Risk of systemic lupus erythematosus (SLE) is high in west Africans compared with Europeans, and risk of rheumatoid arthritis (RA) is high in Native Americans compared with Europeans. These differences are not accounted for by differences in allele or haplotype frequencies in the human leucocyte antigen (HLA) region or any other loci known to influence risk of rheumatic disease. Where there has been admixture between two or more ethnic groups that differ in risk of disease, studies of the relationship of disease risk to proportionate admixture can help to distinguish between genetic and environmental explanations for ethnic differences in disease risk and to map the genes underlying these differences.
Keywords:admixture; genetic; lupus; rheumatoid arthritis
The risks of developing SLE and RA vary with ethnic origin. Prevalence of lupus has been found to be up to eight times higher in African-American and Afro-Caribbean populations than in people of European descent. The consistency with which high prevalence of lupus occurs in populations of west African descent who are living in different environments suggests that genetic factors are likely to underlie the high risk in this group. The high risk for lupus in west Africans compared with in Europeans does not appear to be accounted for by differences in allele frequencies at any of the loci at which associations with SLE have been found, including those in the HLA region. Other populations at high risk for lupus include Pacific islanders and Chinese-Americans, with prevalence rates up to three times higher than in people of European descent living in the same countries. For RA, the highest risks are recorded for Native American populations, in which prevalence is up to four times higher than it is in Europeans. Although the frequency of alleles that code for the high-risk 'shared epitope' at the HLA-DRB1 locus is higher in Native Americans than in Europeans, this only accounts for a population risk ratio of about 1.4, compared with the observed risk ratios of around 4.
Where there has been admixture between ethnic groups that differ in risk for disease, studies of how the risk for disease varies with proportionate admixture can help to distinguish between genetic and environmental explanations for the difference in disease risk and can help to define the genetic model. No adequate studies have yet been undertaken on the risk for lupus in relation to admixture in populations of mixed European/west African descent, or on the risk for RA in relation to admixture in populations of mixed European/Native American descent. If ethnic differences in risk for lupus and RA have a genetic basis, it is possible in principle to map the genes that underlie ethnic differences in risk by studying affected individuals of mixed descent. This approach is an extension of the methods used for linkage analysis of a cross in experimental genetics. Before this can be applied in practice, it is necessary to assemble sets of marker polymorphisms that can be used to assign ancestry on chromosomes of mixed descent.
Ethnic variation in risk for rheumatic disease
Studying ethnic variation in disease risk can yield clues to environmental or genetic factors that influence disease risk. Where variations in risk between populations have been identified, studies of migrants between low-risk and high-risk areas can help to distinguish between genetic and environmental explanations for these differences in risk, and to determine the age at which risk is set. If an ethnic difference in disease risk has an environmental explanation, this difference is expected to 'wear off' within a few generations after migration . For instance, the low risk for multiple sclerosis in tropical countries compared with the risk in northern latitudes persists in those who migrate from tropical countries to the UK as adults , but in second-generation migrants the risk for multiple sclerosis is similar to that in the host population . If, on the other hand, genetic factors underlie an ethnic difference in disease risk, we would expect this ethnic difference to persist in populations where migrants have been settled overseas for many generations, and to be observed consistently in all countries where a given migrant group has settled.
Ethnic variation in risk for systemic lupus erythematosus
Most estimates of SLE prevalence have relied on ascertainment of cases already diagnosed. A study in the UK that used a questionnaire followed by an antinuclear antibody test to screen for undiagnosed cases of SLE  suggested that about 40% of cases are undiagnosed. Estimates of the risk ratio for SLE in one ethnic group compared with another generally assume that the proportion of cases that are undiagnosed and the average survival of diagnosed cases are the same in both groups. If these assumptions hold, the risk ratio can be estimated from the ratio of prevalence rates of diagnosed SLE in the two groups. The assumption that the proportion of cases that are undiagnosed does not vary between ethnic groups is more likely to hold in the UK, where access to health care does not depend on income, than in the USA. Table 1 summarizes prevalence studies in populations of west African descent, with prevalence in populations of European descent in the same countries for comparison. In general, the prevalence of SLE has been found to be far higher in people of west African descent settled in Europe and the Americas than in Europeans [5,6]. In the UK, prevalence in adults is estimated to be around 35 per 100 000 in women of European descent [5,7], compared with 200–250 per 100 000 in women of Afro-Caribbean origin [5,6].
It has been suggested that rates of SLE are low in west African because exposure to malaria and parasitic infections in west Africans in the tropics may result in an altered immunological state, leading to a tolerance of host antigens or absorption of autoantibody . However, there are no population-based data on prevalence of SLE in west Africa itself.
