Beta globin is a major component of adult hemoglobin. The gene for beta globin is located on chromosome 11 and there are over 475 allelic variants. One of these variants, sickle hemoglobin (Hb S), is responsible for sickle cell disease, one of the most prevalent genetic diseases, affecting over 50,000 Americans. Most individuals with sickle cell disease have African and Mediterranean ancestry. It is believed that the high frequency of the (Hb S) variant is maintained in these populations by the increased resistance to malaria infection in heterozygous carriers, those individuals who possess one copy of the normal beta globin gene (Hb A) and one copy of the sickle variant (Hb S). Individuals who are sickle cell carriers are often referred to as having sickle cell trait, but these individuals do not express symptoms of sickle cell disease. Sickle cell disease is inherited in an autosomal recessive manner and therefore, either two copies of the (Hb S) variant or one copy of the (Hb S) variant plus one copy of another beta globin variant (such as Hb C) are required to express the disease. Symptoms of sickle cell disease include chronic anemia, acute chest syndrome, stroke, splenic and renal dysfunction, pain crises and susceptibility to bacterial infections, particularly in children. Thus, sickle cell disease can be quite debilitating. Each year in the US, an average of 75,000 hospitalizations are due to sickle cell disease, costing approximately $475 million. Sickle cell disease is also associated with significant mortality. Among children, the primary causes of mortality are bacterial infections and stroke. In adults, it is more difficult to attribute specific causes to mortality, but it appears that individuals with more symptomatic disease are at risk for early mortality. The severity of the disease expression is quite variable and is modified by several factors. The most influential risk factor for disease severity is genotype. Individuals who have two copies of the (Hb S) variant tend to have the most severe expression of sickle cell disease. Individuals who are compound heterozygotes for (Hb S) and another beta globin variant generally have less severe expression of the disease. However, individuals who have one copy of (Hb S) and one copy of beta 0-thalassemia often have severe expression of the disease. Other risk factors that modify disease severity are haplotype of the beta globin gene cluster, alpha globin gene number and fetal hemoglobin (Hb F) expression. Treatments, such as penicillin prophylaxis, have been developed that can significantly reduce the morbidity and mortality of sickle cell disease. For this reason, several US organizations have supported screening all newborns for sickle cell disease. As a result, almost every US state and territory now screen their newborn infants for this blood disorder, or hemoglobinopathy. Several test methods are available to detect sickle cell disease. Most tests examine an individual’s hemoglobin, although DNA testing is also available. As a result of newborn screening, better medical care, parent education and penicillin prophylaxis, the morbidity and mortality due to the (Hb S) variant is decreasing.

The beta globin gene is located at 11p15.5. It is a member of the globin gene family, a group of genes involved in oxygen transport. Other members of this gene family include the alpha, gamma, delta, epsilon and zeta globin genes. These genes are developmentally regulated such that certain globin protein chains are expressed at specific times during human development. Two beta globin protein chains combine with two alpha globin protein chains and a heme to form the predominant hemoglobin found in human adults, Hb A.

At least 476 beta globin gene variants exist and several result in life threatening illness (1). However, this review will only focus on the (Hb S) variant and its relation to sickle cell disease. Individuals of African descent exhibit the highest frequency of at-risk genotypes but individuals of Mediterranean, Caribbean, South and Central American, Arab and East Indian descent also exhibit high frequencies of at-risk genotypes (2). Table 1 lists the frequencies of specific allelic variants for the beta globin gene among different populations.

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Table 1  Frequency of beta globin gene variants among different ethnic groups in a  California newborn population

Sickle cell disease refers to a collection of autosomal recessive genetic disorders characterized by a hemoglobin variant called (Hb S). The molecular nature of this hemoglobin variant is a substitution of valine for glutamic acid at the sixth amino acid position in the beta globin gene. Individuals who are affected with sickle cell anemia have two copies of this beta globin variant and the primary hemoglobin present in their red blood cells is (Hb S). Individuals who are affected with other types of sickle cell disease are compound heterozygotes, possessing one copy of the (Hb S) variant and one copy of a different beta globin gene variant such as Hb C or Hb beta-thalassemia. Compound heterozygote individuals produce a mixture of variant hemoglobins. Carrier individuals have one copy of the (Hb S) variant and one copy of the normal beta globin gene, producing a mixture of (Hb S) and the normal hemoglobin, Hb A. The carrier state for sickle cell disease is often referred to as sickle cell trait. Although individuals with sickle cell trait do not express sickle cell disease, they are at increased risk for exercise-related sudden death (4). In addition, individuals with sickle cell trait are protected from malaria infection (5) and it is believed that this is the reason the high frequency of the (Hb S) mutation has been maintained.

