Bruce Budowle

PHENOTYPES OF THE FOURTH COMPLEMENT COMPONENT (C4) IN BLACK AMERICANS FROM THE SOUTHEASTERN UNITED STATES

C4 is composed of two tightly linked genes (C4A and C4B) lying within the major histocompatibility complex of chromosome 6 that can be demonstrated by agarose gel electrophoresis. Seven alleles and five alleles at the C4A and C4B loci, respectively, were detected in 169 black individuals from the southeastern United States. Furthermore, the phenotypic frequencies of C4A6, C4A5, C4A4, C4B4, C4B3, and C4BQO were significantly different between black and white Americans.

Associations of properdin factor B with melanoma.

We investigated 98 melanoma patients and 135 normal controls for differences in phenotype and genotype frequencies at the properdin factor B locus. A significant negative association with the Bf-F allele and melanoma was found, resulting in an estimated relative risk of 0.5. The estimated relative risk for developing melanoma among people with the Bf-FF genotype is 0.07. The Bf-S phenotype was significantly increased among the melanoma sample, with an estimated risk of 6.5. The data suggest association of the Bf locus with a melanoma protection and/or susceptibility gene(s).

Properdin factor B in black Type 1 (insulin-dependent) diabetic patients

SummaryThe properdin factor B(Bf) variant F1 was found in 20% of 70 black patients with Type 1 (insulindependent) diabetes compared with 7.3% of 165 control subjects, yielding a significant relative risk of 3.1. In addition, the BfF allele was negatively associated with Type 1 diabetes among blacks, resulting in a relative risk of 0.4. The data suggest that Type 1 diabetes in black Americans may be partially due to admixture of Caucasoid genes.

Properdin factor B and acute lymphocytic leukemia (ALL).

One hundred‐sixty‐four ALL patients were compared to 545 controls for differences in phenotype and gene frequencies at the Properdin factor B locus. In addition, 90 of the ALL patients were immune phenotyped. A significant association with the Bf F allele and ALL was found, resulting in an estimated relative risk of 3.62. There was no difference in the Bf S phenotype between ALL patients and controls. However, those homozygous for the Bf S allele are at a significantly low risk of 0.30 for developing ALL. ALL patients with a non‐B/T cell type were 2.5 times more likely to be Bf SS homozygotes; in contrast, those patients with the pre‐B cell type were 2.5 more likely to be Bf FF homozygotes. These data suggest association of the Bf locus with an ALL protection and/or susceptibility gene(s).

The complement component C4 in black Americans with Type 1 (insulin-dependent) diabetes mellitus

SummaryThe complement component C4 variants C4A4, C4B 4 and C4B QO were found to be significantly increased in 64 black patients with Type 1 (insulin-dependent) diabetes compared with 169 black control subjects, yielding relative risks of 3.3, 2.9 and 3.4, respectively. The increased frequencies of C4B 4 and C4B QO in black Type 1 diabetic patients are similar to those found in Caucasoid Type 1 diabetic patients. The data suggest that Type 1 diabetes in black Americans may be partially due to admixture of genes from whites.

PROPERDIN FACTOR B POLYMORPHISM IN BLACK AMERICANS

Properdin factor B is a genetically‐controlled polymorphism that can be demonstrated by agarose gel electrophoresis. The Bf gene frequencies were determined for 194 blacks from the south‐eastern United States. The frequencies for Bf‐F, Bf‐S, Bf‐F1, and Bf‐Sl are 0.626, 0.327, 0.034, and 0.013, respectively. The south‐eastern blacks have similar Bf frequencies to the South African blacks; however, both these groups are different from blacks from Boston. The frequency differences between south‐eastern blacks and Boston blacks may be due to racial admixture differences found in the two populations.

Age at onset of insulin-dependent diabetes mellitus associated with BfF1.

