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Non-insulin-dependent diabetes mellitus, or type 2 diabetes (T2DM), has become a major public health problem in India. The high prevalence, relatively young age of onset, and strong familial aggregation of T2DM in some Indian communities remains to be explained. Many of the traditional risk factors established for European populations do not appear to be present in Asian Indians. Phase I of the Sikh Diabetes Study (SDS) was launched to build the population resources required to initiate a large-scale genetic epidemiological study of diabetes in an Asian Indian population. The SDS is focused on the Khatri Sikh population of North India. In all, 1,892 subjects were enrolled to participate in the family-based study; 1,623 of these subjects belong to 324 families, each of which has at least 2 siblings affected with T2DM. The sample included 1,288 individuals affected with T2DM (siblings, parents, or relatives) and 335 unaffected siblings, parents, or relatives. The remaining 269 subjects were unrelated nondiabetic control subjects, including unaffected spouses of probands or siblings. This primarily nonvegetarian, nonsmoking endogamous caste group has presented an unusual clinical picture of uneven distribution of adiposity and a high rate of T2DM with secondary complications. Such well-characterized population isolates may offer unique advantages in mapping genes for common complex diseases.

Elevated plasma lipoprotein(a) [Lp(a)] level has been established as an independent risk factor for atherosclerosis and coronary heart disease. Considerable ethnic group differences in the distribution of plasma Lp(a) levels have raised public health concerns. Recently, we have reported that Samoans have the lowest plasma Lp(a) levels of any population group. In the present investigation, we report the contribution of two apolipoprotein(a) (APOA) polymorphisms, the kringle 4 type 2 (K4) repeat and the pentanucleotide repeat (PNR), in affecting plasma Lp(a) levels in an American Samoan sample (n = 309). The K4 repeats ranged in size from 15 to 40. The common alleles contained repeats ranging from 26 to 36 with allele frequencies between 5.5% to 9.7%, and these accounted for 82% of all alleles. An inverse relationship between K4 repeat number and plasma Lp(a) level was observed for single-banded (r = -0.59, p = 0.0001) and double-banded phenotypes (r = -0.50, p = 0.0001). This polymorphism explained 60% of the variation in plasma Lp(a) level in American Samoans. For the PNR polymorphism, five different repeat alleles and eight different genotypes were identified; the most common allele was eight repeats. The *8 PNR allele was associated with a wide range of K4 repeats, the *9 PNR allele with larger K4 repeats (25-40), and the *10 PNR with smaller K4 repeats (15-24). Analysis of variance (ANOVA) revealed that the PNR polymorphism accounts for 2.1% of the variability in plasma Lp(a) levels in this sample, when the K4 repeat polymorphism was taken into account. Our data show that common polymorphisms in the APOA gene are major determinants of plasma Lp(a) variation in American Samoans.

Plasma lipoprotein(a) [Lp(a)]-consisting of a disulfide-linked complex of apolipoprotein B and apolipoprotein (a)--levels are considered to be an independent risk factor for coronary heart disease. There are considerable ethnic group differences in the distribution of plasma Lp(a) levels that raise public health concerns. Although plasma Lp(a) distribution has been determined in various ethnic groups, no such information is available in Pacific Islanders. In this study we have determined the distribution and correlates of plasma Lp(a) in population-based samples of 361 American Samoans (145 men, 216 women) and 560 Western Samoans (265 men, 295 women), aged 20-70 years. Plasma Lp(a) levels were measured using a commercial enzyme-linked immunosorbent assay. The distribution of plasma Lp(a) levels in both groups was highly skewed with 73% and 65% of values in the 0-5 mg/dl range in American Samoans and Western Samoans, respectively. The mean (6.4 mg/dl) and median (2.2 mg/dl) Lp(a) levels in pooled Samoans were significantly lower when compared with other ethnic groups using the same measurement kit. Plasma Lp(a) correlated significantly with total and LDL cholesterol in both genders after correcting for the contribution of Lp(a) cholesterol, and with apolipoprotein B in women after the correction for Lp(a)-apoB, but not with age, smoking, alcohol intake, or body mass index. Our data show that Samoans, Polynesians of Pacific Islands, have strikingly lower Lp(a) levels than all other reported population groups. These data are consistent with the hypothesis that genetic factors account for interethnic group variation in plasma Lp(a) levels.