Sickle cell disease affects more than 50,000 Americans (2). In African-Americans, the birth prevalence of sickle cell anemia (Hb SS) is 1/375, of Hb SC is 1/835, of Hb S/beta-thalassemia is 1/1667 and of sickle cell trait (Hb AS) is 1/12 (2). Thus, sickle cell disease is one of the most prevalent genetic disorders in the US.

Morbidity

(Hb S) has characteristics that distinguish it from the normal Hb A and thus, cause the clinical features of sickle cell disease to be expressed. Upon deoxygenation, (Hb S) polymerizes and causes red blood cells to change from the usual biconcave disc shape to an irregular sickled shape. The unusual shape of these red blood cells and their propensity to adhere to the walls of blood vessels, can clog the vessels, preventing normal blood flow and decreasing the delivery of oxygen to organs and tissues. These "sickle cells" are also extremely susceptible to hemolysis, causing individuals with sickle cell disease to have chronic anemia (2).

In addition to chronic anemia, some of the disabling clinical features associated with sickle cell disease include acute chest syndrome, stroke, splenic and renal dysfunction, pain crises in soft tissues and bones and priapism (2). Children with sickle cell disease are particularly susceptible to bacterial infections (2).

Sickle cell disease is a major public health concern. This genetic disorder has great impact on both the individual and society. Between 1989 and 1993, there were an average 75,000 hospitalizations per year in individuals with sickle cell disease in the US which, in 1996 dollars, cost $475 million annually (6). The average length of stay per hospital visit was 6.1 days and adults tended to have longer stays than children and adolescents (6).

Mortality

Sickle cell disease is also associated with significant mortality. The following table provides average annual age-adjusted mortality rates for 1979-1995 by US state. To generate table 2, we used data from Multiple-Cause Mortality Files (MCMFs) compiled by the National Center for Health Statistics for the years 1979-1995 (7). MCMF’s include demographic and geographic information on the decedent, International Classification of Disease, Ninth Revision (ICD-9) codes for the underlying cause of death, and up to 20 conditions listed on the death certificate. The MCMFs exist in two formats: entity axis and record axis. We selected all records that contained the ICD-9 code 282.6 (sickle cell disease) anywhere in the record axis portion (sickle cell associated deaths). The 1990 U.S. census data by state, age, sex, and race were used as the standard populations to calculate age-adjusted annual mortality rates per 1,000,000 U.S. residents. Table entries with mortality rates of zero indicate there were no deaths among the individuals with sickle cell disease for that category. Table entries represented by "." indicate either no information or no individuals with sickle cell disease were observed in that category.

For data on a specific state, click on that state on the US map.

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Table 2  Average annual state-specific mortality rates (age-adjusted) for sickle  cell disease per 1,000,000 individuals during 1979-1995

In 1987, the highest mortality rate among children (< 20 years) was observed between one and three years of age and this was primarily due to infections and cerebrovascular accidents (8). However, in more recent years, the mortality in this age group appears to be declining, most likely as a result of newborn screening programs (early diagnosis), more comprehensive medical care, parent education and penicillin prophylaxis to prevent infections (9). For adults (> 20 years) with sickle cell disease, it is more difficult to determine a single cause associated with mortality (10). However, early mortality may be observed in individuals with more symptomatic disease, such as those who exhibit fetal hemoglobin (HbF) levels below the 75 th percentile, hemoglobin values below the 10 th percentile, elevated white blood cell counts (>15,100 cells/mm 3), renal insufficiency, acute chest syndrome and seizures (10).

Sickle cell disease is only caused by the beta globin allelic variant (Hb S). All individuals who are homozygous or compound heterozygous for (Hb S) exhibit some clinical manifestations of sickle cell disease. Symptoms usually appear within the first six months of life, however, there is considerable variability in the severity of the disorder (11).

Genotype is the most important risk factor for disease severity. Individuals with Hb SS are most severely affected, followed by individuals with Hb S/beta 0-thalassemia. Individuals with Hb SC and Hb S/beta +-thalassemia tend to have a more benign course of the disease (11). Table 3 shows the US incidence of specific sickle cell complications by genotype.

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Table 3  Incidence of sickle cell complications in the US , based on genotype

Hb SS is not only associated with greater morbidity than other sickle cell genotypes (as shown in table 3 above), it is also associated with greater mortality (see table 4 below).

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Table 4  Median survival of individuals of all ages with sickle cell disease based on  genotype and sex (10)

In addition to genotype, other factors are also correlated with severity of the disease. Haplotype of the beta globin gene cluster (14), as well as alpha globin gene complement (11,15,16) and levels of fetal hemoglobin (Hb F) (16) have all been shown to be associated with clinical expression of sickle cell disease. However, the ability to predict disease course from birth remains limited (16).

