Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study

Previous studies have demonstrated that low density lipoprotein cholesterol (LDL-C) concentration is influenced by both genes and environment. Although rare genetic variants associated with Mendelian causes of increased LDL-C are known, only one common genetic variant has been identified, the apolipoprotein E gene (APOE). In an attempt to localize quantitative trait loci (QTLs) influencing LDL-C, we conducted a genome-wide linkage scan of LDL-C in participants of the Strong Heart Family Study (SHFS). Nine hundred eighty men and women, age 18 years or older, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota) were phenotyped for LDL-C concentration and other risk factors. Using a variance component approach and the program SOLAR, and after accounting for the effects of covariates, we detected a QTL influencing LDL-C on chromosome 19, nearest marker D19S888 at 19q13.41 [logarithm of odds (LOD) = 4.3] in the sample from the Dakotas. This region on chromosome 19 includes many possible candidate genes, including the APOE/C1/C4/C2 gene cluster. In follow-up association analyses, no significant evidence for an association was detected with the APOE*2 and APOE*4 alleles (P = 0.76 and P = 0.53, respectively). Suggestive evidence of linkage to LDL-C was detected on chromosomes 3q, 4q, 7p, 9q, 10p, 14q, and 17q. These linkage signals overlap positive findings for lipid-related traits and harbor plausible candidate genes for LDL-C.     

Anthropometric and body composition characteristics in pre- and postmenopausal Asian Indian women: Santiniketan women study

The present cross-sectional study was aimed to investigate anthropometric and body composition characteristics in pre- and postmenopausal Asian Indian women. A total of 245 healthy women aged 25 to 65 years took part in the study. A random sampling procedure using a local voters' registration list was followed to select the participants. All participants belonged to the Bengalee population and were inhabitants of the Bolpur-Santiniketan area (lying in between 23 degrees 40' north latitude and 87degrees 43' east longitude) West Bengal, India. Before the actual commencement of the study, written information was communicated to select individuals, and an appointment was requested at their respective houses. Anthropometric measures, namely height, weight etc., were collected using standard techniques. Percentages of body fat (%BF) and body mass index (BMI) were measured using an Omron body fat analyser. All subjects were categorized into two groups: premenopausal (Group I; n = 145, mean age = 32.66 +/- 5.75 years) and postmenopausal (Group II; n = 100, mean age = 52.72 +/- 5.62 years). It was observed that 80.00% women were cohabited and 80.82% were housewife with 44.08% of them having an education up to secondary level. Furthermore, 62.45% subjects had monthly family expenditure of > or = 5000 Indian Rupees. One way ANOVA revealed that there was significant group difference for age, age at menarche, MWC, WHR, FM, FFM and %BF across the groups. Intercorrelation matrix (Pearson's correlation) showed that age had significantly positive association with MWC (p < 0.01), MHC (p < 0.05), WHR (p < 0.01), FM (p < 0.01), and %BF (p < 0.01), whereas FFM has had negative association with age. Most interestingly, it was observed that there was significant difference [chi2 (1) = 9.73] for central obesity status across the groups. It seems reasonable to argue that onset of menopause does play a vital role to alter body composition and in turn CVD risk factors.     

The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study

Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic. We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR < 60 ml/min/1.73 m² or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians.     

Effects of Obesity and Body Fat Distribution on Lipids and Lipoproteins in Nondiabetic American Indians: The Strong Heart Study