Similar risk ratios have been reported in studies performed in the USA [9,10] that have compared prevalence rates in African-Americans and European-Americans. In a study of patients registered with the Kaiser Foundation Health Plan in San Francisco, age-adjusted prevalence of SLE in African-American women aged over 15 years was estimated to be 375 per 100000, compared with 81 per 100 000 for European-American women . The relatively high prevalence rates in this study may be attributable to the unrestricted access to health care. In other studies from the USA, coverage of the population by the health care system is likely to vary considerably between ethnic groups. If poorer access to health care results in a lower proportion of cases ascertained in African-Americans, and shorter survival among diagnosed cases, this would reduce the ratio of prevalence in African-Americans to that in European-Americans. The incidence of SLE was estimated to be four times higher in African-American than in European-American women , which is approximately the same as the ratio recorded in studies that compared prevalence rates. From the studies that are available at present, it is not possible to establish whether the difference between the risk ratios of 6–8 reported in the UK and the risk ratios of 4–5 reported in the USA are real or attributable to differences in the extent to which the risk ratios are biased by differential case ascertainment. In most African-American populations the proportion of European admixture varies from 14 to 22%. Most Afro-Caribbean migrants to the UK are from Jamaica, where the average proportion of European admixture is only 7% . If the risk for SLE varies with the proportion of the genome that is of African origin, we would expect the risk ratio for African-Americans compared with European-Americans to be higher than the risk ratio for Afro-Caribbeans compared with Europeans in the UK.
The only prevalence data from the Caribbean are from the island of Curacao , where prevalence in adult women was estimated to be 117 per 100 000 during the period 1980–1989. This is likely to be an underestimate because only a few cases were ascertained from outpatient clinics; even so, it is far higher than the prevalence estimates for women of European descent in the UK. Further evidence for high rates of SLE in the Caribbean comes from the observation that in Birmingham, UK, most Caribbean-born patients reported that their disease had begun before migration .
Although no other ethnic group has been found to have such consistently high risk for SLE as people of west African descent, there is some evidence of high risk in people of Chinese descent who are settled outside China. In a study in Malaysia , Chinese made up 81% of all hospital admissions (to the only teaching hospital in west Malaysia) with SLE, but only 35% of the local population. A later study  estimated prevalence rates (per 100 000) as 46 in Chinese, 26 in Indians and 12 in Malays. High rates in Malaysian Chinese when compared with other ethnic groups might be partly explained by greater access to health care. Excess prevalence of SLE was also reported among Chinese-Americans in Hawaii, however, where prevalence of SLE (per 100 000, both sexes) was estimated to be 24 in Chinese, 20 in Polynesians and six in Europeans . Although these rates were based on small numbers of cases, the differences were statistically significant. These findings were supported by a subsequent study in Hawaii  in which age-adjusted prevalence rates for SLE were 33 per 100 000 in Chinese and 10 per 100 000 in Europeans (both sexes), with cases ascertained from hospital records and death certificates. The high risk in Polynesian islanders is consistent with a study in New Zealand , in which prevalence per 100 000 (both sexes) was estimated to be 50 in Polynesians compared with 15 in Europeans.
Role of known genetic associations in ethnic differences in risk for systemic lupus erythematosus
Several loci have been identified at which variation is associated with risk for SLE. In order to determine whether the high risk for SLE in people of west African descent compared with the risk in Europeans can be accounted for by higher frequencies in west Africans of alleles or haplotypes that have been associated with increased risk for SLE within populations, we have calculated the population risk ratio (which is derived from the risk ratio between the exposed groups under study, in this case west Africans and Europeans) generated by each locus. The population risk ratio is calculated as follows:
Population risk ratio = 1 + pA(R–1) / 1+ pE(R–1)
where pA is the frequency of the high risk genotype in Africans, pE is the frequency of the high risk genotype in Europeans, and R is the risk ratio for the high risk genotype compared with the low risk genotype. This is based on a simple risk assessment where genotypes are classified as either high or low risk.
This calculation provides the risk ratio between west Africans and Europeans that we would predict from the risk ratios between genotypes and the frequency of genotypes in each population. For instance, if the frequency of a high-risk genotype is 50% in west Africans and 0% in Europeans, and this genotype is associated with a twofold risk for disease, this doubled risk for disease in half the west African population will generate a risk ratio of 1.5 between west Africans and Europeans. For each locus we have collated whatever data are available on the risk ratios associated with each genotype within populations and the allele frequencies in west Africans and Europeans. The results are summarized in Table 2.
