Review Article | Published:

Protective alleles and modifier variants in human health and disease

Nature Reviews Genetics volume 16, pages 689701 (2015) | Download Citation


The combination of next-generation sequencing technologies and high-throughput genotyping platforms has revolutionized the pursuit of genetic variants that contribute towards disease. Furthermore, these technologies have provided invaluable insight into the genetic factors that prevent individuals from developing disease. Exploiting the evolutionary mechanisms that were designed by nature to help prevent disease is an attractive line of enquiry. Such efforts have the potential to generate a therapeutic target roadmap and rejuvenate the current drug-discovery pathway. By delineating the genomic factors that are protective against disease, there is potential to derive highly effective, genomically anchored medicines that assist in maintaining health.

Key points

  • Protective alleles confer protection against disease by disrupting protein function, typically via loss-of-function (LoF) effects.

  • Protective alleles have been identified for a range of complex disease phenotypes, such as Alzheimer disease and cardiometabolic disease, often within genes that contain known disease susceptibility variants.

  • Maintenance of health — and prevention of disease — are not attributable solely to individual protective alleles. Coding and non-coding regulatory regions of the genome (modifier variants) are likely to contribute to the overall genomic architecture of health, mimicking the situation with susceptibility to complex diseases.

  • Many protective alleles are low-frequency or rare alleles; studies that discovered these alleles have used large sample sizes across multi-ethnic cohorts, or specific founder populations in which individuals are more likely to harbour rare alleles and gene knockouts.

  • Discovery of LoF protective alleles has stimulated the development of drugs that mimic gene LoF or knockout effects for a range of phenotypes, with a successful example being the development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

  • The existence of protective LoF alleles and gene knockouts in otherwise healthy individuals suggests that drugs mimicking these LoF effects should demonstrate both efficacy and safety. However, evidence suggests that drug-induced gene knockout might not necessarily recapitulate the effects of LoF alleles.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & The genetics of health. Nat. Genet. 38, 1095–1098 (2006). Highlights the importance of protective alleles and modifier effects with respect to health.

  2. 2.

    New drugs cost US$2.6 billion to develop. Nat. Rev. Drug Discov. 13, 877 (2014).

  3. 3.

    et al. Life extension factor klotho enhances cognition. Cell Rep. 7, 1065–1076 (2014).

  4. 4.

    The hunt for missing genes. Science 344, 687–689 (2014).

  5. 5.

    , & The cost of drug development. N. Engl. J. Med. 372, 1972 (2015).

  6. 6.

    , , , & Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014).

  7. 7.

    et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015). Provides empirical evidence supporting the role of human genetics in drug discovery.

  8. 8.

    , & Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).

  9. 9.

    Same genetic mutation, different genetic disease phenotype. Nat. Educ. 1, 64 (2008).

  10. 10.

    , , , & Resistance to HIV infection. J. Urban Health 83, 5–17 (2006).

  11. 11.

    et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

  12. 12.

    et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

  13. 13.

    et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429–1441 (2008).

  14. 14.

    et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

  15. 15.

    Genome editing-based HIV therapies. Trends Biotechnol. 33, 172–179 (2015).

  16. 16.

    et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

  17. 17.

    & A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).

  18. 18.

    et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005). One of the first papers highlighting the role of LoF mutations and protective traits.

  19. 19.

    et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410–422 (2006).

  20. 20.

    et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet. 7, e1002198 (2011).

  21. 21.

    et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann. Intern. Med. 163, 40–51 (2015).

  22. 22.

    , , & Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

  23. 23.

    , , , & PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J. Am. Coll. Cardiol. 55, 2833–2842 (2010).

  24. 24.

    , , & The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193, 445–448 (2007).

  25. 25.

    et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).

  26. 26.

    et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

  27. 27.

    Institute for Clinical and Economic Review. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks: Draft Report CEPAC , (2015).

  28. 28.

    et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543 (2001).

  29. 29.

    et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 25, 948–959 (2010).

  30. 30.

    et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009).

  31. 31.

    et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014).

  32. 32.

    Amgen. A Randomized Phase 3 Study to Evaluate 2 Different Formulations of Romosozumab in Postmenopausal Women With Osteoporosis (NCT02016716) , (2015).

  33. 33.

    et al. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nat. Genet. 47, 78–83 (2015).

  34. 34.

    et al. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat. Commun. 5, 5260 (2014).

  35. 35.

    et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat. Genet. 46, 1333–1336 (2014).

  36. 36.

    et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir. Med. 3, 53–60 (2014).

  37. 37.

    et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

  38. 38.

    et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat. Genet. 43, 43–47 (2011).