Objectives: To examine the relationship between obesity and lipoprotein profiles and compare the effects of total obesity and central adiposity on lipids/lipoproteins in American Indians. Research Methods and Procedures: Participants were 773 nondiabetic American Indian women and 739 men aged 45 to 74 years participating in the Strong Heart Study. Total obesity was estimated using body mass index (BMI). Central obesity was measured as waist circumference. Lipoprotein measures included triglycerides, high‐density lipoprotei in (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, apolipoprotein AI (apoAI), and apolipoprotein B (apoB). Partial and canonical correlation analyses were used to examine the associations between obesity and lipids/lipoproteins. Results: Women were more obese than men in Arizona (median BMI 32.1 vs. 29.2 kg/m²) and South Dakota and North Dakota (28.3 vs. 28.0 kg/m²), but there was no sex difference in waist circumference. Men had higher apoB and lower apoAI levels than did women. In women, when adjusted for center, gender, and age, BMI was significantly related to HDL cholesterol (r = ?0.24, p < 0.001). There was a significant but weak relation with apoAI (r = ?0.14 p < 0.001). Waist circumference was positively related to triglycerides (r = 0.14 p < 0.001) and negatively related to HDL cholesterol (r = ?0.23, p < 0.001) and apoAI (r = ?0.13, p < 0.001). In men, BMI was positively correlated with triglycerides (r = 0.30, p < 0.001) and negatively correlated with HDL cholesterol (r = ?0.35, p < 0.001) and apoAI (r = ?0.23, p < 0.001). Triglycerides increased with waist circumference (r = 0.30, p < 0.001) and HDL cholesterol decreased with waist circumference (r = ?0.36 p < 0.001). In both women and men there was an inverted U‐shaped relationship between obesity and waist with LDL cholesterol and apoB. In canonical correlation analysis, waist circumference received a greater weight (0.86) than did BMI (0.17) in women. However, the canonical weights were similar for waist (0.46) and BMI (0.56) in men. Only HDL cholesterol (?1.02) carried greater weight in women, whereas in men, triglycerides (0.50), and HDL cholesterol (?0.64) carried a large amount of weight. All the correlation coefficients between BMI, waist circumference, and the first canonical variable of lipids/lipoproteins or between the individual lipid/lipoprotein variables and the first canonical variable of obesity were smaller in women than in men. Triglycerides and HDL cholesterol showed clinically meaningful changes with BMI and waist circumference in men. All lipid/lipoprotein changes in women in relation to BMI and waist circumference were minimal. Discussion: The main lipoprotein abnormality related to obesity in American Indians was decreased HDL cholesterol, especially in men. Central adiposity was more associated with abnormal lipid/lipoprotein profiles than general obesity in women; both were equally important in men.     

Joint Association of Nicotinic Acetylcholine Receptor Variants with Abdominal Obesity in American Indians: The Strong Heart Family Study

Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.     

Changes in body fat distribution in relation to parity in American women: a covert form of maternal depletion

Using data from the Third National Health and Nutrition Examination Survey (NHANES III), conducted from 1988-1994, we investigated the effect of reproduction on the distribution of body fat in well-nourished American women. While women tend to gain weight and fat with succeeding pregnancies, if age and body mass index are controlled, increasing parity is associated with a decrease in hip and thigh circumferences, suprailiac and thigh skinfolds, and body fat estimated from skinfolds, while waist circumference increases, resulting in a relative decrease in lower-body fat. The mobilization of fat stores in the lower body during late pregnancy and lactation may help to meet the special needs of the developing brain for essential fatty acids and energy during the time of peak growth. When fat is regained after the postpartum period, relatively more is stored in central vs. peripheral depots, resulting in a patterned change in body shape with parity.     

Relationship of prenatal alcohol use with maternal and prenatal factors in American Indian women

Demographic factors and patterns of substance use among women who did not consume alcohol during pregnancy were compared to women who did consume alcohol during pregnancy. One-hundred seventy-seven Northern Plains Indian women who received prenatal care at an urban clinic in a rural state were screened for substance use as part of the validation study with a self-administered questionnaire. Women who drank during pregnancy were more likely to be single and have less education than women who did not drink. While most of the women in the study had available transportation resources, the women who drank during pregnancy were less likely to have transportation than the women who did not drink. Women who drank during pregnancy consumed more alcohol more frequently before pregnancy than did women who drank before but not during pregnancy. Compared to women who did not drink during pregnancy, women who drank during pregnancy were more likely to smoke cigarettes and use illicit drugs, to have parents who drank, to feel they drank the same or more than other pregnant women, or to have experienced more relationship breakups and physical and emotional abuse. Prenatal patients who drink alcohol during pregnancy need more intensive counseling regarding their multiple risk behaviors.     