Malaria

It is believed that the unusually high frequency of sickle cell trait (Hb AS) in individuals with African and Mediterranean ancestry has been maintained due to the reduced mortality from malaria infections when compared with individuals who do not carry the hemoglobin variant (Hb AA). The (Hb S) variant appears to decrease the risk of infection by the malaria parasite, Plasmodium falciparum. Although malaria is fatal in individuals with Hb SS, the protection from infection appears to operate in a (Hb S) dose-dependant manner (5). That is, individuals with Hb SS have an even lower risk of infection than individuals with Hb AS.

Beta Globin Cluster Haplotypes

The region of chromosome 11 where the beta globin gene is localized also contains several other globin genes and is thus referred to as the beta globin cluster region. There are several polymorphic sites in this region and certain combinations of these polymorphisms, or haplotypes, are found on chromosomes that carry the (Hb S) variant (14). These haplotypes of the beta globin cluster are named for the specific geographic regions of Africa and the Middle East where they predominate (14). In Africa over 90% of patients are homozygous for beta globin cluster haplotypes. However due to genetic admixture, in the US there is quite a bit of heterozygosity for these haplotypes (15).

The beta cluster haplotypes are important because they appear to be associated with differing clinical severity in sickle cell disease. This association is most likely related to the fact that the mean hemoglobin concentrations and the mean fetal hemoglobin levels differ among the haplotypes (15), both which have been shown to be correlated with clinical expression of sickle cell disease (10,16).

Among the three most common haplotypes, the Senegal haplotype is associated with the most benign form of sickle cell disease, followed by the Benin haplotype. The Central African Republic haplotype is associated with the most severe form of the disease (15). In Africa, as well as the US, sickle cell patients with the Central African Republic haplotype have a two-fold increased risk for complications and mortality at an early age when compared with sickle cell patients with other haplotypes (15).

Alpha-Thalassemia

Coinheritance of the alpha globin gene variant, alpha-thalassemia, in individuals with sickle cell disease appears to be protective against some sickle cell complications such as acute chest syndrome, anemia and cerebrovascular accidents (11,15), but it increases susceptibility to other sickle cell complications such as pain crises (11).

Fetal Hemoglobin

Increased levels of fetal hemoglobin (Hb F) are associated with a less severe clinical course of sickle cell disease (16). Some individuals have a genetic predisposition to unusually high levels of Hb F due to adult over-expression of gamma globin chains. This rare condition is called Hereditary Persistence of Fetal Hemoglobin (HPFH) and it is found in 1/188,000 individuals with sickle cell disease (3). Thus, while HPFH is associated with reduced morbidity, the condition is only found in a small minority of individuals with sickle cell disease. Among the majority of individuals with sickle cell disease who do not have HPFH, there is considerable variation in the residual levels of Hb F that are produced. Approximately 40% of this variation is accounted for by the X-linked F-cell production locus, and the beta-S cluster haplotypes account for an additional 14% of the variation (17). Several therapies for sickle cell disease, such as hydroxyurea, are targeted at raising the levels of Hb F in affected individuals.

Table 5 lists the sensitivity and specificity of some of the tests available for detecting sickle cell disease. These tests detect the beta globin gene product and are performed on blood samples, including cord blood and dried blood spots, which are collected at any time following birth. DNA testing can also be performed. DNA samples collected either prenatally, such as amniocytes and chorionic villus samples, or postnatally may be used for DNA testing.

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Table 5  Sensitivity and specificity of tests to detect sickle cell disease

The Agency for Health Care Policy and Research (AHCPR) has recommended hemoglobin electrophoresis, isoelectric focusing and high-performance liquid chromatography as accurate methods for newborn screening (2). They state that DNA analysis may also be used, but that it is costlier than the other methods. They do not recommend sodium metabisulfite preparations or solubility tests as methods for newborn screening. AHCPR has also recommended that all diagnostic laboratories participate in quality assurance and proficiency testing programs, regardless of the type of test they perform (2). The Centers for Disease Control and Prevention conducts quality assurance evaluations of state newborn screening programs.

Tests used in the US may not be cost-effective for sickle cell diagnosis in developing countries. In Kenya, another method, peripheral blood film (PBF) has been demonstrated to be the most cost-effective diagnostic method. The sensitivity and specificity of PBF is 76% and 99.7%, respectively (19).