Associations with variation in the human leucocyte antigen region
Most of the loci at which associations with risk for SLE have been identified are in the HLA region. This region, extending over about 4000 kilobases on chromosome 6, contains the class I genes HLA-A, HLA-B and HLA-C, and the class II gene families HLA-DP, HLA-DQ and HLA-DR. When alleles were typed by their antigenic specificities, the HLA-DR family of genes was considered as a single locus and alleles were designated in the sequence (DR1, DR2 ... DRw6, ...) where the 'w' indicated a provisional or 'workshop' designation. Later five distinct genes (DRA, DRB1-4) were identified within the HLA-DR family, and their alleles were numbered (*0101, *0102, ...) according to their nucleotide sequences. In addition to the genes for HLA antigens, the HLA region includes the genes for complement proteins C2 and C4, the heat shock protein HSP70-2 and tumour necrosis factor-α.
A difficulty in interpreting the associations with disease that have been reported for genes in the HLA region is that in this region there are strong associations between alleles at nearby loci. This allelic association is termed 'linkage disequilibrium' by geneticists. Association between alleles at different loci is a consequence of their origin on the same ancestral chromosomes. Linkage disequilibrium is commonly observed when two loci are so close together (usually less than 1 million base-pairs) that this association has not had time to decay through recombination.
Alleles at the C2 and C4 loci are in strong linkage disequilibrium with alleles at other loci within the HLA region. SLE in Europeans is associated with allele B8 at the HLA-B locus , with allele *0501 at the DQA1 locus , with alleles DR2 and DR3 at the HLA-DR locus [20,21], and with the null allele at the C4A locus . Risk ratios associated with DR3 loci are generally similar in African-Americans (2.7) to the risk ratios in Europeans (2.4). The associations with SLE of B8 at the HLA-B locus and DR3 at the HLA-DR locus are no longer detectable when their association with the null allele at the C4A locus is taken into account [20,22,23], but the association of allele *0501 at the DQA1 locus remains statistically significant after controlling for presence of the C4A null allele . The frequency of the C4A null allele is no higher in African-Americans than in Europeans.
Family-based studies of transmission of haplotypes from parents to affected offspring are required to establish definitively which of these loci influence risk for SLE directly, and which are associated with disease only through linkage disequilibrium with other loci that influence risk directly. Table 1 shows that none of the alleles at loci HLA-B, HLA-DR or C4A that are associated with SLE are more common in west Africans than in Europeans.
A 28 base-pair deletion allele at the C2 locus is strongly associated with SLE, but its frequency is so low (1% in Europeans and zero in west Africans) that this mutation does not contribute to the overall population risk ratio for SLE . The 8.5-kilobase-pair allele at the heat shock protein HSP70-2 locus has been shown to be associated with SLE in African Americans (independent of associations with the null allele at the C4 locus or HLA-DR3) . The frequency of this allele is higher in Africans (0.6) than in Europeans (0.4), but this could account only for a risk ratio of 1.2 between west Africans and Europeans. The -308A allele of the tumour necrosis factor-α gene is independently associated with an increased risk for SLE in Europeans, but the frequency of this allele is not higher in African Americans (0.04) than it is in Europeans (0.12) [26,27].
Associations with loci outside the human leucocyte antigen region
Mannose-binding protein is a serum protein that can activate complement. Variant alleles exist in which either codon 54 or 57 of the mannose-binding protein gene is altered, causing deficient complement activation. These variant alleles are associated with SLE in both African and European populations, with risk ratios of about 1.5. The frequency of the codon 54-variant allele is lower (0.11) in Africans than in Europeans (0.19) , however, so this cannot account for higher risk in west Africans.
Allelic variants of Fcγ RIIa influence the ability to clear circulating immune complexes, and have been associated with risk for lupus nephritis in African-Americans and Europeans. In a multicentre study of 214 SLE patients and 100 non-SLE control-individuals the odds ratio for the risk for SLE in Fcγ RIIA-H131/R131 heterozygotes and R131/R131 homozygotes compared with H131/H131 homozygotes was 1.8 . R131/R131 homozygotes and R131/H131 heterozygotes are not more common in African populations (73% compared with 76% in Europeans), and thus the higher risk in African-Americans is not accounted for.
In summary, the higher risk for SLE in west Africans compared with the risk in Europeans cannot be accounted for by higher frequencies of high-risk alleles or haplotypes at any of the loci at which variation is associated with risk for SLE within populations.