Chronotype and postmenopausal breast cancer risk among women in the California Teachers Study

ABSTRACT

Chronotype is the behavioral manifestation of an individual’s underlying circadian rhythm, generally characterized by one’s propensity to sleep at a particular time during the 24 hour cycle. Evening chronotypes (“night owls”) generally suffer from worse physical and mental health compared to morning chronotypes (“morning larks”) – for reasons that have yet to be explained. One hypothesis is that evening chronotypes may be more susceptible to circadian disruption, a condition where the coordinated timing of biologic processes breaks down. The role of chronotype as an independent or modifying risk factor for cancer has not been widely explored. The objective of the current study was to evaluate the risk of breast cancer associated with chronotype in a case-control study nested within the California Teachers Study (CTS) cohort. The study population consisted of 39686 post-menopausal CTS participants who provided information on chronotype by completing a questionnaire in 2012–2013. 2719 cases of primary invasive breast cancer diagnosed from 1995/1996 through completion of the chronotype questionnaire were identified by linkage of the CTS to the California Cancer Registry. 36967 CTS participants who had remained cancer-free during this same time period served as controls. Chronotype was ascertained by responses to an abbreviated version of the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) and was characterized into five categories: definite morning, more morning than evening, neither morning or evening, more evening than morning, definite evening. Multivariable unconditional logistic regression analyses were performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for each of the chronotypes, adjusted for established breast cancer risk factors. Compared to definite morning types, definite evening types had an increased risk of breast cancer with elevated ORs that were statistically significant in both the crude (OR = 1.24, 95% CI: 1.10–1.40) and fully-adjusted models (OR = 1.20, 95% CI: 1.06–1.35). The risk estimates in the fully-adjusted model for all other chronotypes did not significantly differ from one. These results suggest that evening chronotype may be an independent risk factor for breast cancer among a population of women who are not known to have engaged in any substantial night shift work. Further research in other populations of non-shift workers is warranted.     

Polydactyly in the American Indian.

Polydactyly has an incidence in the American Indian twice that of Caucasians. A minimum estimate of this incidence is 2.40 per 1,000 live births. Preaxial type 1 has an incidence three to four times that reported for Caucasians or Negroes. The overall sex ratio in Indians is distorted with more males affected than females. The preaxial type 1 anomaly has a strong predilection for the hands and always is unilateral in contrast to postaxial type B where more than one-half are bilateral. The evidence to date, consisting of varying incidences of specific types of polydactyly among American whites, Negroes, and Indians in varying enviroments, suggests different gene-frequencies for polydactyly in each population. The incidence in Indians with 50% Caucasian admixture suggests that the factors controlling polydactyly are in large part genetically determined. Family studies and twin studies reported elsewhere offer no clear-cut genetic model which explains the highly variable gene frequencies.     

A novel obesity locus on chromosome 4q: the Strong Heart Family Study

Objective: Obesity is a growing and important public health problem in Western countries and worldwide. There is ample evidence that both environmental and genetic factors influence the risk of developing obesity. Although a number of genes influencing obesity and obesity‐related measures have been localized, it is clear that others remain to be identified. The rate of obesity is particularly high in American Indian populations. This study reports the results of a genome‐wide scan for loci influencing BMI and weight in 963 individuals in 58 families from three American Indian populations in Arizona, Oklahoma, and North and South Dakota participating in the Strong Heart Family Study. Research Methods and Procedures: Short tandem repeat markers were genotyped, resulting in a marker map with an average spacing of 10 centimorgans. Standard multipoint variance component linkage methods were used. Results: Significant evidence of linkage was observed in the overall sample, including all three study sites, for a locus on chromosome 4q35 [logarithm of the odds (LOD) = 5.17 for weight, 5.08 for BMI]. Analyses of the three study sites individually showed that the greatest linkage support for the chromosome 4 locus came from Arizona (LOD = 2.6 for BMI), but that LOD scores for weight were >1 in all three samples. Suggestive linkage signals (LOD >2) were also observed on chromosomes 5, 7, 8, and 10. Discussion: The chromosome 4 locus detected in this scan is in a region lacking any obvious positional candidate genes with known functions related to obesity. This locus may represent a novel obesity gene.     