In 1972, the 92 nd congress of the US passed the National Sickle Cell Anemia Control Act (20). This law called for grant support for screening programs and in 1975, the first US state began a newborn screening program for sickle cell disease (21). However, it was the late 1980’s before most states were performing sickle cell, or hemoglobinopathy newborn screening (2). This was most likely due to the publication of a study in 1986 that showed that oral penicillin could significantly reduce the morbidity and mortality in children with sickle cell disease (22). In 1987, the National Institutes of Health held a conference that supported early diagnosis by newborn screening as being beneficial to infants with sickle cell disease (23). In 1993, another US agency, the Agency for Health Care Policy and Research (AHCPR), also concluded that newborn screening combined with comprehensive health care would significantly reduce the morbidity and mortality in infants with sickle cell disease (2). AHCPR further recommended that all infants should be tested for sickle cell disease, regardless of race (universal screening) since targeting high risk racial or ethnic groups would not identify all affected infants due to the inability to reliably determine the infants’ race by appearance, name or self-report. As of 1992, 40 of the states in the US, as well as the District of Columbia, Puerto Rico and the Virgin Islands, were performing hemoglobinopathy screening, although not necessarily on a universal basis (2).

1. Online Mendelian Inheritance in Man (OMIM TM). Johns Hopkins University, Baltimore, MD. MIM Number: 141900: 6-26-98. WWW URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
2. Sickle Cell Disease Guideline Panel. Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants. Clinical Practice Guideline No. 6. AHCPR Pub. No. 93-0562. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. April 1993.
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4. Kark JA, Posey DM, Schumacher HR and Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 317:781-786 (1987).
5. Aluoch JR. Higher resistance to Plasmodium falciparum infection in patients with homozygous sickle cell disease in western Kenya. Trop Med Int Health 2(6): 568-571 (1997).
6. Davis H, Moore RM Jr, Gergen PJ. Cost of hospitalizations associated with sickle cell disease in the United States. Public Health Rep 112(1): 40-43 (1997).
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8. Leiken SL, Gallagher D, Kinney TR et al. Mortality in children and adolescents with sickle cell disease. The Cooperative Study of Sickle Cell Disease. Pediatrics 84(3): 500-508 (1989).
9. Mortality among children with sickle cell disease identified by newborn screening during 1990-1994-California, Illinois and New York. MMWR 47(9): 169-172 (1998).
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12. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 84(2): 643-649 (1994).
13. Ohne-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 91(1): 288-294 (1998).
14. Nagel RL and Ranney HM. Genetic epidemiology of structural mutations of the beta-globin gene. Semin Hematol 27(4): 342-359 (1990).
15. Powars D and Hiti A. Sickle cell anemia. Beta s gene cluster haplotypes as genetic markers for severe disease expression. Am J Dis Child 147(11): 1197-1202 (1993).
16. Thomas PW, Higgs DR and Serjeant GR. Benign clinical course in homozygous sickle cell disease: a search for predictors. J Clin Epidemiol. 50(2): 121-126 (1997).
17. Chang YP, Maier-Redelsperger M, Smith KD, et al. The relative importance of the X-linked FCP locus and beta-globin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for beta S haplotypes. Br J Haematol 96(4)L 806-814 (1997).
18. Lorey F, Cunningham, Shafer F, Lubin B and Vichinsky E. Universal screening for hemoglobinopathies using high-performance liquid chromatography: clinical results of 2.2 million screens. Eur J Hum Genet 2:262-271 (1994).
19. Aluoch JR. The presence of sickle cells in the peripheral blood film. Specificity and sensitivity of diagnosis of homozygous sickle cell disease in Kenya. Trop Geogr Med 47(2): 89-91 (1995).
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• Table 1 - Frequency of beta globin gene variants among different ethnic groups in a California newborn population (a)
• Table 2 - Average annual state-specific mortality rates (age-adjusted) for sickle cell disease per 1,000,000 individuals during 1979-1995
• Table 3 - Incidence of sickle cell complications in the US , based on genotype
• Table 4 - Median survival of individuals of all ages with sickle cell disease based on genotype and sex
• Table 5 - Sensitivity and specificity of tests to detect sickle cell disease

General Resources

• Ask NOAH about Sickle Cell Disease (last accessed 5/2007)
• March of Dimes (last accessed 5/2007)
• National Heart, Lung and Blood Institute (last accessed 5/2007)

Genetic Databases

• Human Gene Mutation Database (last accessed 5/2007)
• CDC Genomics and Disease Prevention Information System (GDPInfo) (last accessed 5/2007)
• Online Mendelian Inheritance in Man (last accessed 1/2008)

Educational Resources

• Harvard University (last accessed 5/2007)
• National Heart, Blood and Lung Institute (last accessed 5/2007)

Support Groups

• Sickle Cell Disease Association of America (last accessed 5/2007)
• Sickle Cell Foundation of Georgia (last accessed 5/2007)
• Sickle Cell Information Center (last accessed 5/2007)