  39. 39.

    et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011).

  40. 40.

    et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum. Genet. 122, 201–206 (2007).

  41. 41.

    et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

  42. 42.

    et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 67, 1451–1454 (2008).

  43. 43.

    , & Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

  44. 44.

    , , & Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661–673 (2013).

  45. 45.

    Biopharmaceutical benchmarks 2014. Nat. Biotechnol. 32, 992–1000 (2014).

  46. 46.

    et al. Secukinumab in psoriasis: randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE). Br. J. Dermatol. 173, 777–787 (2015).

  47. 47.

    et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 386, 541–551 (2015).

  48. 48.

    Suicide stunner prompts Amgen to dump brodalumab, denting AstraZeneca's rep. FierceBiotech , (2015).

  49. 49.

    et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

  50. 50.

    et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

  51. 51.

    et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

  52. 52.

    , , , & Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

  53. 53.

    et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

  54. 54.

    et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).

  55. 55.

    et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

  56. 56.

    et al. The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J. Biol. Chem. 289, 30977–30989 (2014).

  57. 57.

    et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J. Biol. Chem. 289, 30990–31000 (2014).

  58. 58.

    et al. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol. Aging 34, 1518.e1–1518.e3 (2013).

  59. 59.

    et al. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 72, 209–216 (2014).

  60. 60.

    et al. Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases. Neurobiol. Aging 34, 2441.e7–2441.e8 (2013).

  61. 61.

    et al. Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol. Aging 35, 935.e11–935.e12 (2014).

  62. 62.

    , & What does it take to produce a breakthrough drug? Nat. Rev. Drug Discov. 14, 161–162 (2015).

  63. 63.

    BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res. Ther. 6, 89 (2014).

  64. 64.

    The Myocardial Infarction Genetics Consortium Investigators. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072–2082 (2014).

  65. 65.

    The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).

  66. 66.

    , , & Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).

  67. 67.

    IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. American Heart Association , (2014).

  68. 68.

    et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

  69. 69.

    et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur. Heart J. 35, 960–968 (2014).

  70. 70.

    et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2014).

  71. 71.

    et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).

  72. 72.

    et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46, 357–363 (2014). Demonstrates the importance of human genetic studies across multiple ethnicities for the identification of protective mutations.

  73. 73.

    et al. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51, 597–601 (2008).

  74. 74.

    et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes 63, 2158–2171 (2014).

  75. 75.

    et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58, 2070–2083 (2009).

  76. 76.

    et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J. Clin. Invest. 123, 4513–4524 (2013).

  77. 77.

    et al. Phenotypic extremes in rare variant study designs. Eur. J. Hum. Genet. (2015).

  78. 78.

    et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).

  79. 79.

    et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat. Genet. (2015).

  80. 80.

    et al. Identification of a large set of rare complete human knockouts. Nat. Genet. 47, 448–452 (2015). Demonstrates the increased rate of LoF mutations within founder populations.

  81. 81.

    et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

  82. 82.

    et al. Genetic ancestry and risk of breast cancer among U.S. Latinas with breast cancer. Cancer Res. 68, 9723–9728 (2008).

  83. 83.

    Medical research: missing patients. Nature 513, 301–302 (2014).

  84. 84.

    Individualized medicine from prewomb to tomb. Cell 157, 241–253 (2014).

  85. 85.

    et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat. Neurosci. 18, 807–816 (2015).

  86. 86.

    et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat. Genet. 47, 1107–1113 (2015).

  87. 87.

    et al. Frequency of “ACMG-56” variants in whole genomes of healthy elderly American Society for Human Genetics , abstr. (2014).

  88. 88.

    et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).

  89. 89.

    et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 22, 1760–1774 (2012).

  90. 90.

    et al. Association of human aging with a functional variant of klotho. Proc. Natl Acad. Sci. USA 99, 856–861 (2002).

  91. 91.

    , , & Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. 31, 382–392 (2015).

  92. 92.

    & Chromothripsis: chromosomes in crisis. Dev. Cell 23, 908–917 (2012).

  93. 93.

    et al. Chromothriptic cure of WHIM syndrome. Cell 160, 686–699 (2015).

  94. 94.

    et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524, 230–233 (2015).

  95. 95.

    & Clues from the resilient. Science 344, 970–972 (2014).

  96. 96.

    Google X sets out to define healthy human. , (2014).

  97. 97.

    et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505, 550–554 (2014).

  98. 98.

    The secret to a healthy heart may lie in the genes of elite athletes. Bloomberg Business , (2015).

  99. 99.

    et al. Phenome-wide association studies (PheWASs) for functional variants. Eur. J. Hum. Genet. 23, 523–529 (2015).

