótica/fisiopatología , Sueño/fisiología , Resultado del Tratamiento

RESUMEN

OBJECTIVES: We compare positioning with orthotic therapy in 298 consecutive infants referred for correction of head asymmetry. STUDY DESIGN: We evaluated 176 infants treated with repositioning, 159 treated with helmets, and 37 treated with initial repositioning followed by helmet therapy when treatment failed. We compared reductions in diagonal difference (RDD) between repositioning and cranial orthotic therapy. Helmets were routinely used for infants older than 6 months with DD >1 cm. RESULTS: For infants treated with repositioning at a mean age of 4.8 months, the mean RDD was 0.55 cm (from an initial mean DD of 1.05 cm). For infants treated with cranial orthotics at a mean age of 6.6 months, the mean RDD was 0.71 cm (from an initial mean DD of 1.13 cm). CONCLUSIONS: Infants treated with orthotics were older and required a longer length of treatment (4.2 vs 3.5 months). Infants treated with orthosis had a mean final DD closer to the DD in unaffected infants (0.3 +/- 0.1 cm), orthotic therapy was more effective than repositioning (61% decrease versus 52% decrease in DD), and early orthosis was significantly more effective than later orthosis (65% decrease versus 51% decrease in DD).

Asunto(s)

Plagiocefalia no Sinostótica/terapia , Posición Supina/fisiología , Factores de Edad , Oftalmopatías/etiología , Oftalmopatías/terapia , Femenino , Dispositivos de Protección de la Cabeza , Humanos , Lactante , Estudios Longitudinales , Masculino , Plagiocefalia no Sinostótica/complicaciones , Plagiocefalia no Sinostótica/fisiopatología , Cráneo/anomalías , Resultado del Tratamiento

RESUMEN

The insulin resistance syndrome is increasingly recognized as a risk factor for cardiovascular disease. Lipoprotein lipase (LPL) is a candidate gene for components of the syndrome. A small number of studies have demonstrated association of single nucleotide polymorphisms within LPL and indirect or surrogate measures of insulin resistance, largely based on glucose and insulin values obtained in the fasting state or during an oral glucose tolerance test. To test directly whether LPL is an insulin resistance gene, we performed the hyperinsulinemic-euglycemic clamp in a large family-based population of Mexican Americans who were genotyped at six polymorphisms in LPL that define the most common haplotypes in the population. LPL haplotypes showed linkage to the glucose infusion rate (GINF), a direct physiologic measurement of insulin sensitivity (P = 0.034). In addition, significant associations with GINF were demonstrated for the most common haplotype (P = 0.031) and the fourth most common haplotype (P = 0.007). Haplotype 1 was associated with insulin sensitivity (mean GINF for haplotype 1 carriers = 383.0 mg/min) and haplotype 4 with insulin resistance (mean GINF for haplotype 4 carriers = 344.3 mg/min). This haplotype-based genetic analysis provides compelling evidence that variation in the LPL gene plays a role in determining insulin resistance in this ethnic group with a high prevalence of the insulin resistance syndrome.

Asunto(s)

Resistencia a la Insulina/genética , Lipoproteína Lipasa/genética , Americanos Mexicanos/genética , Adulto , Etnicidad , Femenino , Humanos , Los Angeles , Masculino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/genética , Polimorfismo de Nucleótido Simple , Prevalencia , Esposos

RESUMEN

PURPOSE: To illustrate an approach of deriving haplotypes for genetic association studies, using the lipoprotein lipase (LPL) gene and coronary artery disease. METHODS: Six polymorphisms sufficient to distinguish the most common haplotypes in the 3' end of LPL were identified by genotyping 10 polymorphisms in a small pilot population. These were used to haplotype LPL in large family samples of Mexican-Americans and non-Hispanic Caucasians. A case-control association study was performed comparing Mexican-Americans with and without coronary artery disease. RESULTS: The two ethnic groups exhibited significant genetic differences. Among Mexican-Americans, homozygosity for LPL haplotype 1 was protective against coronary artery disease (OR = 0.50, 95% CI 0.27-0.91). CONCLUSION: This study outlines the haplotype structure of the LPL gene, illustrates the utility of haplotype-based analysis in association studies, and demonstrates the importance of defining haplotype frequencies for different ethnic groups.

Asunto(s)

Enfermedad de la Arteria Coronaria/etnología , Enfermedad de la Arteria Coronaria/genética , Lipoproteína Lipasa/genética , Alelos , Frecuencia de los Genes , Genotipo , Haplotipos , Hispánicos o Latinos , Homocigoto , Humanos , Modelos Logísticos , Americanos Mexicanos , Polimorfismo Genético , Población Blanca