Ethnic variation in risk for rheumatoid arthritis
Comparisons of RA prevalence in different populations are difficult to interpret unless standardized methods are used. Prevalence estimates depend on the methods used to ascertain cases, whether point prevalence or period prevalence is recorded, and whether 'probable' or only 'definite' cases are included. The highest prevalence rates are obtained in surveys that include radiographic screening of all individuals sampled. The results are summarized in Table 3. Lower prevalence rates are generally found in surveys that rely on a two-stage screening process – questionnaire screening for RA followed by radiographs of those who report symptoms. The results are summarized in Table 4. Only two surveys of the European-American population included radiographic screening of the entire sample .
The highest prevalence rates of RA have been recorded in Native American populations such as the Pima, Chippewa and Yakima tribes [30,31,32,33,34]. In surveys based on radiographic screening of the entire population, prevalence in adults from these populations has been estimated to be in the range 32–48 per 1000 for men and 59–70 per 1000 for women. By comparison, in the National Health Examination Survey conducted from 1960 to 1962, using bilateral hand and foot radiographs and serologic tests for rheumatoid factor, RA prevalence in the general US population aged 18–79 years was estimated at 7 per 1000 in men and 16 per 1000 in women.
Lower prevalence rates have been recorded in surveys that have used a two-stage screening process: 31–34 per 1000 in Native American women . In that study the case definition was more restrictive than in other studies. For comparison, in European-Americans and African-Americans, surveys using a two-stage screening process have yielded prevalence rates of 6–7 per 1000 in men and 14–15 per 1000 in women [30,35].
There is no consistent evidence that any other ethnic group apart from Native Americans is at unusually high or low risk for RA. Although people of Afro-Caribbean origin (mainly first-generation and second-generation migrants) in the UK appear to have a lower prevalence of RA compared with that in the general population , in the USA the prevalence of RA is similar in African-Americans and European-Americans [30,37]. In South Africa, prevalence of RA in urban African populations has been estimated to be around 10 per 1000 (both sexes combined), which is similar to the estimates for populations of European descent . However, prevalence of RA in rural South African populations was noted to be significantly lower than in urban populations (0.87% compared with 3.3%, respectively), suggesting that environmental factors play an important role that would explain such marked differences in genetically closely related communities .
Prevalence surveys of Chinese populations in native China  and Hong Kong , using a two-stage screening protocol with questionnaires and radiographs of all those with symptoms, have found prevalence of RA to be lower (around 5 per 1000 in women) than that in comparable surveys of populations of European descent. It is possible that some patients may have been overlooked who did not qualify for radiographic examination. There are no surveys of prevalence of RA in Chinese Americans that can be compared with rates in Europeans.
Other rheumatic conditions such as ankylosing spondylitis appear also to be commoner in Native Americans than in Europeans. Using four different subsamples of Native American adult males aged over 25 years, the prevalence of sacro-iliitis grade 2 or more on radiography (based on Rome 1962 criteria) was estimated at 100 per 1000 . This compares with a prevalence of about 10 per 1000 in men from the general US population.
Studies that compared the sequences of HLA antigens have pointed to a direct effect of variation at the HLA-DRB1 locus on susceptibility to RA . At this locus all of the alleles that are associated with high risk for RA share an identical amino acid sequence in positions 70-74: the 'shared epitope' . These alleles include *0101 (included in DR1), *0401/*0404/*0405/*0408 (included in DR4), *1001 (DRw10), *1402 (included in DRw14) and *1601/*1602 (DRw16) [45,46,47,48]. Although others have concluded that the high risk for RA in Native Americans compared with Europeans can be largely explained by the higher frequency of shared epitope alleles in Native Americans, this interpretation has not been supported by calculation of the population risk ratio. In Europeans the total frequency of 'shared epitope' alleles is about 25%, mainly alleles *0101, *0401 and *0404. Thus, approximately 44% of Europeans have at least one copy of a 'shared epitope' allele. In Native Americans about 82% have at least one copy of allele *1402 , from which the allele frequency can be estimated as 0.58. The frequency of other 'shared epitope' alleles in Native Americans is about 0.04 , and thus approximately 86% of Native Americans have at least one copy of a 'shared epitope' allele. In both Europeans and Native Americans, the risk ratio for RA associated with the presence of at least one copy of a 'shared epitope' allele is about 2.7 [45,48]. On this basis, we can calculate the population risk ratio generated by the HLA-B1 locus to be about 1.4 in Native Americans compared with that in Europeans. This accounts for only a small fraction of the observed risk ratios of approximately 4 between these two groups.
Table 1. Prevalence of systemic lupus erythematosus in European, Afro-Caribbean and African American women
Table 2. Extent to which known genetic associations can account for west African/European difference in risk for systemic lupus erythematosus
Table 3. Ethnic variation in prevalence of rheumatoid arthritis: studies using radiography for primary screening
Table 4. Ethnic variation in prevalence of rheumatoid arthritis: studies using two-stage screening