Evidence for a major gene for cortical cataract.

PURPOSE: To examine the possible presence of a major gene determining susceptibility to cortical cataract. METHODS: The percentage of the lens area involved with cortical opacity, summed over both eyes, was evaluated in 1275 individuals from the Beaver Dam Eye Study. After adjusting for the effects of age and sex, these measures of cortical cataract were subjected to sibling correlational analysis, commingling analysis, and segregation analysis. The Box and Cox power transformation was applied to the data for the commingling and segregation analyses. Using regressive models, four modes of transmission were examined, and under each mode three hypotheses and a general model were fitted by maximum likelihood and compared. RESULTS: Sister-sister and brother-brother correlations of the adjusted measures of cortical cataract are significant and similar; the brother-sister correlation is not significantly different either from these correlations or from zero. Two commingled distributions give the best fit to the data, especially after power transformation. Under each of four modes of transmission, the hypothesis that best fits the data is one in which there are only two distributions (and, hence, dominance under mendelian transmission), the power transformation parameter is fixed at the estimate obtained from commingling analysis, and there is residual sibling correlation. The data thus suggest the existence of a major effect for cortical cataract. Random environmental influences can be rejected as a cause of this major effect. Our analysis indicates the existence of a significant effect of sex on the residual variance. Allowing for this, the data suggest transmission of a single major gene, though this may not be the sole cause of the commingled distributions. CONCLUSIONS: Assuming a common variance for the two sexes, a single major gene can account for 58% of the variability of age- and sex-adjusted measures of cortical cataract. With the variance sex dependent, a major gene can account for 75% and 45% of the total variability among males and females, respectively.

Tuberculin reactivity after newborn BCG immunization in mono- and dizygotic twins.

SETTING: Studies showing significantly higher concordance of tuberculosis among monozygotic twins than dizygotic twins have provided support for genetically determined susceptibility to tuberculosis. OBJECTIVE: We wished to explore whether the development of delayed type hypersensitivity to tuberculin after newborn BCG immunization of twins suggested genetic regulation of the response to BCG in humans. DESIGN: Our study population consisted of 17 monozygotic twin pairs, 18 dizygotic twin pairs, and 64 single infants 3-34 months of age from Santiago, Chile. All had a BCG scar and were tuberculin tested by one trained nurse. RESULTS: The mean birth weight of both groups of twins was significantly lower than that of singletons and the percentage of individuals who failed to respond to tuberculin was approximately twice as high in twins as in singletons. After adjustment for birth weight and age by regression analysis, it was found that the distribution of tuberculin reactivity in both monozygotic and dizygotic twins was not significantly different from that of singletons. Both twin pair correlations is adjusted tuberculin reactivity were significantly greater than zero (P < 0.01) and led to a heritability estimate of 0.28. However, the monozygotic twin correlation was not significantly larger than the dizygotic twin correlation so that heritability is poorly estimated. CONCLUSION: These results are consistent with a genetic regulation of the response to newborn BCG immunization in humans by a mechanism capable of producing similar responses in identical and nonidentical twins alike.

Tuberculin reactivity in families of infants who failed to develop tuberculin reactivity after BCG immunization at birth.

SETTING: Some infants immunized with BCG in the newborn period fail to develop any measurable tuberculin reactivity despite a local reaction at the site of immunization. OBJECTIVE: We wished to determine the possibility of a genetic regulation of this phenomenon by comparing the tuberculin reactivity of BCG-immunized parents and siblings of infants who failed to respond to BCG, and of infants who developed tuberculin reactivity after immunization. DESIGN: We studied 65 parents and siblings of 33 nonresponder infants, and 35 parents and siblings of 14 infants who had developed tuberculin reactivity. Tuberculin reactivity was analyzed by multiple regression analysis considering the BCG immunization status of each individual, and the 2 groups were compared by analysis of covariance. RESULTS: 96 of these family members had one or more BCG scars. The percentages of tuberculin reactors and non-reactors among BCG-immunized family members of both index infant groups were not significantly different. CONCLUSION: These observations suggest that maturational differences among newborns, rather than genetic regulation, account for the lack of development of cellular immunity against tuberculin after BCG immunization in some infants.

Evaluation of tuberculin reactivity in BCG-immunized siblings.

The purpose of the present study was to determine in BCG-immunized sibships < or = 14 yr of age whether the correlations of intensity of tuberculin reactivity support a genetic regulation of the response to BCG immunization. The study population consisted of 659 healthy children living in 265 households exposed to an adult with tuberculosis: 38 children did not have a BCG scar, 327 children had one BCG scar, and 294 had two BCG scars from vaccinations at birth and at 6 yr of age. There were 603 full siblings, 16 half-siblings, and 40 unrelated children. Tuberculin testing was performed by one trained nurse. Sibling correlations of the intensity of the tuberculin response were calculated after adjusting for various nongenetic covariates that could be important in predicting it. The sibling correlations were significant at the 1% significance level. There was no significant correlation of tuberculin reactivity among unrelated children in the same household. These results are consistent with genetic regulation of the development and persistence of tuberculin reactivity after BCG immunization.

Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study.

Sibling correlations were evaluated and segregation analysis was performed on age-dependent maculopathy scores of the right and left eyes of individuals from 564 families in the Beaver Dam Eye study. There is evidence of significant sibling correlations. The data fit a mixture of two normal distributions, especially after undergoing the Box and Cox power transformation. In each eye, the hypothesis of mendelian transmission of a major effect cannot be rejected under the tau AB free model, but is rejected under the tau's free model. The hypothesis of a random environmental major effect is rejected. Similar major gene parameter estimates are found for both eyes. The results are consistent with a major effect accounting for 62% and 59%, in the right and left eyes, respectively, of the determination of age-related maculopathy scores. A single major gene can account for about 89% and 97% of this variability due to a major effect, or for about 55% and 57% of the total variability, in the right and left eyes, respectively.