Recently, Properdin Factor B (Bt), particularly the rare variant BfF1, has been found associated with Type 1 diabetes in white (Dornan et al. 1980, Kirk et al. 1979, Raum et al. 1979, Walsh et al. 1980) and black Americans (Budowle et al. 1982). Furthermore, there have been reports of an association of Bf with age at onset among white Type 1 diabetic patients. Bertrams and co-workers (1981) and Barbosa and co-workers (1979) observed that the BfF1 frequency was predominantly increased (not significantly) among patients with an age at onset less than 16 years; in addition, Bernal and colleagues (1979) and Kirk and colleagues (1979b) found similar associations of BfF1 with slightly different ages at onset of 16 years or less and 10 years or less, respectively. To our knowledge, there are no reports of Bf associated with age at onset in black Americans with Type 1 diabetes. We, therefore, examined the associations of Bfwith age at onset in white and black Americans with Type 1 diabetes. Serum samples from 127 white and 70 black Type 1 diabetic patients from the southeastern United States were typed for Factor B according to the method of Alper and Johnson (1969). All diabetic patients were under the age of 40 at onset of diabetes, insulin dependent, and ketosis prone. All cases were at least third generation American. For the age at onset analysis, the patient populations were separated into two cohorts (15 years and less and greater than 15 years) as previously reported (Bertrams et al. 1981). The comparisons of Bf with age at onset were made by use of the Chi-square analysis, or, when designated, Fishers exact test. A probability level of 0.05 was considered significant. The odds ratio was estimated according to the method of Woolf (1955).

Immunogenetics of Melanoma

Human melanoma of the skin is a disease that has received a great deal of attention from basic scientists and clinicians over the last several years. One reason for this increased interest is that the incidence of the disease is rapidly increasing in the United States as well as in other countries (Crombie, 1979; Cutler and Young, 1975; Elwood and Lee, 1974; Magnus, 1977; Ohsumi and Seiji, 1977). In attempting to understand the etiology of melanoma, one must consider two major factors: the genetic makeup of the host and environmental insults (Clark et al., 1977; Klepp and Magnus, 1979; McGovern, 1977). Ultimately, one would like to be able to identify highly susceptible individuals in the population early in life and provide measures to minimize or prevent insult by environmental agents. With this in mind, we will attempt to review the current state of knowledge with regard to the immunogenetics of melanoma in order to establish whether this goal is in sight. The authors have taken the liberty of selecting data by others that illustrate the current level of understanding in this area rather than attempting an all-encompassing review. Since the highest melanoma mortality rate in the United States is found in Alabama (Mason and McKay, 1974), we will review the immunogenetic data collected from patients mainly residing in the state of Alabama treated at the Melanoma Clinic of the University of Alabama in Birmingham. The clinical and pathological characteristics of this patient group have previously been published (Balch et al., 1978, 1979a,b, 1980, 1981; Balch, 1980).

Association of HLA-linked factor B with gestational diabetes mellitus in black women

The factor B BfF allele was found significantly less frequently in nonobese black women with gestational diabetes mellitus than in the control group. The BfS allele was found more frequently, although not significantly so. These data suggest similar genetic associations among nonobese black women with gestational diabetes mellitus and those with insulin-dependent diabetes mellitus.

The Occurrence of Melanoma and Its Relationship with Host, Lifestyle and Environmental Factors

Human melanoma of the skin is a malignancy whose incidence is rapidly increasing in the United States as well as in other countries [1–7]. The highest melanoma mortality rate in the U.S. is found in Alabama [8]. In order to understand the reasons for this increased incidence, one must consider three major interacting factors, the constitutional makeup of the host, the lifestyle of the host and environmental exposure [9–11]. This review will look at the studies of each of these factors in an effort to better understand the etiology of melanoma. We have tried to consider the majority of reports which bear on this subject. However, some selection of data has obviously occurred, and we have relied heavily on the reviews of others to make certain points. Reference when appropriate is also made to our own data collected from patients, greater than 95% of whom reside in the State of Alabama, treated at the Melanoma Clinic of the University of Alabama in Birmingham (UAB). Finally, we will propose a model based on our review which, taking into account both host specific, environmental factors and their interactions, could explain the incidence of melanoma in most Caucasian populations. Provided the relative contributions of these three factors to the etiology of melanoma can be discerned, one should be able to identify highly susceptible individuals in the population and therefore suggest measures to alter lifestyle to minimize exposure to environmental agents.