Linkage and association of candidate obesity genes in Mexican-Americans from Starr County, Texas

Obesity and related chronic diseases represent a tremendous public health burden among Mexican Americans, a young and rapidly-expanding population. This study investigated the impact of variation within eight candidate obesity genes, which include leptin (LEP), leptin receptor (LEPR), neuropeptide Y (NPY), NPYY1 receptor (NPYY1), glucagon-like peptide-1 (GLP-1), GLP-1 receptor (GLP1R), beta-3 adrenergic receptor (β3AR), and uncoupling protein (UCP1), on variation in human obesity status and/or quantitative traits related to obesity in Mexican Americans from Starr County, Texas. The Trp64Arg polymorphism within β3AR was typed in 820 random individuals and 240 pedigrees (N = 2,044). The Arg allele frequency was significantly greater in obese versus non-obese individuals (0.20 versus 0. 15, respectively). In addition, within the random sample, the Arg allele was associated with significantly greater body weight (p = 0.031) and body mass index (BMI, p = 0.008) than the Trp allele. In the family sample, the Trp64Arg locus was also linked to percent fat (p = 0.045) but not to body weight or BMI. No linkage between obesity, diabetes, hypertension, or gallbladder disease and the Trp64Arg mutation was observed in families using affected sib pair linkage analysis or the transmission disequilibrium test. Microsatellite markers proximate to the remaining seven genes were typed in 302 individuals from 59 families. Sib pair linkage analysis provided evidence for linkage between obesity and NPY within affected sibling pairs (p = 0.042; n = 170 pairs). NPY was also linked to weight (p = 0.020), abdominal circumference (p = 0.031), hip circumference (p = 0.012), DBP (p ≤ 0.005), and a composite measure of body mass/fat (p ≤ 0.048) in all sibling pairs (n = 545 pairs). Additionally, LEP was linked to waist/hip ratio (p ≤ 0.009), total cholesterol (p ≤ 0.030), and HDL cholesterol (p ≤ 0.026), and LEPR was linked to fasting blood glucose (p ≤ 0.018) and DBP (p ≤ 0.003). Subsequent to the linkage analyses, the NPY gene was sequenced and eight variant sites identified. Two variant sites (-880I/D and 69I/D) were typed in a random sample of 914 individuals. The 880I/D variant was significantly associated with waist/hip ratio (p = 0.035) in the entire sample (N = 914) and with BMI (p = 0. 031), abdominal circumference (p = 0.044), and waist/hip ratio (p = 0.041) in a non-obese subsample (BW < 30 kg/m2, n = 594). The 69I/D variant was a rare mutation observed in only one pedigree and was not associated with obesity or body size/mass within this pedigree. Results of this study indicate that variation at or near β3AR, LEP, LEPR, and NPY may exert effects which increase obesity susceptibility and influence obesity-related measures in this population. ^

Role of {\it Mycobacterium avium-intracellulare\/} complex infection in AIDS mortality

Disseminated MAC (dMAC) is the third most prevalent opportunistic infection in AIDS patients. In order to understand the role MAC infection plays in affecting survival of AIDS patients, a cohort of 203 suspected dMAC veterans seen at the Houston Veterans Affairs Medical Center between August 14, 1987 and December 31, 1991 were analyzed. The criteria for suspected dMAC infection was HIV+ men having a CD4+ level $\le$200 cells/mm$\sp3,$ on zidovudine treatment $\ge$1 month and who had any of the following: (a) a confirmed respiratory MAC infection, (b) fever $\ge$101$\sp\circ\rm F$ for $\ge$48 hours, (c) unexplained weight loss of 10 lbs or $\ge$10% BW over 3 months or (d) Hgb $\le$7.5 g/dl or decrease in Hgb $\ge$3.0 g/dl, while on 500-600 mg/day AZT. The study was conducted before the commencement of an effective MAC anti-mycobacterial therapy, so the true course of MAC infection was seen without the confounder of a therapeutic regimen. Kaplan-Meier and Cox regression survival analysis was used to compare 45 MAC culture positive and 118 MAC culture negative veterans. The 1 year survival rate of veterans with documented dMAC infection was 0.37 compared to 0.50 for veterans not acquiring dMAC infection. Significant differences between subgroups were also seen with the variables: PCP prophylaxis, the AIDS indicator disease Candida esophagitis, CD4+ lymphocyte level, CD4 percent lymphocyte level, WBC level, Hgb and Hct levels. Using multivariate modeling, it was determined that PCP prophylaxis (RR = 6.12, CI 2.24-16.68) was a predictor of survival and both CD4% lymphocytes $\le$6.0% (RR = 0.33, CI 0.17-0.68) and WBC level $\le$3000 cells/mm$\sp3$ (RR = 0.60, CI 0.39-0.93) were predictors of mortality. CD4+ level $\le$50 cells/mm$\sp3$ was not a significant predictor of mortality. Although MAC culture status was a significant predictor of mortality in the univariate model, a positive dMAC culture was not a significant predictor of AIDS mortality in the multivariate model. A positive dMAC culture, however, did affect mortality in a stratified analysis when baseline laboratory values were: CD8+ lymphocytes $>$600 cells/mm$\sp3,$ Hgb $>$11.0 g/dl, Hct $>$31.0% and WBC level $>$3000 cells/mm$\sp3.$ ^