Genetic etiology of nuclear cataract: evidence for a major gene.

Sibling correlations and segregation analysis were used to examine the familial distribution of age-sex-adjusted measures of nuclear sclerosis in 1,247 individuals from 564 sibships in the Beaver Dam Eye Study. There are highly significant sibling correlations for all sibs, and separately for sister-sister, sister-brother, and brother-brother pairs. Two transformed normal distributions give the best fit to the data. The hypothesis of mendelian transmission of a major effect cannot be rejected, but the hypothesis of a random environmental major effect is rejected. The parameters of the tau AB free model showed close similarity to the values expected under a mendelian hypothesis. Our results suggest that a single major gene can account for 35% of the total variability of age-sex-adjusted measures of nuclear sclerosis.

Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study.

A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.

IgG subclass responses to human immunodeficiency virus-1 antigens: lack of IgG2 response to gp41 correlates with clinical manifestation of disease.

To analyze differential antibody responsiveness of potential pathogenetic significance, sera from 66 patients with human immunodeficiency virus-1 (HIV-1) infections at various Walter Reed (WR) stages of the disease were analyzed to determine the subclass distribution of HIV antibodies. Although all IgG subclasses were involved in the HIV antibody response, the frequency was highest for IgG1 and the lowest for IgG4. When IgG subclass responses to different HIV antigens were compared qualitatively, IgG1 was the major subclass reactive with env, pol, and gag antigens; IgG2 and IgG3 were almost equally represented in response to gag gene products; and IgG4 showed minimal reactivity to p24 antigen in all HIV-infected patients regardless of their clinical presentation. In contrast, significantly lower levels of IgG2 anti-gp41 were observed in patients at WR 5 and 6 (5%) when compared to those at stage WR 1 and 2 (88%). The IgG2 response to a recombinant gp 120/41 antigen, however, remained unchanged, suggesting that the lack of IgG2 response may be associated with lack of responsiveness to the carbohydrate epitope on gp41. Indeed, parallel measurements of IgG antibody responses to group A carbohydrate were also lower in patients at WR 5 and 6 stages, without affecting antibody responses to polyribosyl ribitol phosphate and phosphocholine. As antibody responses to group A carbohydrate with its N-acetyl D-glucosamine (GlcNAc) determinant were lower at the WR 5 and 6 stage of HIV disease, GlcNAc may be one of the antigenic determinants on gp41 that plays a critical role in some of the pathologic events of HIV infection.

Clinical and epidemiological features of HIV infection at a referral clinic in Zambia.

Among 1,350 patients with serologically confirmed HIV-1 infection evaluated at the Dermatovenerealogy Clinic, University Teaching Hospital. Lusaka, through March 1987, 125 (9.3%) had AIDS, 1,178 (87.3%) had AIDS-related complex, and 46 (3.5%) were asymptomatic. The male to female ratio of cases was 1.5:1 and women were younger (mean age of 26.2 years) than were men (mean age of 31.2 years). HIV-infected persons had significantly more lifetime sex partners than uninfected persons; other risk factors were a prior history of venereal disease, blood transfusion, travel abroad, and a positive syphilis serology. Clinical features in decreasing order of frequency were weight loss, persistent generalized lymphadenopathy, chronic cough, multidermatomal herpes zoster, diarrhea, recurrent fevers, tuberculosis, and oropharyngeal candidiasis. The WHO clinical case definition for the diagnosis of AIDS had a low positive predictive value for the 125 Zambians with AIDS, but among all those infected with HIV, the positive predictive value was 76.4%. Thirty (35.3%) of 85 patients who were HIV seronegative when first examined acquired HIV infections during a 12- to 39-month (means = 21.8 months) period of observation. Heterosexual intercourse unrelated to prostitution appears to be the major mode of HIV transmission in Lusaka.

PIP: The clinical and epidemiologic characteristics of the 1st 1350 individuals diagnosed at Zambia's Dermatovenerealogy Clinic in Lusaka between August 1985-December 1986 as a positive for human immunodeficiency virus (HIV) infection were evaluated. 125 (9.3%) of these seropositive individuals presented with aggressive Kaposi's sarcoma or an opportunistic infection and were thus diagnosed with acquired immunodeficiency syndrome (AIDS), 1178 (87.3%) had AIDS-related complex (ARC), and a further 47 (3.5%) were asymptomatic. The male to female ratio of HIV-positive cases was 1.5 to 1. Female patients were younger (mean age 26.1 years) than male patients (mean age, 31.2 years). The only sexual practice acknowledged by the vast majority of cases was heterosexual vaginal intercourse, although infected men and women had significantly more lifetime sexual partners than uninfected controls. Other significant risk factors for HIV seropositivity were (for men) blood transfusion, travel outside of Zambia, and a history of syphilis; for women, these risk factors were blood transfusion and a history of venereal disease. The most common clinical features in AIDS and ARC patients were, in decreasing order of frequency, weight loss greater than 10%, generalized lymphadenopathy, chronic cough, multidermatomal herpes zoster, recurrent diarrhea, recurrent fever, tuberculosis, and oropharyngeal candidiasis. The provisional WHO clinical case definition of AIDS in Africa has a positive predictive value of 82.1 for the sample as a whole, but only 46.3 for the 125 patients diagnosed with AIDS. 17 of the HIV-positive patients had died by the 18-month follow-up.