The Samoan islands were politically separated into American Samoa and Western Samoa in the early 1900s. Economic modernization is far more extensive in American Samoa. However, the Samoan archipelago has maintained a remarkable degree of sociocultural homogeneity, including intermarriage. The sociocultural exchanges presumably led to genetic homogeneity between the two Samoas. Detailed genetic comparisons and characterizations of Samoans are scanty, however. As part of a multidisciplinary study of modernization and cardiovascular risk factors in adults, we analyzed nine hypervariable nuclear DNA (HVR) and four serum protein polymorphisms in the two Samoan groups. The average heterozygosities at both DNA and serum protein loci are comparable in the two groups. As expected, the HVR loci reveal a high degree of variability (heterozygosity 30-87%) compared with the serum protein loci (heterozygosity 1-52%). A large proportion of alleles at the HVR loci, ranging from 50% to 100%, are shared between American and Western Samoa. With the exceptions of the D1S80 locus in American Samoa and the D13S118 locus in Western Samoa, the genotype distributions at all loci conform to their respective Hardy-Weinberg expectations. Sporadic occurrence of the F13B*2 allele at the F13B locus in Samoans indicates a low level of European admixture because this allele is unique to Europeans. The calculated zero values of kinship coefficients and standard genetic distances indicate minimal population differentiation between the two Samoan groups.

Apolipoprotein A-IV (apoA-IV protein; APOA4 gene) is structurally polymorphic in various mammalian species, including human, baboon, dog, horse, and mouse. To analyze the extent of genetic variation in the chimpanzee APOA4 gene, we screened 115 common chimpanzees (Pan troglodytes) (86 unrelated wild captured parents and 29 captive-born offspring) using isoelectric focusing followed by immunoblotting for protein polymorphism and using polymerase chain reaction (PCR) assay for DNA polymorphism. At the protein level the unrelated sample of chimpanzees is highly variable, having four alleles, APOA4*1, APOA4*2, APOA4*3, and APOA4*4, with frequencies of 0.192, 0.430, 0.331, and 0.047, respectively. The chimpanzee APOA4 locus, with four common alleles and a gene diversity of 67%, is more variable than previously reported variations in baboons (five alleles with 52% gene diversity) and humans (two alleles with 15% gene diversity). PCR amplification of chimpanzee DNAs, using a pair of human oligonucleotide primers covering a region of 300 nucleotides in the third exon, revealed a common 12-nucleotide deletion (allele frequency = 0.192) that correlates exactly with the APOA4*1 allele detected by isoelectric focusing and immunoblotting. DNA sequencing of the 300-nucleotide PCR amplified product revealed the deletion of 12 nucleotides near the carboxyl terminal region of the mature apoA-IV protein. This in-frame deletion, which codes for and eliminates four amino acids [glutamic acid (GAG), glutamine (CAG), glutamine (CAG), and glutamine (CAG)], occurs in a region that is evolutionarily conserved among rats, mice, chimpanzees, and humans. The partial DNA sequencing of the 3' end of the chimpanzee APOA4 gene revealed 99% identity with the human APOA4 gene.

Obesity, as defined by any number of metrics, aggregates in families but does not segregate as a simple Mendelian trait. Because of the frequent association of obesity with a number of common chronic diseases, researchers are greatly interested in identifying the genes that contribute to obesity and their mode of action. The lack of a consensus regarding the biological basis of obesity makes the selection of appropriate candidate genes difficult. Several approaches to selecting plausible candidate genes for the study of obesity are outlined here. The study of rare human phenotypes that result in extreme obesity may identify genes that through polymorphic genetic variation may have an effect on body mass, body composition, or fat distribution. The study of human genes homologous to the mouse genes that lead to obesity in particular strains of inbred mice may also give clues to the location and identity of obesity-related genes. Human populations in which obesity is particularly prevalent may serve as a substrate for identifying such genes in the general population.

Using isoelectric focusing and immunoblotting techniques, we have screened 937 plasma or serum samples from Nigerian blacks (N = 380), Papua New Guineans (N = 110), Aleuts (N = 62), Mayans (N = 139), Dogrib Indians (N = 45), and Eskimos from Kodiak and St. Lawrence islands (N = 201) for the hemopexin (HPX) polymorphism. We compared these data with our previously published data for US whites (N = 267) and US blacks (N = 194). Except for Nigerian blacks and US blacks, HPX was found to be monomorphic for the common HPX*1 allele in all populations tested. In addition to the commonly occurring HPX*1 allele, two other less common alleles, HPX*2 and HPX*3, were observed with respective frequencies of 1.8% and 4.6% in US blacks and 1.7% and 9.0% in Nigerian blacks. These data strongly suggest that the HPX*2 and HPX*3 alleles are unique alleles restricted to the black gene pool and are of potential significance in microevolutionary studies and in defining African admixture in hybrid populations. In addition to their importance in anthropogenetic studies, these unique HPX mutations also have potential biological significance in hemolytic disorders.