  100. 100.

    Cholesterol, racial variation and targeted medicines. Nat. Med. 11, 122–123 (2005).

  101. 101.

    & Genetics of human gene expression: mapping DNA variants that influence gene expression. Nat. Rev. Genet. 10, 595–604 (2009).

  102. 102.

    TV-45070 for the treatment of pain. XENON , (2015).

  103. 103.

    et al. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. Hum. Mutat. 31, E1670–E1686 (2010).

  104. 104.

    et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004).

  105. 105.

    et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat. Genet. 45, 1399–1404 (2013).

  106. 106.

    , , , & The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur. J. Hum. Genet. 23, 561–563 (2015).

  107. 107.

    et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30, 216–224 (2015).

  108. 108.

    et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350, 2682–2688 (2004).

  109. 109.

    Pfizer initiates Phase 2 study of PF-06252616 in Duchenne muscular dystrophy. Pfizer , (2014).

  110. 110.

    The COMPASS Study: a Study of Volanesorsen (Formally ISIS-APOCIIIRx) in Patients With Hypertriglyceridemia (NCT02300233) , (2015).

  111. 111.

    et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

  112. 112.

    et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).

  113. 113.

    Australo-Anglo-American Spondyloarthritis Consortium et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

  114. 114.

    Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer's disease. J. Alzheimers Dis. 9, 341–347 (2006).

  115. 115.

    et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS ONE 10, e0122271 (2015).

Download references


Financial support was provided by the US National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Award UL1TR0001114. A.R.H. was supported through the UK National Institute for Health Research Academic Foundation Programme.

Author information

Author notes

    • Andrew R. Harper
    •  & Shalini Nayee

    These authors contributed equally to this work.


  1. Wellcome Trust Centre for Human Genetics, University of Oxford and Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7BN, UK.

    • Andrew R. Harper
  2. Department of Oral Medicine, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.

    • Shalini Nayee
  3. Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, California 92037, USA.

    • Eric J. Topol


  1. Search for Andrew R. Harper in:

  2. Search for Shalini Nayee in:

  3. Search for Eric J. Topol in:

Competing interests

E.J.T. consults for Illumina, Genapsys and Edico Genome and is a co-founder of Cypher Genomics. The other authors declare no competing interests.

Corresponding authors

Correspondence to Andrew R. Harper or Shalini Nayee or Eric J. Topol.



(LoF). When an allele causes either partial or complete loss of gene expression. Complete loss of gene function is often termed a gene-knockout effect.

Next-generation sequencing

A high-throughput method of sequencing DNA, facilitating single-base-pair resolution across the entire genome.


(GoF). When an allele causes higher levels of gene expression than the 'normal' physiological level of gene expression.


The period of life during which an individual has optimal health, free from life-limiting disease.

Genome-editing techniques

Methods in which nucleases are used to induce specific variants within DNA, usually to bring about a phenotypic change (examples of techniques include CRISPR–Cas9 (clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9) and zinc-finger nucleases).

Monoclonal antibodies

Antibodies for a specific antigen made by identical immune cells cloned from a unique parent cell. Within pharmacology, monoclonal antibody-based drugs (denoted by the suffix -mab) are a form of biologic therapy that target specific antigen epitopes. These drugs were initially derived entirely from mouse antibodies, which resulted in high immunogenicity.

Humanized monoclonal antibody

A type of monoclonal antibody formed from mouse and human DNA sources. Humanized monoclonal antibody drugs consist primarily of human domains, with murine sequences being limited to the complementarity-determining region of the antibody, which results in lower immunogenicity than that associated with murine or chimeric monoclonal antibody drugs.

Variants with unknown significance

Variants for which there is insufficient information to determine whether the variant confers a benign or functional (pathogenic or protective) effect.

Allelic heterogeneity

The phenomenon in which multiple alleles within a locus confer the same phenotypic effect.

Founder populations

Populations that descend from a small number of 'founder' individuals, and therefore have reduced genetic diversity compared with outbred populations.


Where an individual has only one functional copy of a gene (rather than two functional copies), resulting in reduced levels of gene expression that alter the phenotype.

Transcription factor-binding site

A sequence of DNA that can be bound by transcription factors and thereby regulate transcription of coding regions of the genome.


A term used to describe the occurrence of two or more cell populations that are derived from a single zygote but harbour different genotypes.


Antisense oligonucleotides that are engineered to bind to specific mRNA sequences and inhibit protein synthesis, enabling researchers to determine the effects of reduced expression of the targeted gene.

About this article

Publication history



Further reading