Linkage Analysis of Factors Underlying Insulin Resistance: Strong Heart Family Study

In previous work in non‐diabetic participants of the Strong Heart Family Study, we identified three heritable principal components of nine insulin resistance (IR) phenotypes: 1) a glucose/insulin/obesity factor, 2) a blood pressure factor, and 3) a dyslipidemia factor. To localize quantitative trait loci (QTL) potentially influencing these factors, we conducted a genome scan of factor scores in Strong Heart Family Study participants. Approximately 599 men and women, ≥18 years of age, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota), were examined between 1997 and 1999. We used variance components linkage analysis to identify QTLs for the IR factors. With age, sex, and study center as covariates, we detected linkage of the glucose/insulin/obesity factor to chromosome 4 (robust logarithm of the odds (LOD) = 2.2), the dyslipidemia factor to chromosome 12 (robust LOD = 2.7), and the blood pressure factor to chromosome 1 (robust LOD = 1.6). The peak linkage signals identified for these IR factors support several positive findings from other studies and occur in regions harboring interesting candidate genes. The corroboration of existing QTLs will bring us closer to the identification of the functional genes that predispose to IR.     

Negotiating a Multicultural Canon: Finding the "Indian" in American Indian Law

The Encyclopedia of Native American Legal Tradition. Bruce Elliot Johansen. ed. Westport, CT: Greenwood Press, 1998. 410 pp.
Linking Arms Together: American Indian Treaty Visions of Law and Peace, 1600-1800. Robert A. Williams Jr. New York: Oxford University Press, 1997. 192 pp.     

Apoptosis in raloxifene-treated postmenopausal women

As raloxifene is a mixed estrogen receptor agonist and antagonist, it exerts different effects on apoptosis in different tissues. In this study, we aimed to evaluate apoptosis in the peripheral lymphocytes of postmenopausal women treated with raloxifene and compare it with untreated control subjects. In this way, we expected to deduce some results about the effect of raloxifene on the immune system and to serve as a guide for future studies on this newly proposed effect of a well-known agent. Twenty osteoporotic postmenopausal women treated with raloxifene for 12 months were included in this study. Another 20 osteoporotic postmenopausal women matched for age and postmenopausal years, but without any medication, were chosen as the control group. Apoptosis was evaluated using a morphological and DNA fragmentation assay, in the peripheral lymphocytes of these women. Our results revealed a decrease in the apoptosis percentages of the patients treated with raloxifene (14.6%) with respect to the control subjects (15.8%), but the difference was not statistically significant (p=0.467). This study indicated that raloxifene treatment had no apoptotic effect on peripheral human lymphocytes compared to controls.     

Randomly and Non-Randomly Missing Renal Function Data in the Strong Heart Study: A Comparison of Imputation Methods

Kidney and cardiovascular disease are widespread among populations with high prevalence of diabetes, such as American Indians participating in the Strong Heart Study (SHS). Studying these conditions simultaneously in longitudinal studies is challenging, because the morbidity and mortality associated with these diseases result in missing data, and these data are likely not missing at random. When such data are merely excluded, study findings may be compromised. In this article, a subset of 2264 participants with complete renal function data from Strong Heart Exams 1 (1989–1991), 2 (1993–1995), and 3 (1998–1999) was used to examine the performance of five methods used to impute missing data: listwise deletion, mean of serial measures, adjacent value, multiple imputation, and pattern-mixture. Three missing at random models and one non-missing at random model were used to compare the performance of the imputation techniques on randomly and non-randomly missing data. The pattern-mixture method was found to perform best for imputing renal function data that were not missing at random. Determining whether data are missing at random or not can help in choosing the imputation method that will provide the most accurate results.