Apolipoprotein A-IV exhibits a common two-allele polymorphism in several human populations studied to date. Using isoelectric focusing and immunoblotting, we have analyzed plasmas from 188 non-insulin-dependent diabetic and 238 normoglycemic Hispanic individuals from the San Luis Valley, Colorado, to determine APOA4 genotype frequencies and to estimate the impact of the genotypes on quantitative traits. The frequencies of the two common alleles, APOA4*1 and APOA4*2, were 0.929 and 0.069, respectively, in normal subjects and 0.901 and 0.096, respectively, in diabetics. The third rare allele, APOA4*3, was detected sporadically in both groups. We studied the impact of APOA4 polymorphism on the levels of total plasma cholesterol, HDL cholesterol and its subfractions (HDL3 and HDL2), LDL cholesterol, triglycerides, glucose, and insulin. We observed no significant effect of the APOA4 polymorphism on any trait in diabetics. However, we did note a significant sex-specific effect in normoglycemic females on the level of total HDL cholesterol (p = 0.001) and its subfractions HDL2 (p = 0.043) and HDL3 (p = 0.001). The effect of the APOA4*2 allele in normal Hispanic females was to lower the total HDL, HDL2, and HDL3 cholesterol by 8.75 mg/dl, 2.37 mg/dl, and 5.36 mg/dl, respectively, compared to the common APOA4*1 allele.

Apolipoprotein H (APOH) (beta-2-glycoprotein I) polymorphism has been studied in 1159 Asians. The sample included 872 Chinese, 179 Asiatic Indians (Dravidian), 91 Filipinos, and 17 Malays. APOH polymorphism was determined by isoelectric focusing of sera in thin-layer polyacrylamide gels containing 3 M urea followed by immunoblotting. The frequencies of the three alleles--APOH*1, APOH*2, and APOH*3--were found to be 0.031, 0.900, and 0.069 in the Chinese; 0.061, 0.866, and 0.073 in the Dravidian Indians; 0.055, 0.923, and 0.022 in the Filipinos; and 0.088, 0.882, and 0.029 in the Malays. The phenotypic distribution was at Hardy-Weinberg equilibrium in all the populations.

A tribal aboriginal community, the Mowanjum, from the Kimberley region in Western Australia has been screened to determine the extent of genetic variation in the products of genes coding for apolipoproteins, which are intimately involved in lipid metabolism. Of the seven systems tested, APOE and APOH revealed common structural variations, but their distribution patterns are significantly different from those found in European populations. Australian Aborigines were found to be unique because they have no APOE*2 and APOH*3 alleles and have strikingly high frequencies of the APOE*4 (26%) and APOH*1 (13%) alleles. The contrast in variation observed at these apolipoprotein loci between Australian Aborigines and Europeans not only makes these loci useful genetic markers in biologic anthropology studies but also provides a unique opportunity to investigate the role of genetic-environment interaction in determining interpopulation differences in cardiovascular disease risk factors.

The importance of surnames in genetic studies has been recognized for a century or so. While the ethnic affiliations of individuals are ordinarily established in genetic studies by admixture analysis based on gene frequencies, often there are implicit assumptions in these attempts that are difficult to validate in the absence of detailed ethnohistories. In northern Chile and western Bolivia, where genetic admixture has been known to occur among the Aymara Indians and Spanish Caucasoids, the naming pattern (parental patriand matrinyms) allowed us to classify individuals on the basis of the frequency of Aymara names into 9 'ethnic' groups. From a sample of 2525 individuals it is shown that admixture occurred in lineages nonrandomly, implying assortative mating of surnames. Admixture and genetic distance analysis on the basis of 31 genetic markers on approximately 1700 of these individuals reveals that there is a reasonable agreement of ethnic classification of individuals by name and phenotype data on genetic markers. The Aymara-named groups are shown to be predominantly Amerindian (89%) in their genetic profiles. Individuals whose current naming pattern is basically Spanish also exhibit a substantial fraction of genes of Amerindian origin (67%). Presence of some rare alleles not found in Amerindian or Spanish Caucasoids in the admixed groups suggest infiltration of Negroid genes in the past.